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this issue

Medicographia
Vol 35, No. 4, 2013
117
A
Ser vier
publication
Hypertension and
cardiovascular prevention:
where are combinations going?
E DITORIAL
377
Hypertension management: achievements and further needs
Prise en charge de l’hypertension : acquis et perspectives
G. Mancia, Italy
T HEMED
385
ARTICLES
Why do we need antihypertensive combinations?
R. E. Schmieder, Germany
395
Antihypertensive combinations: what is missing?
J. Blacher, France
403
When more than two drugs are needed to further decrease blood pressure
A. Greenstein, K. Khavandi, T. Heagerty, United Kingdom
411
Treating both hypertension and dyslipidemia: a synergistic approach
N. R. Poulter, United Kingdom
418
Antihypertensive treatment in ischemic heart disease: is there an ideal pill?
E. V. Shlyakhto, Russia
426
Is fixed-combination antihypertensive therapy needed in
post-stroke patients?
J. Chalmers, H. Arima, Australia
433
Which patients should benefit from ACE inhibitor–b-blocker therapy?
K. Amosova, Ukraine
Contents continued on next page
Medicographia
Vol 35, No. 4, 2013
117
A
C ONTROVERSIAL
Ser vier
publication
QUESTION
441 Multiple-drug combinations in hypertension and cardiovascular
prevention: should they be used in primary or secondary prevention?
M. Alami, Morocco - C. Amodeo, Brazil - I. Attia, Egypt - M. Bastos,
Portugal - A. Bhagwat, India - K. J. Filipiak, Poland - R. O’Hanlon,
Ireland - E. J. Ramos, Philippines - H. A. Remah Mohammed,
Saudi Arabia - M. Rizzo, Italy - R. S. Tan, Singapore - S. L. Tokgozoglu,
Turkey - M. Vrablik, Czech Republic
C OVERAM
455 Optimizing combination therapy for cardiovascular protection: evidence
from landmark trials
N. Clavreul, France
I NTERVIEW
464 Combinations in hypertension and cardiovascular prevention: are they
additive or synergistic?
S. Taddei, Italy
U PDATE
468 Can genetics influence the choice of antihypertensive combination
therapy?
P. Hamet, J. Tremblay, Canada
A
TOUCH OF
F RANCE
474 Claude Bernard (1813-1878) and experimental medicine.
“Physiology, physiology, it’s in me…”
C. Régnier, France
485 The Théâtre des Champs Elysées: the venue that launched
a masterpiece
D. Marsh, France
‘‘
EDITORIAL
Even when BP is effectively
reduced, and control achieved,
the CV risk remains substantially
higher than that of normotensive
individuals matched for age, sex,
and other demographic and clinical characteristics. This is also the
case for the risk of renal events, as
shown by the observation that in
patients with diabetic or nondiabetic nephropathy, the rate of renal
deterioration remains much greater
than in the control population even
when antihypertensive treatment
has been optimized…”
Hypertension management:
achievements and
further needs
by G. Mancia, Italy
odern medicine owes much to research on hypertension. To mention a
few contributions, studies on hypertension have discovered that elevated blood pressure (BP) is associated with an increased incidence
of cardiovascular (CV) and renal morbid or fatal events. These findings
cancelled the previous belief that high BP is a compensatory phenomenon that
preserves vital organ perfusion against a primitive thickening of the small arteries,
and they prompted the start of research on risk factors, which then led to a progressively more accurate quantification of CV risk. Furthermore, in the attempt to discover the cause—or causes—of BP elevation, research on hypertension has substantially contributed to the identification of a variety of systems involved in CV control,
among which the neural and renin-angiotensin-aldosterone systems. Finally, through
extensive use of randomized controlled trials, hypertension research has been able
to prove that the risk associated with BP elevation is not irreversible, which means
that when BP is reduced by treatment, so is the incidence of the hypertension-related CV and renal complications, this being the case in both sexes and at virtually
all ages, including those above 80 years.1,2 However, despite many decades of research and discoveries, several issues related to hypertension have not yet been
resolved. This editorial will address some of these unresolved issues.
M
Giuseppe MANCIA, MD, PhD
Centro Interuniversitario di
Fisiologia Clinica e Ipertensione
Milan, ITALY
Residual risk in treated hypertensive patients
Address for correspondence:
Giuseppe Mancia, Centro
Interuniversitario di Fisiologia Clinica
e Ipertensione, Milan, Italy
(e-mail: [email protected])
Medicographia. 2013;35:377-384
www.medicographia.com
As mentioned above, reducing BP by treatment is associated with a reduction in
the risk of CV (stroke, coronary heart disease, and heart failure) or renal (end-stage
renal disease) morbid or fatal events, the beneficial effects being proportional to the
magnitude of the BP reduction to systolic and diastolic BP values below 140 mm Hg
and 85 mm Hg, respectively.1,2 However, even when BP is effectively reduced, and
control achieved, the CV risk remains substantially higher than that of normotensive
individuals matched for age, sex, and other demographic and clinical characteristics.3,4 This is also the case for the risk of renal events, as shown by the observation
that in patients with diabetic or nondiabetic nephropathy, the rate of renal deterioration (and the incidence of renal insufficiency and dialysis) remains much greater than
in the control population, even when antihypertensive treatment has been optimized
in terms of BP values achieved and antihypertensive drugs employed.5
Several hypotheses have been made to try to understand the reasons for the high
residual risk exhibited by well-treated hypertensives. The possibility cannot be excluded that in hypertension, CV and renal risks are at least in part irreversible, perhaps because of a genetic component unrelated to, or independent of, BP values.
It is also possible, however, that the treatment of hypertension does not pay suffi-
Hypertension management: achievements and further needs – Mancia
MEDICOGRAPHIA, Vol 35, No. 4, 2013
377
EDITORIAL
cient attention to (i) additional risk factors, eg, those generated by alterations in lipid and glucose metabolism, which are
much more common in individuals in whom BP is high than in
those in whom it is normal6; (ii) the failure to consistently reduce BP over time, given the documented relationship between on-treatment visit-to-visit BP variability and CV risk7,8;
and/or (iii) the inability to effectively reduce BP values of recognized prognostic importance,9,10 such as those measured
over 24 hours or at home, which are more difficult to control.11
A final attractive hypothesis is that the high residual risk of
well-treated hypertensive patients depends on the fact that
treatment often starts too late, ie, when organ damage is already present and no longer entirely reversible. This is supported by the observation in the PAMELA population study
Office BP control <140/90 mm Hg
Home BP control <132/83 mm Hg
24h BP control <125/79 mm Hg
Patients with
echocardiographic LVH (%)
40
32 33
29
30
19
20
20
17
10
4
0
5
NT
10
HT treated/
uncontrolled
HT treated/
controlled
Figure 1. Prevalence of echocardiographic left ventricular hypertrophy in normotensives, treated hypertensives with uncontrolled
blood pressure, and treated hypertensives with controlled blood
pressure from the PAMELA population.
Blood pressure control was determined by office-, home-, or 24h-blood pressure values.
Abbreviations: BP, blood pressure; HT, hypertensive; LVH, left ventricular hypertrophy; NT, normotensive; PAMELA, Pressioni Arteriose Monitorate E Loro
Associazioni.
After data from reference 12: Mancia et al. Hypertension. 2002;39:744-749.
(Pressioni Arteriose Monitorate E Loro Associazioni) that in
treated hypertensive patients, echocardiographic left ventricular hypertrophy (ie, cardiac organ damage)—although less
common when BP control was achieved than when it was not
achieved—never returned to the prevalence seen in the normotensive control population, this being the case also when
presence or absence of BP control was determined by outof-office BP values (Figure 1).12 This implies that, in order to
reduce residual risk, earlier initiation of antihypertensive treatment may be necessary. It further implies that treatment initiation may have to be guided by detection of asymptomatic
organ damage rather than just BP, and that changes in asymptomatic organ damage may also have to be used to measure
the effects of treatment.
378
Which targets for antihypertensive treatment?
Antihypertensive treatment aims at reducing BP to values that
have been shown to maximize CV and renal protection in randomized controlled trials, currently believed to be between
140 and 130 mm Hg systolic and 90 to 80 mm Hg diastolic.2
How should CV and renal protection be established is a debated question, however. Several investigators, as well as virtually all regulatory agencies, maintain that the CV benefits
of antihypertensive treatment must be established by a reduction in the incidence and risk of the so-called “hard end
points,” such as stroke and myocardial infarction, because
these events are reliably diagnosed and their clinical significance is obvious. However, this means that only patients capable of generating a sufficient number of events—ie, those
at high risk—can be studied, leaving the question of whether,
and to what extent, BP-lowering interventions can be beneficial in young or otherwise low-to-moderate risk individuals
unaddressed. Expanding the number and type of end points
that can be accepted as a measure of benefit is therefore a
crucial aspect of future research on antihypertensive treatment.
The process was started by including as end points such
events as incipient heart failure and revascularization procedures, although diagnosis of incipient heart failure can be difficult and revascularization procedures are variably affected by
health care policies in different countries and hospitals. It will
have to continue by also considering regression or delayed
progression of asymptomatic organ damage as demonstrations of a treatment-dependent benefit. This will, in turn, make
it possible to suitably address the following questions of fundamental importance for public health: (i) are BP lowering interventions protective in the most common form of hypertension, ie, in individuals with mild BP elevation who are at
relatively low CV risk? (ii) do BP reductions have a beneficial
effect in subjects with a BP in the high normal range, in whom
the CV risk profile is often suboptimal and the risk of developing hypertension much higher than in the remaining normotensive population? (iii) can basing treatment initiation and targets on initial and subsequent changes in asymptomatic organ
damage lead to a more complete CV protection and a lower
residual risk than taking only BP as a target?
Which measures of organ damage?
In order to be considered as a marker of the beneficial effects
of antihypertensive treatment, measures of organ damage
should fit a number of requirements. The marker should reflect a type of damage that is frequently associated with BP
elevation. Alterations in organ function and/or structure should
be reproduced in a sensitive and consistent fashion. Measures should be obtained in a relatively short time, at low cost,
and with no need for excessive specialization of the operator.
Most importantly, however, there should be evidence that, in
hypertension—and possibly also in the general population—
a marker has a prognostic value, ie, that it reflects increased
incidence and increased risk of clinical events in a proportional manner. This should also be the case for treatment-induced
EDITORIAL
Number of drugs used
36.8%
1 drug
2 drugs
≥3 drugs
40.9%
22.3%
*<140/90 mm Hg (<130/80 mm Hg in diabetics)
BP control rate*
50
40
Patients (%)
changes. At present, many markers of organ
damage have been shown to be prognostically relevant; while as far as treatment-induced changes are concerned, a correlation
with the incidence and risk of CV mortality
and morbidity has only been documented
(with few important exceptions, however) for
urinary protein excretion, glomerular filtration
rate, and echocardiographic or electrocardiographic estimates of left ventricular mass or
hypertrophy.13-16 Treatment-induced changes
in arterial stiffness have also been related to
CV events but in one small study only.17
41.0
36.6
30
22.3
20
10
0
1
2
3
Number of drugs
Much more validating research thus needs Figure 2. Use of monotherapy and combination therapy to achieve blood pressure
to be done before use of organ damage (BP) targets (<140/90 mm Hg, or <130/80 mm Hg in diabetics) in patients under
measures can be safely recommended as GP care.
In about 37% of the patients, the treatment consisted of monotherapy.
a proxy of the protective effect of antihyper- After data from reference 22: Giannattasio et al. Am J Hypertens. 2012;25:1182-1187.
tensive treatment. Research in this direction
is worthwhile, however, because the concept has a strong stration of two or more antihypertensive drugs with different
pathophysiological rationale, which is that clinical events are
and complementary mechanisms of action exerts a much
always preceded by asymptomatic organ damage. Put in a greater antihypertensive effect than monotherapy,23 and that
different way, there cannot be a clinically manifest event in a
(ii) while a single drug can control BP in no more than 1 out
healthy organ perfused by healthy arteries.
of 4 or 5 patients,24 two drugs can be successful in 60% of
hypertensive individuals, and three drugs in 80% to 90%.23
BP control and combination treatment
This implies that the goal of achieving BP control in a much
One of the major problems faced by antihypertensive treat- greater fraction of the hypertensive population will only be
achieved by substantially increasing the currently low use of
ment is the low rate of BP control in the hypertensive popucombination treatment in clinical practice.
lation, with the percentage of hypertensive individuals with BP
values less than 140/90 mm Hg rarely exceeding 20%-30%
of the patients with BP elevation.18 Given the well-document- Should combination treatment be used as a first step and
ed much higher CV risk of patients with uncontrolled BP,19 in a fixed-dose single tablet format? Single tablet fixed-dose
combinations are very popular because reducing the numthis low rate of control is responsible for the persistent position of hypertension as the first cause of death worldwide.20 ber of daily tablets has been shown to improve adherence
to treatment25 and promote BP control.26 Furthermore, the recThe reasons why only a limited number of hypertensive pa- ommendation of hypertension guidelines to consider combinations of two drugs for treatment initiation in hypertensive
tients achieve BP control in real life can be ascribed to deficiencies of the health care systems, the failure of physicians patients with a high CV risk,1 although never addressed by
to change treatment when BP is not controlled (clinical inerrandomized controlled trials, has recently found support from
tia), and the low adherence of patients to the prescribed treatthe observation that its adoption in real life is associated with
ment regimen. Clinical inertia is common21 and often consists reduced treatment discontinuation rates27 as well as a 25%
in the failure to move from monotherapy to the combination reduced risk of hospitalization for cerebrovascular and coroof two or three antihypertensive drugs when BP is not ade- nary events.28 Thus, a more widespread use of fixed-dose
quately controlled (Figure 2).22 However, there is overwhelmcombinations of drugs for treatment initiation may further iming evidence that (i) as BP is a multiregulated variable, admin- prove the treatment of hypertension. ■
References
1. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
2. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task
Force document. J Hypertens. 2009;27:2121-2158.
3. Andersson OK, Almgren T, Persson B, Samuelsson O, Hedner T, Wilhelmsen L.
Survival in treated hypertension: follow up study after two decades. BMJ.1998;
317:167-171.
4. Zanchetti A. Bottom blood pressure or bottom cardiovascular risk? How far can
cardiovascular risk be reduced? J Hypertens. 2009;27:1509-1520.
5. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic
Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis.
2002;39(suppl 1):S5-S266.
6. Mancia G, Facchetti R, Bombelli M, et al. Relationship of office, home, and ambulatory blood pressure to blood glucose and lipid variables in the PAMELA
population. Hypertension. 2005;45:1072-1077.
7. Mancia G, Parati G, Bilo G, et al. Assessment of long-term antihypertensive
treatment by clinic and ambulatory blood pressure: data from the European
379
EDITORIAL
Lacidipine Study on Atherosclerosis. J Hypertens. 2007;25:1087-1094.
8. Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension. 2007;50:299-305.
9. Parati G, Stergiou GS, Asmar R, et al; ESH Working Group on Blood Pressure
Monitoring. European Society of Hypertension practice guidelines for home
blood pressure monitoring. J Hum Hypertens. 2010;24:779-785.
10. O’Brien E. Ambulatory blood pressure monitoring: 24 hour blood pressure control as a therapeutic goal for improving cardiovascular prognosis. Medicographia. 2010;32:241-249.
11. Mancia G, Parati G. Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: a meta-analysis. J Hypertens. 2004;
22:435-445.
12. Mancia G, Carugo S, Grassi G; Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) Study. Prevalence of left ventricular hypertrophy in hypertensive patients without and with blood pressure control: data from the PAMELA
population. Pressioni Arteriose Monitorate E Loro Associazioni. Hypertension.
2002;39:744-749.
13. Schmieder RE, Mann JF, Schumacher H, et al; ONTARGET Investigators.
Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol. 2011;22:1353-1364.
14. Ninomiya T, Perkovic V, de Galan BE, et al; ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813-1821.
15. Devereux RB, Wachtell K, Gerdts E, et al. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA. 2004;292:23502356.
16. Okin PM, Devereux RB, Jern S, et al; LIFE Study Investigators. Regression of
electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA. 2004;292:23432349.
17. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact
of aortic stiffness attenuation on survival of patients in end-stage renal failure.
Circulation. 2001;103:987-992.
18. Kearney PM, Whelton M, Reynolds K, Whelton PK, He J. Worldwide prevalence of hypertension: a systematic review. J Hypertens. 2004;22:11-19.
19. Benetos A, Thomas F, Bean KE, Guize L. Why cardiovascular mortality is higher
in treated hypertensives versus subjects of the same age, in the general population. J Hypertens. 2003;21:1635-1640.
20. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ; Comparative Risk
Assessment Collaborating Group. Selected major risk factors and global and
regional burden of disease. Lancet. 2002;360:1347-1360.
21. Banegas JR, Segura J, Ruilope LM, et al; CLUE Study Group Investigators.
Blood pressure control and physician management of hypertension in hospital
hypertension units in Spain. Hypertension. 2004;43:1338-1344.
22. Giannattasio C, Cairo M, Cesana F, et al. Blood pressure control in Italian Essential Hypertensives Treated by General practitioners. Am J Hypertens. 2012;25:
1182-1187.
23. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
24. Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium
blockers, and diuretics for the control of systolic hypertension. Am J Hypertens.
2001;14:241-247.
25. Bangalore S, Kamalakkannan G, Parkar S, Messerli F. Fixed-dose combinations
improve medication compliance: a meta-analysis. Am J Med. 2007;120:713719.
26. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of
fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55:399-407.
27. Corrao G, Parodi A, Zambon A, et al. Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily
life practice. J Hypertens. 2010;28:1584-1590.
28. Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. Hypertension. 2011;58:566-572.
Keywords: blood pressure control; hypertension; marker; organ damage; prognostic value; risk
380
ÉDITORIAL
ÉDITORIAL
‘‘
Même lorsque la PA est efficacement réduite, et qu’un contrôle
est obtenu, le risque CV reste substantiellement supérieur à celui des
individus normotendus... Cela est
également le cas pour le risque
d’événements rénaux, comme le
montre le fait que, chez les patients
atteints de néphropathie diabétique ou non diabétique, le taux de
détérioration rénale reste très supérieur à celui de la population témoin, même lorsque le traitement
antihypertenseur a été optimisé… »
Prise en charge de
l’hypertension :
acquis et perspectives
p a r G . M a n c i a , I TA L I E
L
a médecine moderne doit beaucoup aux recherches sur l’hypertension. Pour
ne mentionner que quelques contributions, les études sur l’hypertension ont
permis de découvrir qu’une augmentation de la pression artérielle (PA) était
associée à une élévation de l’incidence des événements cardio-vasculaires
(CV) et rénaux morbides ou mortels. Ces résultats ont démenti la théorie selon laquelle une augmentation de la PA était un phénomène de compensation préservant
la perfusion des organes vitaux contre un épaississement primitif des petites artères,
et ils ont suscité des recherches sur les facteurs de risque, qui ont conduit à une
quantification progressivement plus exacte du risque CV. En outre, les recherches
destinées à découvrir la cause – ou les causes – de l’élévation de la PA ont contribué de manière substantielle à l’identification d’un certain nombre de systèmes participant au contrôle CV, parmi lesquels les systèmes neuraux et rénine-angiotensine-aldostérone. Enfin, l’utilisation généralisée des essais randomisés contrôlés a
permis à la recherche de démontrer que le risque associé à une élévation de la PA
n’était pas irréversible, ce qui signifie que, lorsqu’un traitement permet de réduire les
valeurs de la PA, il en va de même de l’incidence des complications CV et rénales
liées à l’hypertension, pour les deux sexes et pratiquement pour toutes les tranches
d’âge, y compris les patients âgés de plus de 80 ans1,2. Cependant, malgré plusieurs décennies de recherches et de découvertes, un certain nombre de questions
liées à l’hypertension n’ont toujours pas trouvé de réponse. Cet éditorial porte sur
quelques-uns de ces problèmes non résolus.
Risque résiduel chez les patients hypertendus traités
Comme il a été mentionné ci-dessus, la réduction de la PA par traitement est associée à une diminution du risque d’événements CV (accident vasculaire cérébral,
coronaropathie et insuffisance cardiaque) ou rénaux (insuffisance rénale de stade
terminal) morbides ou mortels, les effets bénéfiques étant proportionnels à l’amplitude de la réduction de la PA aux valeurs systoliques et diastoliques respectivement inférieures à 140 mm Hg et 85 mm Hg1,2. Cependant, même lorsque la PA est
efficacement réduite, et qu’un contrôle est obtenu, le risque CV reste substantiellement supérieur à celui des individus normotendus appariés selon l’âge, le sexe et
les autres caractéristiques démographiques et cliniques3,4. Cela est également le
cas pour le risque d’événements rénaux, comme le montre le fait que, chez les patients atteints de néphropathie diabétique ou non diabétique, le taux de détérioration rénale (ainsi que l’incidence de l’insuffisance rénale et de la dialyse) reste très
supérieur à celui de la population témoin, même lorsque le traitement antihypertenseur a été optimisé vis-à-vis des valeurs cibles de la PA et des antihypertenseurs
utilisés5.
Prise en charge de l’hypertension : acquis et perspectives – Mancia
381
ÉDITORIAL
Plusieurs hypothèses ont été formulées pour tenter de comprendre pourquoi les patients hypertendus traités de manière
satisfaisante ont un risque résiduel élevé. Il n’est pas exclu que
dans l’hypertension, les risques CV et rénaux soient au moins
en partie irréversibles, probablement à cause d’une composante génétique non liée à, ou indépendante des valeurs de
la PA. Il est cependant également envisageable que le traitement de l’hypertension ne prenne pas suffisamment en compte
(i) les facteurs de risque supplémentaires, par exemple ceux
induits par des altérations du métabolisme des lipides et du
glucose, qui sont beaucoup plus fréquents chez les personnes
présentant une PA élevée que chez celles ayant une PA normale 6; (ii) l’incapacité de réduire la PA avec le temps, compte
Contrôle de la PA chez le médecin < 140/90 mm Hg
Contrôle de la PA à domicile < 132/83 mm Hg
Contrôle de la PA sur 24 heures < 125/79 mm Hg
Patients présentant une HVG
à l’échocardiographie (%)
40
32 33
29
30
19
20
20
17
10
4
0
5
NT
10
HT traités /
non contrôlés
HT traités /
contrôlés
Figure 1. Prévalence de l’hypertrophie ventriculaire gauche mise
en évidence par échocardiographie chez des patients normotendus, des patients hypertendus traités avec une pression artérielle
non contrôlée et des patients hypertendus traités avec une pression artérielle contrôlée dans la population de l’étude PAMELA.
Le contrôle de la pression artérielle a été déterminé par des valeurs de la PA
mesurées au cabinet médical, à domicile ou sur 24 heures.
Abréviations: PA, pression artérielle ; HT, hypertendu ; HVG, hypertrophie ventriculaire gauche ; NT, normotendu ; PAMELA, Pressioni Arteriose Monitorate
E Loro Associazioni.
D’après la référence 12 : Mancia et al. Hypertension. 2002;39:744-749.
tenu de la relation documentée entre les fluctuations de la PA
sous traitement entre les visites et le risque CV ; 7,8 et/ou (iii)
l’impossibilité de réduire efficacement les valeurs de la PA présentant une importance pronostique reconnue9,10, notamment
celles mesurées sur une période de 24 heures ou à domicile,
qui sont également plus difficiles à contrôler11.
Néanmoins, une dernière hypothèse séduisante suppose que
le risque résiduel élevé des patients hypertendus bien traités dépend d’un début trop tardif du traitement, c’est-à-dire
lorsque des lésions organiques sont déjà présentes et qu’elles
ne sont plus entièrement réversibles. Cela est confirmé par
l’observation effectuée au cours de l’étude de population PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni)
montrant que, chez les patients hypertendus traités, l’hypertrophie ventriculaire gauche (une lésion cardiaque) mise en
382
évidence à l’échocardiographie – bien qu’elle soit moins fréquente avec une PA contrôlée que lorsque celle-ci ne l’est
pas – n’est jamais revenue à la prévalence observée dans la
population témoin normotendue, cela étant observé également lorsque le contrôle de la PA (ou l’absence de contrôle)
a été estimé par des valeurs mesurées en dehors du cabinet
médical (Figure 1)12. Par conséquent, pour réduire le risque
résiduel, une initiation plus précoce au traitement antihypertenseur peut être nécessaire. Cela conduit également à penser que la mise en place du traitement peut devoir être guidée par la détection de lésions organiques asymptomatiques
plutôt que par les seules valeurs de la PA, et que les changements intervenant au niveau des lésions organiques asymptomatiques pourraient également être utilisés pour mesurer
les effets du traitement.
Quels sont les objectifs du traitement
antihypertenseur ?
Le traitement antihypertenseur est destiné à réduire la PA à des
valeurs dont l’action préventive CV et rénale maximale a été
mise en évidence au cours d’essais randomisés contrôlés,
c’est-à-dire comprises actuellement entre 140 et 130 mm Hg
pour la PA systolique et 90 et 80 mm Hg pour la PA diastolique 2. Toutefois, les modalités de mise en place d’une protection CV et rénale restent controversées. Plusieurs chercheurs et pratiquement toutes les agences réglementaires
maintiennent que les bénéfices CV d’un traitement antihypertenseur doivent être établis par une réduction de l’incidence
et du risque de ce qu’il est convenu d’appeler les « critères
durs », notamment l’accident vasculaire cérébral et l’infarctus
du myocarde, dans la mesure où ces événements peuvent
être diagnostiqués de manière fiable et que leur signification
clinique est évidente. Cependant, cela signifie que seuls les
patients susceptibles de présenter un nombre suffisant d’événements – c’est-à-dire, les patients à haut risque – peuvent
être étudiés, en négligeant la question de savoir si, et dans
quelle mesure, les mesures antihypertensives peuvent être
bénéfiques à des sujets jeunes ou exposés à un risque faible
à modéré. Augmenter le nombre et le type de paramètres pouvant être acceptés comme critères d’évaluation du bénéfice
constitue par conséquent un aspect essentiel des futures recherches sur les traitements antihypertenseurs. Cette dynamique a commencé en incluant comme critère d’évaluation
des événements comme l’insuffisance cardiaque débutante
et les procédures de revascularisation, bien que le diagnostic de l’insuffisance cardiaque débutante soit difficile à établir
et que les procédures de revascularisation puissent varier selon les politiques de soins de santé dans les différents pays et
les différents établissements hospitaliers. Il faudra également
prendre en compte la régression ou la progression retardée
des lésions organiques asymptomatiques comme preuve
d’un bénéfice thérapeutique. Il sera ainsi possible de répondre de manière adéquate aux questions suivantes, fondamentales pour la santé publique : (i) les mesures antihypertensives apportent-elles une protection dans la forme la plus
ÉDITORIAL
fréquente d’hypertension, c’est-à-dire chez les sujets présentant une élévation modérée de la PA et exposés à un risque
CV relativement faible ? (ii) La réduction de la PA a-t-elle un
effet bénéfique chez les sujets dont la PA se situe à la limite
supérieure de l’intervalle normal, chez lesquels le profil de
risque CV est souvent sous-optimal et le risque de développer une hypertension plus élevée que dans le reste de la population normotendue ? (iii) Baser le début du traitement et
les valeurs cibles sur les changements initiaux et ultérieurs
des lésions asymptomatiques des organes, au lieu de se limiter uniquement à la PA comme cible thérapeutique, peut-il
conduire à une protection CV plus complète et à une diminution plus importante du risque résiduel ?
Comment mesurer les lésions organiques ?
niques asymptomatiques. En d’autres termes, un événement
cliniquement manifeste ne peut pas survenir dans un organe
sain perfusé par des artères saines.
Contrôle de la PA et associations thérapeutiques
L’un des problèmes majeurs qui caractérise le traitement antihypertenseur est le faible taux de contrôle de la PA dans la population hypertendue, le pourcentage de sujets hypertendus
présentant des valeurs de la PA inférieures à 140/90 mm Hg
ne dépassant que rarement 20 % à 30 % des patients hypertendus18. Compte tenu du risque CV très supérieur et bien
documenté auquel sont exposés les patients présentant une
PA non contrôlée19, ce faible taux de contrôle est à l’origine de
la place constante de l’hypertension comme première cause
de décès à travers le monde20.
Patients (%)
Pour les considérer comme des marqueurs des effets bénéLes raisons pour lesquelles, dans la pratique, le contrôle de la
fiques du traitement antihypertenseur, les mesures des lésions
organiques doivent répondre à un certain nombre d’exigences. PA n’est atteint que chez un nombre limité de patients hypertendus peuvent être imputées aux déficiences des systèmes
Le marqueur doit refléter un type de lésion fréquemment associée à une élévation de la PA. Les altérations fonctionnelles de soins de santé, au fait que les médecins ne changent pas
et/ou structurelles des organes doivent pouvoir être repro- le traitement lorsque la PA n’est pas contrôlée (inertie clinique)
duites de façon sensible et constante. Les mesures doivent et à la faible observance par les patients du traitement presêtre obtenues relativement rapidement, à
faible coût et sans nécessité de spécialisaContrôle
tion excessive pour l’opérateur. Plus imporNombre de médicaments
de la pression artérielle*
50
tant encore, des preuves doivent montrer
41,0
que, dans l’hypertension – et le cas échéant
36,8 %
40
36,6
également dans la population générale – un
1
marqueur montre une valeur pronostique,
médicament
30
c’est-à-dire qu’il reflète l’augmentation de
2
22,3
médicaments
20
l’incidence et du risque d’événements cli≥3
niques de manière proportionnelle. Cela doit
médicaments
10
également être le cas des changements in40,9 %
duits par le traitement. À l’heure actuelle,
22,3 %
0
de nombreux marqueurs des lésions orga1
2
3
Nombre de médicaments
niques se sont avérés significatifs sur le plan
*< 140/90 mm Hg (< 130/80 mm Hg chez les diabétiques)
pronostique ; tandis qu’en ce qui concerne
les changements induits par le traitement, Figure 2. Utilisation d'une monothérapie et d'une association thérapeutique pour
une corrélation avec l’incidence et le risque contrôler la pression artérielle (<140/90 mm Hg ou <130/80 mm Hg chez les diabéde mortalité et de morbidité CV n’a été do- tiques) chez des patients suivis par des médecins généralistes.
environ 37 % des patients, le traitement est une monothérapie.
cumentée (avec quelques exceptions impor- Chez
D’après la référence 22 : Giannattasio et al. Am J Hypertens. 2012;25:1182-1187.
tantes, cependant) que pour l’excrétion des
protéines urinaires, le taux de filtration glomérulaire et les escrit. L’inertie clinique est fréquente 21, et consiste souvent à ne
timations de la masse ou de l’hypertrophie ventriculaire gauche pas passer d’une monothérapie à une association de deux
par échocardiographie ou électrocardiographie13-16. Un rap- ou trois antihypertenseurs lorsque la PA n’est pas contrôlée
port a été établi entre les changements induits par le traite- de manière adéquate (Figure 2) 22 . Cependant, de très nomment dans la rigidité artérielle et les événements CV, mais seubreuses preuves démontrent que (i) dans la mesure où la PA
lement dans une petite étude17. Un nombre très supérieur est un paramètre multirégulé, l’administration de deux antid’études de validation doit donc être effectué avant que les hypertenseurs ou plus présentant des mécanismes d’action
mesures des lésions organiques puissent être recomman- différents et complémentaires exerce un effet antihypertendées de manière sûre comme substitut de l’effet protecteur seur très supérieur à celui d’une monothérapie 23, et que (ii)
du traitement antihypertenseur. Les recherches dans cette alors qu’un médicament unique peut contrôler la PA au maxivoie sont néanmoins nécessaires, car le concept repose sur
mum chez un patient sur 4 ou 5 24, deux médicaments seront
la forte justification physiopathologique suivante : les événe- efficaces chez 60 % des hypertendus, et trois médicaments
ments cliniques sont toujours précédés par des lésions orga- chez 80 % à 90 % d’entre eux 23. Il en résulte que l’objectif
383
ÉDITORIAL
d’atteindre un contrôle de la PA chez un pourcentage très
supérieur de la population hypertendue ne pourra être atteint
qu’en augmentant de manière substantielle l’utilisation, actuellement insuffisante, des associations thérapeutiques en
pratique clinique.
Une association thérapeutique doit-elle être utilisée en première instance et sous forme d’un comprimé unique à dose
fixe ? Les associations sous forme de comprimé unique à
dose fixe sont très populaires, car il a été montré que la réduction du nombre de comprimés par jour améliorait l’observance du traitement 25 et favorisait le contrôle de la PA26. En
384
outre, la recommandation des directives sur l’hypertension
préconisant d’envisager une association de deux médicaments comme traitement initial chez des patients hypertendus
présentant un risque CV élevé1, bien qu’elle n’ait jamais été
traitée au cours d’essais randomisés contrôlés, a récemment
été étayée par l’observation selon laquelle son application en
pratique réelle est associée à une réduction des taux d’interruption du traitement 27 et à une diminution de 25 % du risque
d’hospitalisation pour événements vasculaires cérébraux et
coronaires 28. Par conséquent, une utilisation plus large des
associations à dose fixe de comprimés en traitement initial permettrait d’améliorer le traitement de l’hypertension. ■
‘‘
HYPERTENSION
AND
C A R D I O VA S C U L A R
WHERE
Antihypertensive combination
therapy has been recommended
as potential first-line therapy in recent consensus guideline statements, especially for higher-risk
patients such as those with stage
2 or 3 hypertension. The combination of a RAS-targeting agent, such
as an ACE inhibitor or an ARB, together with a diuretic, particularly
if metabolically neutral (eg, indapamide), or a CCB, or both, provides synergy with regard to the
lowering of BP.”
ARE
PREVENTION:
C O M B I N AT I O N S
GOING?
Why do we need
antihypertensive
combinations?
b y R . E . S c h m i e d e r, G e r m a n y
H
Roland E. SCHMIEDER, MD
University Hospital Erlangen
Nephrology and Hypertension
Erlangen, GERMANY
Dr. Roland E. Schmieder, University
Hospital Erlangen, Nephrology and
Hypertension, Ulmenweg 18,
91054 Erlangen, Germany
(e-mail:
[email protected])
ypertension is a worldwide problem and the leading cause of mortality. Most hypertensive patients have additional cardiovascular risk
factors or diseases. In most of these patients, more than one antihypertensive drug is necessary to achieve goal levels of blood pressure. Data
from several hypertension management clinical trials have shown that on average two or more antihypertensive agents are needed to reach current blood
pressure targets. As physiological and pharmacological synergies result in
more effective drug combinations, guidelines recommend adding a drug from
another class to the initially prescribed drug. According to the European Society of Hypertension and the European Society of Cardiology guidelines, the
most rational antihypertensive combinations are combinations involving angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs),
angiotensin II receptor blocker (ARBs), and thiazide (-like) diuretics. The combination of an ACE inhibitor with the thiazide-like diuretic indapamide has
been shown to be effective in lowering blood pressure and preventing or reducing cardiovascular morbidity in many trials, such as STRATHE (Strategies
of Treatment in Hypertension: Evaluation), PROGRESS (Perindopril pROtection aGainst Recurrent Stroke Study), HYVET (HYpertension in the Very Elderly
Trial), PICXEL (Perindopril/Indapamide in a Double-Blind Controlled Study versus Enalapril in Left Ventricular Hypertrophy), REASON (PREterax in Regression of Arterial Stiffness in a ContrOlled Double-BliNd study), LIFE (Losartan
Intervention For Endpoint reduction in hypertension), and ADVANCE (Action
in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation ). Likewise, the combination of an ACE-inhibitor and a CCB has been
tested in trials like EUROPA (EUropean trial on Reduction Of cardiac events
with Perindopril in stable coronary Artery disease), ASCOT-BLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm), or ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) and there is evidence of beneficial
effects in the prevention of cardiovascular events and new-onset diabetes, or
rehabilitation after stroke. Thus, combination therapy should be individualized
according to the comorbidities of hypertensive patients.
Medicographia. 2013;35:385-394 (see French abstract on page 394)
Why do we need antihypertensive combinations? – Schmieder
385
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
ypertension is a worldwide problem and the leading
cause of mortality.1 In 2001, it was estimated that 7.6
million premature deaths and 92 million disability-adjusted life years could be attributed to high blood pressure
(BP) worldwide.1 Most hypertensive patients have additional
cardiovascular risk factors or diseases (eg, diabetes). As well
as arterial stiffness, endothelial dysfunction, and atherosclerosis, high cholesterol, obesity, smoking, physical inactivity, and
oxidative stress also contribute to an increase in systolic BP
(SBP) with age, thereby accelerating the aging of the arteries
and potentially causing ischemic heart disease and stroke.1-3
H
Based on extensive prospective observational data, it was
shown that both SBP and diastolic BP (DBP) have a strong
and linear relationship with adverse cardiovascular events in
all age groups.4 Although the relationship varies with age and
sex, a 20-mm Hg difference in SBP or a 10-mm Hg difference
in DBP is, on average, associated with a doubling of cardiovascular risk.4 Therefore, adequate BP control is considered to be
essential in reducing this risk. The benefits of more aggressive therapeutic approaches in hypertension are especially
pronounced in high-risk groups such as patients with diabetes mellitus or chronic kidney disease (CKD).5,6
SELECTED
ACRONYMS
ACCOMPLISH Avoiding Cardiovascular events in COMbination therapy in Patients LIving with Systolic
Hypertension (trial)
ADVANCE
Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation
(trial)
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial
Blood Pressure–Lowering Arm
CAFE
Conduit Artery Function Evaluation
EUROPA
EUropean trial on Reduction Of cardiac events
with Perindopril in stable coronary Artery
disease
HYVET
HYpertension in the Very Elderly Trial
LIFE
Losartan Intervention For Endpoint reduction
in hypertension
NHANES
National Health And Nutrition Examination
Survey
PICXEL
Perindopril/Indapamide in a double-blind
Controlled study versus Enalapril in Left
ventricular hypertrophy
PREMIER
PREterax in albuMInuria rEgRession
PROGRESS
Perindopril pROtection aGainst Recurrent
Stroke Study
REASON
PREterax in Regression of Arterial Stiffness in
a ContrOlled Double-BliNd study
STRATHE
Strategies of Treatment in Hypertension:
Evaluation
TRINITY
The TRIple therapy with olmesartan medoxomil,
amlodipine, and hydrochlorothiazide in
hyperteNsIve patienTs studY
386
Drugs that have been proven to be particularly useful in the
treatment of elevated BP are calcium channel blockers (CCBs),
thiazide(-like) diuretics and agents that target the renin-angiotensin system (RAS), ie, angiotensin-converting enzyme (ACE)
inhibitors and angiotensin II receptor blockers (ARBs).5-9
Management of hypertension
Improvement in cardiovascular outcomes and survival is the
ultimate goal of antihypertensive treatment. However, despite
the wide range of available antihypertensive drugs, the management of hypertension remains insufficient. About 30% of
hypertensive individuals are unaware of their condition and
receive no treatment at all. Of the remaining 70% who do, only
34% achieve the recommended target of SBP <140 mm Hg
and DBP <90 mm Hg.10 This is of concern because of the
proven benefits of reducing BP, which translate into reductions in the incidence of myocardial infarction (MI) (20%-25%),
heart failure (>50%), and stroke (35%-40%).10
Large clinical trials have demonstrated that adequate BP
control can be achieved and sustained in most patients with
hypertension only with the use of multiple antihypertensive
drugs.11,12 Both the European Guidelines (ESH-ESC 2007 and
ESH-ESC 2013)5,13 and the American Guidelines (JNC 7)6,14
recommend that a significant proportion of hypertensive patients—in fact, the majority of patients—receive treatment with
two or more drugs.
The objective of the study of Corrao et al15 was to assess
whether antihypertensive combination therapy provides greater cardiovascular protection in daily clinical practice. This population-based study was carried out in a cohort of 209 650
patients aged 40 to 79 who were newly treated with antihypertensive drugs.15 Patients who were started on combination therapy had an 11% reduction in cardiovascular risk compared with those who received monotherapy. This was also
SELECTED
ACE
ARB
BP
CAD
CCB
CKD
CV
DBP
HCTZ
LVH
LVM
MI
RAS
SBP
ABBREVIATIONS
angiotensin-converting enzyme
angiotensin II receptor blocker
blood pressure
coronary artery disease
calcium channel blocker
chronic kidney disease
cardiovascular
diastolic blood pressure
hydrochlorothiazide
left ventricular hypertrophy
left ventricular mass
myocardial infarction
renin-angiotensin system
systolic blood pressure
HYPERTENSION
AND
WHERE
the case for coronary (–8%) and cerebrovascular (–12%) events,
when considered separately.15 In a study by Neutel et al,16 combination therapy showed greater efficacy than high doses of
the individual agents in increasing arterial compliance and
reducing left ventricular mass.11 Furthermore, a meta-analysis
of 42 factorial trials of antihypertensive agents (10 968 patients)
showed that combining drugs from two different classes is
approximately fivefold more effective than doubling the dose
of one drug.17 Compared with patients who received monotherapy during follow-up, those who were started on combination therapy and remained on it for the entire period of observation had a 26% reduction in cardiovascular risk. As such,
the indication for using a combination of BP drugs should be
broadened.15,18
ARE
PREVENTION:
GOING?
◆ Condition
ISH (elderly)
Metabolic syndrome
Diabetes mellitus
Pregnancy
Blacks
diuretic, CA
ACE inhibitor, ARB, CA
ACE inhibitor, ARB
CA, methyldopa, β-blocker
diuretic, CA
◆ Subclinical organ damage
Left ventricular hypertrophy
Asymptomatic atherosclerosis
Microalbuminuria
Renal dysfunction
ACE inhibitor, CA, ARB
CA, ACE inhibitor
ACE inhibitor, ARB
ACE inhibitor, ARB
◆ Clinical event
Previous stroke
Previous MI
any BP-lowering agent
b-blocker, ACE inhibitor,
ARB
b-blocker, CA
diuretic, b-blocker, ACE
inhibitor, ARB, antialdosterone agent
ARB, ACE inhibitor
b-blocker, non-dihydropyridine CA
ACE inhibitor, ARB, loop
diuretic
CA
Treatment with a two-drug antihypertensive combination is
especially recommended in high risk patients to minimize the
development or progression of target organ damage or vascular complications,19 and also in patients with stage 2 hypertension.5,14 The JNC 7 guidelines recommend initial combination therapy when BP is >20/10 mm Hg above goal BP.
Moreover, results from controlled clinical trials have shown
that two or more antihypertensive drugs are required for most
hypertensive patients to achieve BP control.6,20 The recommendation for a combination of two agents as initial therapy
is reflected in current hypertension guidelines, including the
consensus statement by the Hypertension in African Americans Working Group (HAAWG),21 the Guidelines of the Task
Force for the Management of Arterial Hypertension,13 and
JNC 7.14
Table I. Preferred drugs according to clinical conditions in the 2007
ESH/ESC Guidelines.
Antihypertensive combinations offer the possibility of combining agents with different pharmacological profiles to achieve
additive effects with enhanced tolerability.13,22 The US National Health and Nutrition Examination Survey (NHANES) recommends the use of two or more drug classes to achieve the
goal of BP control.
Which antihypertensive combinations for which
patients?
Compliance – the importance of treatment
adherence
Compliance represents a major problem in hypertension because of the asymptomatic nature of this chronic disease (at
least at the onset), and because in the majority of patients,
more than one agent is required to achieve BP targets.
Compared with free combinations, fixed-dose combinations
offer better treatment adherence because the treatment regimen is simplified.23,24 Two meta-analyses reported reductions
in noncompliance of 26% and 21%, respectively, with fixeddose combinations compared with a regimen of the same two
agents given separately.25,26 A further advantage of combination therapy is the ability to reach BP control more rapidly than
with monotherapy or free-combination,27 due to its expected
positive impact on compliance, which should improve longterm clinical outcomes.10,28
Angina pectoris
Heart failure
Atrial fibrillation (recurrent)
Atrial fibrillation (permanent)
End-stage renal
disease/proteinuria
Peripheral artery disease
Abbreviations: ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor antagonist; CA, calcium antagonist; ISH, isolated systolic
hypertension; MI, myocardial infarction.
After reference 5: Mancia G, et al. J Hypertens. 2007.25(6):1105-1187. © 2007,
The European Society of Cardiology (ESC) and European Society of Hypertension (ESH).
JNC7 is not specific as regards which drug combinations
should be used but it does state that ‘‘thiazide-type’’ diuretics are often used as one of the components. According to
the European Society of Hypertension and the European Society of Cardiology Guidelines, the most rational antihypertensive combinations are combinations involving ACE inhibitors,
CCBs, ARBs, thiazide (-like) diuretics (ie, hydrochlorothiazide
[HCTZ], chlorthalidone, or indapamide), depending on clinical conditions (Table I, and Figure 1 [ page 388]).5,13
The recently updated British Hypertension Society/National
Institute for Health and Clinical Excellence (BHS/NICE) recommendations of 2011 show a simple algorithm. These recommendations are based on the fact that, on average, younger
people have higher renin levels and respond better (in terms
of BP reduction) to “A” drugs (ACE inhibitors or ARBs), whereas older people or black people of African origin tend to have
lower renin levels and respond better in terms of BP reduction
387
HYPERTENSION
WHERE
ARE
A
AND
PREVENTION:
GOING?
B
2007 ESH/ESC Guidelines
Thiazide diuretics
2009 ESH Reappraisal
Diuretics
β-Blockers
ARBs
ARBs
Figure 1. Recommended combinations of antihypertensive drugs.
Panel A. Antihypertensive drug combinations recommended as
preferred (thick lines) or possible (dash lines) in the 2007 ESH/ESC
Guidelines. Panel B. The five combinations retained for priority
use in the 2009 reappraisal of the 2007 ESH/ESC Guidelines.
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; CCB, calcium channel blockers,
ESC, European Society of Cardiology; ESH, European Society
of Hypertension.
After reference 4: Poulter NR. J Hypertens. 2011.29(suppl 1):
S15-S21. © 2011, Lippincott Williams & Wilkins.
Hypertension: Evaluation), a randomized, controlled study in patients with uncomplicated esCCBs
CCBs
α-Blockers
sential hypertension, 9 months of treatment with
perindopril/indapamide lowered SBP by 26.6
mm Hg and led to normalization of BP in 62%
ACE inhibitors
ACE inhibitors
of patients.30 The combination of a RAS inhibitor
and a diuretic, an effective BP-lowering regimen,
protects against hypertension-associated complications, such
to “C” drugs (CCBs).4 When combination is required, “A+C” is
as cardiovascular events and stroke. This has been demonrecommended but if a diuretic is considered, in patients who
are intolerant to CCBs for instance, use of thiazide-like diuret- strated in interventional studies, such as PROGRESS (Perindoics such as indapamide is advised, as these drugs are safer pril pROtection aGainst Recurrent Stroke Study), where the
combination of the ACE inhibitor perindopril and the thiazidethan older drugs such as HCTZ.
like diuretic indapamide reduced the risk of stroke, MI, and
heart failure in patients with previous stroke or transient isDrug combinations and their studies
chemic attack (Table II).31
◆ RAS inhibition and thiazide-like diuretics
Inhibitors of the RAS, including ACE inhibitors and ARBs, have
demonstrated efficacy in treating hypertension and prevent- Beneficial effects on mortality have also been noted in elderly
ing or reducing cardiovascular morbidity, such as strokes patients in the HYVET stroke trial.33 HYVET (Hypertension in
(Table II).10,19,29 In the STRATHE trial (Strategies of Treatment in
the Very Elderly Trial) proved the benefits of effective BP reduc-
Antihypertensive
combination
RR in
All-cause
diabetic
mortality complications
Study
PROGRESS11
Perindopril +
Amlodipine
RR in MI/
coronary
events
RR in LVH/
heart
failure
Cardiovascular
mortality
3
3
3
NA
NA
NA
NA
3 (–14%)
3 (– 9%)
3 (–21%)
NA
3
3
3 (–18%)
3 (–21%)
NA
NA
3 (–30%)
3
3 (–64%)
3 (–23%)
PICXEL48
NA
NA
NA
NA
NA
3
NA
PREMIER
46
NA
NA
3 (–16%)
NA.
NA
NA
NA
49
NA
NA
NA
NA
NA
3
NA
LIFE 51
NA
NA
NA
3
NA
3
NA
ASCOT-BPLA58
3 (–11%)
3
3
3 (–23%)
3 (–13%)
NA
3 (–24%)
ACCOMPLISH 66
NA
NA
NA
NA
3
NA
NA
3 (– 46%)
NA
NA
NA
3 (–28%)
3 (–54%)
3 (– 41%)
REASON
Losartan + HCTZ
RR in
stroke/
TIA
HYVET 33
ADVANCE
Perindopril +
Indapamide
RR in CKD/
microalbumineria
EUROPA
35
57
Table II. Different antihypertensive combinations and their effects in cardiovascular and other end points in major clinical trials.
Abbreviations: ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension; ADVANCE, Action in
Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–
Lowering Arm; CKD, chronic kidney disease; EUROPA, EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease; HCTZ,
hydrochlorothiazide, HYVET; HYpertension in the Very Elderly Trial, LIFE, Losartan Intervention For Endpoint reduction in hypertension; LVH, left ventricular hypertrophy; NA, not applicable; PICXEL, Perindopril/Indapamide in a Double-Blind Controlled Study versus Enalapril in Left Ventricular Hypertrophy; PREMIER, PREterax in
albuMInuria rEgRession; PROGRESS, Perindopril pROtection aGainst Recurrent Stroke Study; REASON, PREterax in Regression of Arterial Stiffness in a ContrOlled
Double-BliNd study; RR, relative risk; TIA, transient ischemic attack.
388
HYPERTENSION
AND
WHERE
ARE
PREVENTION:
GOING?
18%, all-cause mortality by 14%, and new-onset microalbuminuria by 21% (Figure 2, Table II).32,44-46 With regard to treatment tolerability, this combination appeared well tolerated in
more than 80% of patients. This result has important practical implications for health services delivery, since only one follow-up visit is needed to establish a patient’s suitability for longterm treatment with this regimen.32
tion with indapamide (in combination with perindopril in the
majority of patients) on cardiovascular outcomes in very elderly hypertensive patients.33 This trial demonstrated that even
in patients aged 80 or older, antihypertensive treatment not
only reduced BP by 15.0/6.1 mm Hg compared with placebo,
but also prevented cardiovascular events, thereby contributing to prolonging life.13,33 Indapamide and perindopril reduced
all-cause mortality by 21%, cardiovascular mortality by 23%,
and stroke-related mortality by 39% when compared with
treatment with placebo. There was also a 30% improvement
in stroke rates and a 64% improvement in heart failure rates.41
The echocardiographic substudy of the ADVANCE trial demonstrated that treatment with perindopril and indapamide resulted in a reduction in left ventricular mass (LVM) over 4 years,
but did not improve left ventricular diastolic function.43 The results of the ADVANCE study also showed that the reductions
in relative cardiovascular risk, and diabetic and renal events
achieved with a perindopril/indapamide combination were consistent among subgroups of patients with diabetes defined by
CKD stage.42 As a mirror of their substantially increased car-
The choice of a combination should be based on systematic effects (ie, ACE-inhibitors/ARBs and thiazide [-like] diuretics) as well as on comorbidities and other cardiovascular risk
factors (Table I) as specified by the ESH-ESC 2007 and 2013
guidelines.5,13
Number (%) of patients with event
Perindopril/
indapamide
(n=5569)
Placebo
(n=5571)
Combined macro + micro
861 (15.5)
938 (16.8)
9% (0 to 17)
Macrovascular events
480 (8.6)
520 (9.3)
8% (–4 to 19)
Microvascular events
439 (7.9)
477 (8.6)
9% (–4 to 20)
408 (7.3)
471 (8.5)
14% (2 to 25)
Cardiovascular death
211 (3.8)
257 (4.6)
18% (2 to 32)
Noncardiovascular death
197 (3.5)
212 (3.8)
Total coronary events
468 (8.4)
535 (9.6)
Total cerebrovascular events
286 (5.1)
303 (5.4)
1243 (22.3)
1500 (26.9)
21% (15 to 27)
All deaths
Total renal events
Hazard ratio
Relative risk
reduction (95% CI)
8% (–12 to 24)
14% (2 to 24)
6% (–10 to 20)
181 (3.3)
216 (3.9)
18% (–1 to 132)
1094 (19.6)
1317 (23.6)
21% (14 to 27)
Red squares = point estimates (with area proportional
to number of events); horizontal lines = 95% CI.
Diamonds = point estimate and 95% CI for overall effects.
0.5
New or worsening nephropathy
New microalbuminuria
More recently, in the ADVANCE trial (Action in Diabetes and
Vascular Disease),32 a fixed combination of perindopril/indapamide (4 mg/1.25 mg) was used for 4.3 years on top of standard antihypertensive therapy in both normotensive and hypertensive patients with type 2 diabetes mellitus.42 With a total
of 11 140 patients, this was the largest trial ever carried out in
this type of population. BP reduction was significantly greater
with the perindopril/indapamide combination throughout the
study: –15.6 mm Hg for SBP and –2.2 mm Hg for DBP.43 This
effect was associated with a reduced incidence (–19%) of diabetes-related complications and a reduction in the incidence
of coronary events and cardiovascular and all-cause death.32
Perindopril/indapamide reduced cardiovascular mortality by
1.0
Favors
perindopril/
indapamide
Favors
placebo
2.0
Figure 2.
ADVANCE:
effects on primary
and selected
secondary trial
end points.
Abbreviations:
ADVANCE, Action in
Diabetes and Vascular disease: PreterAx
and DiamicroN MR
Controlled Evaluation; CI, confidence
interval.
After reference 32:
Patel A, et al. Lancet.
2007;370(9590):
829-840. © 2007,
Elsevier Ltd.
diovascular risk, the aldosterone/renin ratio (ARR) was greater
in patients with CKD stage ⱖ3, underlining the importance
of early recognition of CKD in patients with diabetes and the
value of this preventive therapy.42
Importantly, the diuretic used in the PROGRESS, ADVANCE,
and HYVET trials (ie, indapamide) is a thiazide-like metabolically neutral diuretic compound that differs favorably from the
widely used HCTZ in terms of metabolic effects and sustained
24-hour BP lowering. Consequently, it should be considered
suitable for first-line therapy in hypertensive patients.47-51 This
is further supported by evidence from clinical studies that examined the intermediate end points of hypertensive disease.
389
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
The beneficial effects of perindopril/indapamide treatment on
renal function were also illustrated in the PREMIER trial (PREterax in albuMInuria rEgRession),35 which enrolled 457 hypertensive patients with diabetes and albuminuria. Treatment with
perindopril and indapamide for 1 year led to significant BPindependent reductions in albumin excretion rates compared
with treatment with enalapril. Further analysis demonstrated
a 16% increase in albuminuria regression.52
The PICXEL study (Perindopril/Indapamide in a double-blind
Controlled study versus Enalapril in Left ventricular hypertrophy) compared the efficacy of a strategy based on first-line
combination with perindopril and indapamide versus monotherapy with enalapril in reducing left ventricular hypertrophy
(LVH) in hypertensive patients.30,34 In this 1-year multicenter
study, patients received an increasing dose of perindopril,
indapamide, or enalapril.34 SBP and DBP decreased significantly more in the perindopril/indapamide group than in the
enalapril group.34 The authors concluded that, in hypertensive patients with LVH, a strategy based on first-line combination with perindopril and indapamide achieved a greater BP
decrease with a significantly greater LVH reduction than a strategy based on monotherapy with enalapril.34
Further support for the role of perindopril comes from the
REASON study (PREterax in Regression of Arterial Stiffness
in a ContrOlled Double-BliNd).36 In this study comparing the
antihypertensive effects of the combination of indapamide
(0.625 mg)/perindopril (2 mg) with the b-blocking agent atenolol (50 mg), 214 patients with essential hypertension underwent
two-dimensional guided M-mode echocardiography.53 Compared with atenolol, treatment with perindopril/indapamide
improved arterial structure and stiffness. Patients with LVH
showed the greatest LVM regression with a mean regression
of 22.5 g after 12 months of treatment with perindopril and
indapamide, compared with an 8.9-g regression after treatment with atenolol.53 Last but not least, the SBP reduction
was found to be significantly greater with perindopril and indapamide than with atenolol (–21.2 vs –15.3 mm Hg).53
The LIFE study (Losartan Intervention For Endpoint reduction
in hypertension),37 documented the cardiovascular protective effects of using a treatment strategy combining an ARB
(losartan) with HCTZ in hypertensive patients with left LVH.
In most patients, the combination of losartan with HCTZ was
more effective than the combination of atenolol and HCTZ in
the prevention of stroke but there were no differences between
the two treatments regarding the reduction in coronary outcomes (Table II).
◆ RAS inhibition and calcium channel blockers
There is already solid proof that the ACE inhibitor perindopril
and the CCB amlodipine are effective as monotherapy for hypertension,54-58 and they have been available to physicians for
many years. They are frequently prescribed in free combina-
390
tion in hypertension and stable coronary artery disease (CAD),
particularly since the emergence of large clinical trials, such
as EUROPA (EUropean trial on Reduction Of cardiac events
with Perindopril in stable coronary Artery disease)40 or ASCOTBPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood
Pressure–Lowering Arm).38
The fixed-combination of perindopril and amlodipine is a credible option in the field of stable CAD.5,10 Its efficacy was established in the EUROPA trial.40,59,60 In this trial, addition of
perindopril to CCB significantly reduced total mortality by 46%
and reduced the primary end point (a composite of cardiovascular mortality, nonfatal MI, and resuscitated cardiac arrest) by 35%.60 There were 41%, 54%, and 28% reductions in
cardiovascular mortality, hospitalization for heart failure, and
MI, respectively.61 This effect was independent of BP at baseline.
ASCOT-BPLA was the first clinical trial to demonstrate an
effective reduction in mortality among hypertensive patients
treated with a CCB in combination with a RAS inhibitor.38,60
ASCOT-BPLA included over 19 257 patients with hypertension and at least three or more prespecified cardiovascular
risk factors. The trial compared the effect of a standard antihypertensive regimen (b-blocker/bendroflumethiazide–based
regimen) versus a newer regimen of dihydropyridine CCB ±
ACE inhibitor, respectively, amlodipine and perindopril). The
newer regimen was clearly superior in terms of preventing cardiovascular events. This trial was stopped prematurely after a
median of 5.5 years, because of significant beneficial effects
on all-cause mortality associated with allocation to the amlodipine/perindopril–based regimen.62 A significant decrease
of 11% in deaths from all causes and of 24% in cardiovascular mortality was achieved with the amlodipine/perindopril regimen, despite the reduction in BP being almost comparable
to that of the b-blocker/diuretic combination.60 Other secondary end points also favored amlodipine/perindopril, with a 23%
reduction in fatal and nonfatal stroke, and a 13% reduction in
total coronary events. (Figure 3, Table II).
Various substudies of ASCOT (Anglo-Scandinavian Cardiac
Outcomes Trial) have provided further information to support
the superior efficacy of an amlodipine/perindopril regimen in
patients with type 2 diabetes mellitus.38,62 ASCOT included a
large subpopulation with type 2 diabetes mellitus (n=5137) in
which there was a 14% difference in the end point of major
cardiovascular events in favor of the amlodipine/perindopril
group.63 This was accompanied by a 25% lower incidence of
fatal and nonfatal stroke, 48% less peripheral artery disease,
and 57% fewer noncoronary revascularization procedures.63
These results are in line with other studies of ACE inhibitor/
CCB combinations in hypertensive patients with diabetes. In
a review article, Ferrari described a study in which 214 patients received either a combination of ACE inhibitor and CCB
or ACE inhibitor monotherapy for 3 months.10 The conclusion
HYPERTENSION
AND
WHERE
ARE
PREVENTION:
GOING?
Unadjusted HR (95% Cl)
Primary
Nonfatal MI (incl silent) + fatal CHD
0.90 (0.79-1.02)
Secondary
Nonfatal MI (excl silent) + fatal CHD
Total coronary end point
Total CV event and procedures
All-cause mortality
Cardiovascular mortality
Fatal and nonfatal stroke
Fatal and nonfatal heart failure
0.87 (0.76-1.00)
0.87 (0.79-0.96)
0.84 (0.78-0.90)
0.89 (0.81-0.99)
0.76 (0.65-0.90)
0.77 (0.66-0.89)
0.84 (0.66-1.05)
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Life-threatening arrhythmias
New-onset diabetes mellitus
New-onset renal impairment
1.27 (0.80-2.00)
0.68 (0.51-0.92)
0.98 (0.81-1.19)
0.65 (0.52-0.81)
1.07 (0.62-1.85)
0.70 (0.63-0.78)
0.85 (0.75-0.97)
Post hoc
Primary end point + coronary revascularization
CV death + MI + stroke
0.86 (0.77-0.96)
0.84 (0.76-0.92)
0.50
0.70
1.00
amlodipine/perindopril better
1.45
2.00
atenolol/thiazide better
Figure 3. A summary of all end points in ASCOT-BPLA.38
Data from the ASCOT-BPLA trial showing that the newer amlodipine/perindopril regimen was clearly superior in terms of preventing CV events overall — and significantly so — for most of the end points considered.
Abbreviations: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm; CHD, coronary heart disease; CV, cardiovascular; CI,
confidence interval; HR, hazard ratio; MI, myocardial infarction.
After reference 4: Poulter NR. J Hypertens. 2011;29(suppl 1):S15-S21. © 2011, Lippincott Williams & Wilkins.
of the study was that the fixed combination was more effective than monotherapy with respect to achieving diabetic BP
goals. Fixed-combination perindopril/amlodipine can therefore be predicted to reproduce the positive results of ASCOT
in diabetic hypertensives, thereby providing additional reductions in total and cardiovascular mortality.10
A pharmacoeconomic analysis has recently been applied to
the results of ASCOT. As might be expected, the actual cost
of treatment with the “older” treatment of b-blocker/diuretic
was lower than the “newer” combination of perindopril/amlodipine.64 However, for the b-blocker/diuretic combination,
these lower costs were rapidly offset by increases in other
costs driven by the number of hospitalizations and the cost
of procedures, concomitant treatments, and events.10 Moreover, this analysis failed to take into account the costs associated with microvascular complications, excess mortality due
to new-onset diabetes, or rehabilitation after stroke.10 These
can all be reasonably predicted to be lower in perindopril/amlodipine–treated patients and the authors concluded that the
perindopril/amlodipine combination was cost-effective in patients with moderate hypertension and additional risk factors.64
The CAFE study (Conduit Artery Function Evaluation)—a substudy of ASCOT—examined the impact of the two BP-lowering regimens compared in the ASCOT trial on derived central
aortic pressures and hemodynamics in 2199 patients for up
to 4 years. The amlodipine/perindopril regimen was associated with substantial reductions in central aortic pressures
compared with the atenolol/HCTZ regimen.65 The CAFE population had the same baseline characteristics as the overall
ASCOT population, and there were no significant differences
between the two groups. However, central aortic SBP was
significantly lower in the amlodipine/perindopril group (difference, 4.3 mm Hg). The authors concluded that the differential effects on central BP of the two antihypertensive regimens
may be, at least in part, responsible for the differential effects
on cardiovascular outcomes.60
In addition, the ACCOMPLISH study (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with
Systolic Hypertension)39 provided outcome evidence in favor
of the combination of an ACE inhibitor and a CCB. This trial
included 11 506 patients with hypertension who were at high
risk of cardiovascular events (most patients had type 2 dia-
391
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
Outcome
Composite of death from cardiovascular
causes and cardiovascular events
Component
Death from cardiovascular causes
Myocardial infarction (fatal or nonfatal)
Stroke (fatal or nonfatal)
Hospitalization for unstable angina
Coronary revascularization procedure
Resuscitation after sudden cardiac arrest
0.50
1.0
HR (95% Cl)
P values
Figure 4. Effects on primary and other end points
in ACCOMPLISH.39
0.80 (0.72-0.90)
<0.001
0.80 (0.62-1.03)
0.78 (0.62-0.99)
0.84 (0.65-1.08)
0.75 (0.50-1.10)
0.86 (0.74-1.00)
1.75 (0.73-4.17)
0.08
0.04
0.17
0.14
0.05
0.20
Data from the ACCOMPLISH
trial showing superiority of a
CCB/ACE inhibitor combination
over an ACE inhibitor/HCTZ
combination on most cardiovascular outcomes.
Abbreviations: ACCOMPLISH,
Avoiding Cardiovascular Events
through Combination Therapy in
Patients Living with Systolic Hypertension; ACE, angiotensinconverting enzyme; CCB, calcium
channel blocker; CI, confidence
interval; HCTZ, hydrochlorothiazide; HR, hazard ratio.
After reference 4: Poulter NR.
J Hypertens. 2011;29(suppl 1):
S15-S21. © 2011, Lippincott
Williams & Wilkins.
2.00
Favors
Favors
CCB/
ACE inhibitor/
ACE inhibitor
HCTZ
betes and/or CAD). BP was reduced very effectively in both
treatment arms and to a similar extent, without significantly affecting the rates of postural hypotension. This trial also showed
the significant benefit of a benazepril/amlodipine combination
on major cardiovascular events compared with a benazepril/
HCTZ combination (Figure 4, Table II).4
Is there a rationale for a fixed-dose triple
combination?
The increased BP-lowering efficacy of the different fixed-dose
combinations of either an ACE inhibitor or an ARB and a thiazide-like diuretic, or an ACE inhibitor and a CCB, has been
proven.28 Furthermore, even though the combination of two
drugs may significantly improve efficacy, it is estimated that
about 15% to 20% of patients require combination therapy
with three agents to control BP effectively.13 Recent clinical
studies have shown that triple therapy with an ARB, a CCB,
and a diuretic significantly reduces BP compared with dual
combination therapy. The clinical benefit of triple combination
therapy with olmesartan 40 mg, amlodipine 10 mg, and HCTZ
25 mg was compared with that of dual combinations of the
individual components in TRINITY (the TRIple therapy with
olmesartan medoxomil, amlodipine, and hydrochlorothiazide
in hyperteNsIve patienTs studY). This study was conducted
on 2492 patients with moderate to severe hypertension.66 After 12 weeks, reductions in seated DBP and SBP were significantly greater with triple combination therapy than with any
of the dual combinations. These results suggest that there are
a number of options for a fixed combination of three antihypertensive agents (eg, perindopril/amlodipine/indapamide).
Having established the potential of triple combinations, it will
now be necessary to assess their long-term efficacy and safety profile.
Conclusion
Antihypertensive combination therapy has been recommended as potential first-line therapy in recent consensus guideline
statements, especially for higher-risk patients such as those
with stage 2 or 3 hypertension. The combination of a RAS-targeting agent, such as an ACE inhibitor or an ARB, together
with a diuretic, particularly if metabolically neutral (eg, indapamide), or a CCB, or both, provides synergy with regard to the
lowering of BP. Furthermore, the dual combination of perindopril/indapamide and perindopril/amlodipine has been documented as improving cardiovascular outcomes and reducing total mortality. n
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54. Weir MR. Calcium channel blockers: their pharmacologic and therapeutic role
in hypertension. Am J Cardiovasc Drugs. 2007;7(suppl 1):5-15.
393
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
55. Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for
hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. J Am Coll Cardiol. 2002;39(2):315-322.
56. Julius S, Cohn JN, Neutel J, et al. Antihypertensive utility of perindopril in a
large, general practice-based clinical trial. J Clin Hypertens (Greenwich). 2004;
6(1):10-17.
57. Telejko E. Perindopril arginine: benefits of a new salt of the ACE inhibitor perindopril. Curr Med Res Opin. 2007;23(5):953-60.
58. Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease:
evidence with perindopril. Expert Rev Cardiovasc Ther. 2005;3(1):15-29.
59. McInnes GT. Antihypertensive drugs in combination: additive or greater than
additive? J Hum Hypertens. 2007;21(12):914-916.
60. Vandzhura V. Coveram in the management of hypertension: improving each
and every component of antihypertensive efficacy for lifesaving benefits. Medicographia. 2010;32:281-289.
61. Bertrand ME, Ferrari R, Remme WJ, Simoons ML, Deckers JW, Fox KM; EUROPA Investigators. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary
artery disease. Post hoc analysis of the EUROPA study. Am Heart J. 2010;
159(5):795-802.
62. Poulter NR, Wedel H, Dahlöf B, et al; ASCOT Investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in
(ASCOT-BPLA). Lancet. 2005;366(9489):907-913.
63. Ostergren J, Poulter NR, Sever PS, et al; ASCOT investigators. The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes. J Hypertens. 2008;26(11):2103-2111.
64. Lindgren P, Buxton M, Kahan T, et al; ASCOT trial investigators. Economic evaluation of ASCOT-BPLA: antihypertensive treatment with an amlodipine-based
regimen is cost effective compared with an atenolol-based regimen. Heart.
2008;94(2):e4.
65. Williams B, Lacy PS, Thom SM, et al; CAFE Investigators; Anglo-Scandinavian
Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing
Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213-2125.
66. Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter, randomized, double-blind,
12-week, parallel-group study. Clin Ther. 2010;32(7):1252-1269.
Keywords: antihypertensive drug; blood pressure; combination therapy; hypertension
POURQUOI
AVONS - NOUS BESOIN D ’ASSOCIATIONS ANTIHYPERTENSIVES
?
L’hypertension est un problème mondial et la cause principale de mortalité. La plupart des patients hypertendus ont
des maladies ou des facteurs de risque cardiovasculaires supplémentaires et pour la majorité d’entre eux, plus d’un
médicament est nécessaire pour atteindre les valeurs cibles de pression artérielle : deux ou trois en moyenne d’après
plusieurs études cliniques sur la prise en charge de l’hypertension. Les associations utilisant les synergies pharmacologiques et physiologiques étant plus efficaces, les recommandations préconisent d’ajouter un médicament d’une
autre classe que celle initialement prescrite. D’après les directives de l’European Society of Hypertension et de l’European Society of Cardiology, les associations antihypertensives les plus pertinentes sont celles impliquant inhibiteurs de l’enzyme de conversion (IEC), antagonistes calciques (AC), antagonistes du récepteur de l’angiotensine II
(ARA II) et diurétiques thiazidiques. L’association d’un IEC avec le diurétique thiazidique indapamide s’est montrée
efficace pour faire baisser la pression artérielle et prévenir ou diminuer la morbidité cardiovasculaire dans de nombreuses études comme STRATHE, PROGRESS, HYVET, REASON, LIFE et ADVANCE. Les études EUROPA, ASCOT
ou ACCOMPLISH ont évalué l’association d’un IEC et d’un AC, une association qui s’est montrée efficace dans la
prévention des événements cardiovasculaires, la prévention de l’apparition d’un diabète et dans la réadaptation après
un accident vasculaire cérébral. L’association médicamenteuse doit donc être personnalisée selon les comorbidités
des patients hypertendus.
394
‘‘
HYPERTENSION
AND
WHERE
There are physiological and
pharmacological synergies that
justify the greater effectiveness of
drug combinations.... From a public health perspective, it would
seem desirable to see a substantial increase in the use of combination treatment in clinical practice
from the relatively low prevalence
of today. This could help attain the
goal of substantially improving
blood pressure control in the hypertensive population from its
present low rate of control worldwide.”
ARE
PREVENTION:
GOING?
Antihypertensive
combinations:
what is missing?
b y J . B l ac h e r, Fra n c e
A
Jacques BLACHER, MD, PhD
Faculty of Medicine
Paris-Descartes University
Paris, FRANCE
ll the epidemiological studies show that hypertension remains inadequately screened, treated, and controlled. It has been shown that
when antihypertensive monotherapy is not sufficient to control blood
pressure, the combination of two agents from any two classes of antihypertensive drugs increases the level of blood pressure reduction much more than
doubling the dose of one agent. Most of the existing guidelines focus on combinations that use a blocker of the renin-angiotensin-aldosterone system and
either a thiazide diuretic or a calcium channel antagonist. Other combinations
are underpromoted; specifically, the combination of a thiazide diuretic and a
calcium channel antagonist. However, this combination has been used in several therapeutic trials and has shown similar or greater benefits than comparator drugs. In VALUE (Valsartan Antihypertensive Long-Term Use Evaluation), ELSA (European Lacidipine Study on Atherosclerosis), FEVER (Felodipine
EVEnt Reduction), and COPE (COmbination therapy of hypertension to Prevent cardiovascular Events), the calcium channel antagonist/thi-azide combinations were effective both in terms of systolic blood pressure reduction and
prevention of cardiovascular complications. Furthermore, in addition to a wellaccepted effect on systolic blood pressure, this combination could also have
beneficial effects over and above blood pressure reduction; namely, its effects
on central blood pressure and on systolic blood pressure variability. Finally,
therapeutic innovation in hypertension will perhaps come more from the combination of older drugs than from the discovery of new drugs.
ypertension is the leading chronic disease worldwide.1 It is known to increase
the risk of stroke, coronary heart disease, heart failure, renal failure, and cognitive disorders, and was responsible for between 7 and 8 million deaths
worldwide in 2011.2 Antihypertensive treatment has been shown to reduce cardiovascular complications.3 In France, an estimated 12 million patients receive pharmacological treatment for hypertension, most of them receiving combination therapy.4
H
Prof Jacques Blacher,
Université Paris Descartes, Assistance
Publique-Hôpitaux de Paris, Unité
HTA, Prévention et Thérapeutique
Cardiovasculaires Centre de
Diagnostic et de Thérapeutique,
Hôtel-Dieu, Place du Parvis
Notre-Dame, 75004 Paris, France
For over 30 years, national and international societies have issued numerous sets
of guidelines for the management of hypertension, yet hypertension still remains inadequately screened, treated, and controlled.5 In France, 20% of patients known
to be hypertensive are not treated, and 50% of treated hypertensive patients are
not controlled, thus showing that the impact of the guidelines is insufficient at the
population level.6
Antihypertensive combinations: what is missing? – Blacher
395
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
To improve the management of hypertension, combination
therapies need to be promoted. Most of the existing guidelines
focus on combinations using a blocker of the renin-angiotensinaldosterone system and another drug (thiazide diuretic or calcium channel antagonist), whereas others combinations are
underpromoted; namely, the combination of a thiazide diuretic and a calcium channel antagonist. This article will focus on
the existing data in favor of such a combination.
Which strategy after the failure of an initial
monotherapy?
According to the 2007 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines,7 antihypertensive treatment should most of the time start with
a single drug, which should initially be administered at a low
dose. If blood pressure is not controlled, either a full dose of
the initial agent can be given or patients can be switched to
an agent of a different class (which should also be administered first at a low dose and then at full dose). Switching to an
agent from a different class is mandatory in cases where the
first agent had no blood pressure–lowering effect or induced
important side effects. This ‘‘sequential monotherapy’’ approach allows one to find the drug to which any individual patient best responds, both in terms of efficacy and tolerability.
However, although the so-called ‘‘responder rate’’ for any agent
in monotherapy is approximately 50% (response meaning
here systolic and diastolic blood pressure reduction of >20
mm Hg and >10 mm Hg, respectively), the ability of any agent
used alone to achieve target blood pressure values (<140/90
mm Hg) does not exceed 20%-30% in the overall hypertenSELECTED
ABBREVIATIONS AND ACRONYMS
ACE
ADVANCE
Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation
(trial)
ALLHAT
Antihypertensive and Lipid-Lowering treatment
to prevent Heart Attack Trial
ASCOT
Anglo-Scandinavian Cardiac Outcomes Trial
ASH
American Society of Hypertension
CCB
COPE
COmbination therapy of hypertension to Prevent
cardiovascular Events (trial)
ELSA
European Lacidipine Study on Atherosclerosis
ESC
European Society of Cardiology
ESH
European Society of Hypertension
FEVER
Felodipine EVEnt Reduction (trial)
HYVET
NICE
National Institute for Health and Care Excellence
VALUE
Valsartan Antihypertensive Long-Term Use Evaluation (trial)
396
sive population, except in subjects with grade 1 hypertension.
Furthermore, the procedure is laborious and frustrating for
both doctors and patients, leading to low compliance.
In its 2009 reappraisal,8 the ESH task force tempered its position, mostly because of the publication of an important metaanalysis.9 This meta-analysis of 42 studies showed that combining two agents from any two classes of antihypertensive
drugs increases the blood pressure reduction much more (5
times) than doubling the dose of one agent.9 Admittedly, the
advantage of combination therapy over monotherapy may
partly be due to the fact that if any agent used in monotherapy is ineffective or scarcely effective in a number of patients,
thus its combination with an agent that is effective in these
patients must induce a greater response than doubling the
dose of an ineffective agent. However, although it is possible that the use of two drugs together implies the administration of one drug that is futile, searching for the most effective
monotherapy in every given patient is painstaking, and, as
mentioned, may discourage compliance.
It is also important to note that in most trials, a combination
of two or more drugs has been the most widely used treatment regimen to effectively reduce blood pressure and reach
the predetermined goal. Use of combination therapy has been
found to be even more frequently needed in diabetic, renal,
and high-risk patients, and in general whenever lower blood
pressure targets are pursued.8 For example, in a large-scale
trial on high-risk hypertensives, the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial), about 9 out of 10 patients
were given two or more antihypertensive drugs in order to reduce blood pressure to <140/90 mm Hg.10
Furthermore, there are physiological and pharmacological
synergies that justify the greater effectiveness of drug combinations, and this strategy appears to be that on which the
selection of antihypertensive medication may increasingly be
based. From a public health perspective, it would seem desirable to see a substantial increase in the use of combination
treatment in clinical practice from the relatively low prevalence
of today.4,6 This could help attain the goal of substantially improving blood pressure control in the hypertensive population
from its present low rate of control worldwide.2
Finally, for all these reasons, in the 2013 French Society of Hypertension guidelines, we have proposed a direct switch to
combination therapy when blood pressure is not adequately
controlled by initial monotherapy.11
What is the ideal combination therapy?
The ideal combination therapy should be: (i) effective in terms
of systolic blood pressure reduction, with at least complete
(not partial) additive effects of both monotherapies, and at best,
synergistic effects; (ii) pertinent in terms of pathophysiological effects: this should be achieved by combining agents that
HYPERTENSION
AND
WHERE
either interfere with distinctly different pressor mechanisms
or effectively block counterregulatory responses; and (iii) evidence-based; that is to say that this combination should have
demonstrated a beneficial effect on cardiovascular morbid
and fatal events in comparison with a monotherapy, or best,
another combination treatment.
Unfortunately, the blood pressure effects of combination therapies in hypertension are frequently underadditive, pathophysiological considerations are frequently contradicted by different clinical trials, and there are very few therapeutic trials
◆ Evidence has continued to grow that in the vast majority of
hypertensive patients, effective blood pressure control can
only be achieved by combination of at least two antihypertensive drugs.
◆ Addition of a drug from another class to the initially prescribed
one should thus be regarded as a recommendable treatment strategy, unless the initial drug needs to be withdrawn
because of the appearance of side effects or the absence of
any blood pressure–lowering effect.
◆ The combination of two antihypertensive drugs may offer ad-
vantages also for treatment initiation, particularly in patients at
high cardiovascular risk in which early blood pressure control may be desirable.
◆ Whenever possible, use of fixed dose (or single pill) combina-
tions should be preferred, because simplification of treatment
carries advantages for compliance to treatment.
ARE
PREVENTION:
GOING?
comparing two different bitherapies with clinical events outcomes. Thus, preferences should take into account a combination of the previous criteria and a large degree of uncertainty.
In their 2009 guidelines, the ESH/ESC reported that (Table I):
Trial evidence of outcome reduction has been obtained particularly for the combination of a diuretic with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor antagonist
or a calcium antagonist, and in recent large-scale trials for the ACE
inhibitor/calcium antagonist combination.8
In a recent position paper, Gradman et al, on behalf of the
American Society of Hypertension (ASH), differentiated the
possible drug combinations in hypertension into three groups:
the preferred, the acceptable, and the less-effective combinations (Table II).12 It is important to note that the calcium channel blocker (CCB)/diuretic combination was considered as
“preferred” by the European guidelines and just “acceptable”
by the ASH. It will be interesting to see if such discrepancy still
exists in the forthcoming European and American guidelines.
Focus on an “acceptable bitherapy”: the calcium
channel blocker/diuretic combination
Despite the fact that small pharmacological studies have
raised doubts about the synergistic effects of adding a diuretic to a calcium channel antagonist (for review see reference 8), this combination was included in the meta-analysis
by Wald et al9 and did not detract from the demonstration of
◆ As mentioned in the 2007 European Society of Hypertension/
European Society of Cardiology guidelines, several two-drug
combinations are suitable for clinical use. However, trial evidence of outcome reduction has been obtained particularly
for the combination of a diuretic with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor antagonist or a calcium antagonist, and in recent large-scale trials
for the ACE inhibitor/calcium antagonist combination. The angiotensin receptor antagonist/calcium antagonist combination also appears to be rational and effective. These combinations can thus be recommended for priority use.
◆ Despite trial evidence of outcome reduction, the b-blocker/
diuretic combination favors the development of diabetes and
should thus be avoided, unless required for other reasons, in
predisposed patients. Use of an ACE inhibitor–angiotensin
receptor antagonist combination presents a dubious potentiation of benefits with a consistent increase of serious side
effects. Specific benefits in nephropathic patients with proteinuria (because of a superior antiproteinuric effect) expect
confirmation in event-based trials.
◆ In no less than 15%-20% of hypertensive patients, blood pres-
sure control cannot be achieved by a two-drug combination.
When three drugs are required, the most rational combination appears to be a blocker of the renin–angiotensin system,
a calcium antagonist, and a diuretic at effective doses.
Table I. 2009 European Society of Hypertension position concerning combination therapy.
After reference 8: Mancia G et al; European Society of Hypertension. J Hypertens. 2009;27:2121-2158. © 2009, Lippincott Williams & Wilkins.
◆ Preferred
ACE inhibitor/diuretic
ARB/diuretic
ACE inhibitor/ CCB
ARB/CCB
◆ Acceptable
b-Blocker/diuretic
CCB (dihydropyridine)/b-blocker
CCB/diuretic
Renin inhibitor/diuretic
Renin inhibitor/ARB
Thiazide diuretics/K+-sparing diuretics
◆ Less effective
ACE inhibitor/ARB
ACE inhibitor/b-blocker
ARB/b-blocker
CCB (nondihydropyridine)/b-blocker
Centrally-acting agent/b-blocker
Table II. 2011 American Society of Hypertension position concerning combination therapy.
Abbreviations: ARB, angiotensin receptor blocker; ACE, angiotensin-converting
enzyme; CCB, calcium channel blocker.
After reference 12: Gradman AH et al; American Society of Hypertension Writing Group. J Am Soc Hyper. 2010;4:42-50. © 2010 American Society of Hypertension.
397
HYPERTENSION
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ARE
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PREVENTION:
GOING?
FEVER14
2005
COPE16
2011
CCB/DIU
vs BB/DIU
CCB/DIU
vs ARB/DIU
CCB/DIU
vs DIU
CCB/DIU
vs ARB/CCB or CCB/BB
Untreated or treated
Treated
Uncontrolled on DIU
Uncontrolled on CCB
Baseline: 163/101 mm Hg
End: 141/86 mm Hg
End: 137/78 mm Hg
End: 141/84 mm Hg
End: 134/77 mm Hg
Strokes
CV & all deaths
PEP: similar effect
MI
Mancia (Italy)
Zanchetti (Italy)
Safar (France)
Julius (USA)
Zanchetti (Italy)
Weber (USA)
‘‘
Liu (China)
Zhang (China)
Zanchetti (Italy)
a greater blood pressure–lowering effect of combining calcium channel antagonists with other drugs compared with
doubling the calcium channel antagonist dose in monotherapy. Even more importantly, the association of a calcium channel antagonist with a diuretic has been used in several therapeutic trials, where it has shown similar or greater benefits than
the comparators. These trials are detailed hereafter and summarized in Table III.
◆ The VALUE trial
The VALUE trial (Valsartan Antihypertensive Long-Term Use
Evaluation) included patients with high-risk hypertension, most
with previous histories of coronary disease, stroke, or diabetes.
Patients were randomized to either a valsartan-based or amlodipine-based treatment, and were followed-up for as long
as 6 years. Most patients were on previous antihypertensive
therapy, and at the start of the study were switched immediately to the starting dose of their randomly assigned drug. If
needed, to achieve blood pressure control (<140/90 mm Hg),
doses could be titrated (valsartan 80 mg to 160 mg; amlodipine 5 mg to 10 mg) and hydrochlorothiazide (12.5 mg to 25
mg) and other drugs added during the first 6 months of the
study. The primary study end point was a composite of fatal
and nonfatal cardiac events (including sudden cardiac death,
myocardial infarction, hospitalization for heart failure, and death
associated with percutaneous or surgical coronary interventions). Although there was no statistically significant difference
in the primary end point between groups at the end of the trial, the greater blood pressure reduction (–3.8/–2.2 mm Hg)
seen in amlodipine- versus valsartan-treated patients in the
first 6 months was accompanied by a statistically significant
difference in cardiovascular event rate in favor of the more effectively-treated group.13
◆ The FEVER trial
The FEVER trial (Felodipine EVEnt Reduction) was a multicenter, double-blind, randomized, placebo-controlled, parallelgroup trial. It enrolled 9800 Chinese patients, of either sex, aged
50 to 79 years, with one or two additional cardiovascular risk
398
PEP: tendance in favor
of CCB/DIU
Strokes
‘
Strokes
Coronary events
CV & all deaths
‘
‘
‘
VALUE13
2004
‘
ELSA15
2002
Matsuzaki (Japan)
Table III. The calcium
channel blocker/diuretic
combination is at least as
effective as or superior to
other antihypertensive
strategies.
Abbreviations: ARB, angiotensin
receptor blocker; BB, 웁-blocker;
CCB, calcium channel blocker;
COPE, COmbination therapy of
hypertension to Prevent cardiovascular Events (trial); CV, cardiovascular; DIU, diuretic; ELSA,
European Lacidipine Study on
Atherosclerosis; FEVER, Felodipine EVEnt Reduction (trial); MI,
myocardial infarction; PEP, primary
end point; VALUE, Valsartan Antihypertensive Long-Term Use
Evaluation (trial).
factors or disease, whose blood pressure was in the range
of 140-180 mm Hg (systolic) or 90-100 mm Hg (diastolic) 6
weeks after switching from their previous antihypertensive therapy to low-dose (12.5 mg a day) hydrochlorothiazide. These
patients were randomly assigned to either low-dose felodipine extended release or placebo, and followed at 3-month
intervals for an average of 40 months. The intention-to-treat
analysis included 9711 patients. Add-on therapy was given
to 33.9% of the hydrochlorothiazide + felodipine patients and
to 42.3% of the hydrochlorothiazide + placebo patients. In the
felodipine group, systolic blood pressure/diastolic blood pressure decreased (from randomization to study end) from 154.2/
91.0 mm Hg to 137.3/82.5 mm Hg, and in the placebo group
from 154.4/91.3 mm Hg to 142.5/85.0 mm Hg, with an average difference throughout the trial of 4.2/2.1 mm Hg. In the
felodipine group, the primary end point (fatal and nonfatal
stroke) was reduced by 27% (P<0.001). Among the secondary end points, all cardiovascular events were reduced by 27%
(P<0.001), all cardiac events by 35% (P=0.012), death by any
cause by 31% (P=0.006), coronary events by 32% (P=0.024),
heart failure by 30% (P=0.239), and cardiovascular death by
33% (P=0.019) in the felodipine group.14
◆ The ELSA study
The ELSA trial (European Lacidipine Study on Atherosclerosis)
was a randomized, double-blind trial in 2334 patients with hypertension that compared the effects of 4 years of treatment
based on either lacidipine or atenolol on an index of carotid
atherosclerosis: the mean of the maximum intima-media thickness in far walls of common carotids and bifurcations (CBMmax). This index has been shown by epidemiological studies to be predictive of cardiovascular events. If blood pressure
was not at goal, after increasing the study drug dose in each
group, 12.5 mg hydrochlorothiazide was added. Although
clinic blood pressure reductions were identical in both groups,
a significant (P<0.0001) effect of lacidipine was found compared with atenolol, with a treatment difference in 4-year CBMmax progression of 0.0227 mm (intention-to-treat population) and 0.0281 mm (completers). No significant difference
HYPERTENSION
AND
WHERE
between treatments was found for any cardiovascular events,
although the relative risk for stroke, major cardiovascular events,
and mortality showed a trend favoring lacidipine (plus hydrochlorothiazide).15
◆ The COPE study
In COPE (COmbination therapy of hypertension to Prevent
cardiovascular Events), a randomized, open-label, blinded end
point trial, 3501 hypertensive outpatients aged between 40
and 85 years who did not achieve target blood pressure
(<140/90 mm Hg) with the CCB benidipine 4 mg/day were
randomly equally assigned to receive an angiotensin receptor blocker, a b-blocker, or a thiazide diuretic in addition to
Figure 1. Typical pressure
waveforms and characteristics
related to reflected waves in
high and low arterial stiffness.
Tr: arrival time (msec) of reflected waves
at central aorta (time from the onset of left
ventricular ejection (T0 ) to inflection point
A). AP=P1-P2 the augmentation of aortic
systolic pressure induced by the return
of the reflected wave, where P1 is the
pressure at the first inflection point A and
P2 is the pressure at the second inflection
point B. Augmentation index (AIx) (%) is
defined by the formula: AIx = 100 AP/PP,
where PP is the aortic pulse pressure
(systolic minus diastolic pressure). Ts: the
end of systole (ejection duration).
After reference 17: Protogerou AD et al.
J Hypertens. 2007;25:265-272. © 2007,
Lippincott Williams & Wilkins.
ARE
◆ Central blood pressure
The blood pressure waveform varies substantially between
the peripheral conduit (brachial) and the central elastic (aorta)
arteries, mainly due to a gradual increase in systolic blood
pressure as the wave propagates distally. This phenomenon
is called blood pressure amplification and is principally generated by the presence of an arterial stiffness gradient and
Low stiffness
A
A
P1
B
AP
P1
GOING?
pressure difference. Thus, some strategies are undoubtedly
associated with a cardiovascular benefit that goes above and
beyond blood pressure reduction. The two best candidates
to explain part of this benefit are the concepts of central hemodynamics and blood pressure variability.
High stiffness
P2
PREVENTION:
B
P2
AP
Dicrotic notch
Dicrotic notch
Pulse
pressure
Onset of
left ventricular
ejection
Tr
Tr
T0
Period
Period
Ts
Ts
benidipine. Median follow-up was 3.61 years. At the end of
the treatment, 64.1%, 66.9%, and 66.0% of patients in the
benidipine+angiotensin receptor blocker, benidipine+b-blocker, and benidipine + thiazide groups, respectively, achieved target blood pressure. The cardiovascular composite end point
occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively; the hazard ratio was 1.26 in the benidipine + angiotensin receptor blocker group (P=0.3505) and 1.54 in the
benidipine + b-blocker group (P=0.0567) compared with the
benidipine + thiazide group. The secondary analyses revealed
that benidipine + thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P=0.0109) and benidipine
+ angiotensin receptor blocker significantly reduced new-onset diabetes (P=0.0240) compared with benidipine + b-blocker. Finally, there was a trend toward a superior net benefit in
the benidipine + thiazide group.16
wave reflections along the arterial bed (Figure 1).17 More and
more clinical studies suggest that central blood pressure may
provide additional information regarding cardiovascular risk
beyond peripheral blood pressure. Recent evidence suggests,
beyond any doubt, that antihypertensive drugs affect peripheral and central blood pressure differentially and alter pressure amplification. We previously published a review paper
showing that18: (i) it is clear that there are important differences
between the classes of antihypertensive drugs regarding their
effects on blood pressure amplification; (ii) it seems that the
newer antihypertensive drugs (ACE inhibitors, angiotensin receptor blockers, and dihydropyridine CCBs), as well as nitrates, have a more beneficial effect on blood pressure amplification than the older drugs (diuretics and b-blockers); and
(iii) there is compelling evidence regarding the detrimental effect of b-blockers (mainly atenolol) on central blood pressure.
Beneficial effects of calcium channel blocker/
diuretic combination over and above blood
pressure reduction
Nevertheless, very few comparative studies have been performed that focus on central blood pressure parameters. In
a double-blind crossover study, the effects on central aortic
pressure of the four major drug classes were measured and
compared with placebo. Central aortic pressure and various
indices were determined using the SphygmoCor® apparatus.
The study was undertaken in patients aged 65 to 85 years
with systolic blood pressure of >150 mm Hg at study entry.
The main benefits of antihypertensive treatment are due to
lowering of blood pressure per se, and are largely independent of the drugs employed. Nevertheless, several therapeutic trials have shown differences in the rate of cardiovascular
complications between groups without any significant blood
399
ARE
AND
PREVENTION:
GOING?
Results were reported for 32 patients who had satisfactory
applanation tonometry in all five periods. This study revealed
that CCBs and diuretics caused a greater fall in brachial artery systolic blood pressure than ACE inhibitors or b-blocker
drugs. On placebo, central aorta augmentation pressure and
index were 23 mm Hg and 33.3%; on ACE inhibitors the values were 18 mm Hg and 30%; on b-blockers, 26 mm Hg and
38.5%; on CCBs, 16 mm Hg and 28%; and on diuretics, 17
mm Hg and 28.8%. The augmentation pressure on b-blocking drugs was greater than on the other three drug classes
(P<0.05), and augmentation pressures on ACE inhibitors,
CCBs, and diuretics were less than on placebo (P<0.05). The
lowest central aortic pressures were achieved with CCBs and
diuretics.19
To my knowledge, the effects of combination therapies on
central hemodynamics have never been assessed.
◆ Blood pressure variability
Unexplained differences between classes of antihypertensive
drugs in their effectiveness in terms of cardiovascular prevention might be due to class effects on intra-individual variability in blood pressure. In order to test this hypothesis, Webb
et al performed a systematic review to assess any such effects in randomized controlled trials.20 In their meta-analysis,
blood pressure variability was expressed as the ratio of the
variances or as coefficient of variation. Compared with other
drugs, inter-individual variation in systolic blood pressure was
reduced by CCBs (variance ratio 0.81; 95% confidence interval, 0.76-0.86; P<0.0001) and nonloop diuretic drugs (variance ratio 0.87; 95% confidence interval, 0.79-0.96; P=0.007),
and increased by ACE inhibitors (variance ratio 1.08; 95% confidence interval, 1.02-1.15; P=0.008), angiotensin receptor
blockers (variance ratio 1.16; 95% confidence interval, 1.071.25; P=0.0002), and b-blockers (variance ratio 1.17, 95%
confidence interval, 1.07-1.28, P=0.0007). CCBs followed by
thiazide diuretics could thus be considered as the two best
drugs in terms of reduction of blood pressure variability (Figure 2).
As with central hemodynamics, to my knowledge, the effects
of combination therapies on blood pressure variability have
never been assessed.
Which calcium channel blocker, which diuretic?
In the absence of therapeutic trials comparing drugs within a
single antihypertensive class, preferences have to take into
account indirect comparisons, level of proof for every single
drug, and a large degree of uncertainty.
With regard to thiazide or thiazide-like diuretics, among the
four previously described therapeutic trials,13-16 three used hydrochlorothiazide. We could thus believe that hydrochlorothiazide should be the primary recommended thiazide diuretic.
However, some data are at odds with such a statement. First,
400
1.50
Pooled variance ratio
WHERE
A
1
0.75
Pooled increase in CV (%)
HYPERTENSION
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CCB CCBND
DIU
ARB
ACEI
BB
AB
Placebo
DIU
ARB
ACEI
BB
AB
Placebo
B
40
30
20
10
0
CCB CCBND
Treatment allocation
Figure 2. Changes in systolic blood pressure group variation at
follow-up compared with baseline as variance ratio (A) and percentage increase in coefficient of variation (B) in clinical trials of
various antihypertensive drugs.
Error bars represent the 95% confidence intervals. (A) is plotted on a logarithmic
scale. The apparent increase in variance ratio and coefficient of variation (CV)
from baseline to follow-up was mainly a consequence of the requirement in
many trials for narrow ranges of blood pressure at randomization, which tended
to lead to an increase in group standard deviation on follow-up; however, this
effect applied almost equally to all drug classes.
Abbreviations: AB, 움1-blocker; ACEI, angiotensin-converting enzyme inhibitor;
ARB, angiotensin receptor blocker; BB, 웁-blocker; CCB, calcium channel
blocker; CCBND, non-dihydropyridine calcium channel blocker; DIU, nonloop
diuretic drug.
After reference 20: Webb AJ et al. Lancet. 2010;375:906-915. © 2010,
Elsevier Ltd.
recently reviewed old data are in favor of a superiority of chlortalidone over hydrochlorothiazide.21 Second, indapamide has
been tested in two major therapeutic trials, HYVET (HYpertension in the Very Elderly Trial)22 and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation),23 and was associated with both a net
benefit in terms of cardiovascular end points and also in terms
of total mortality. Finally, the most recent National Institute for
Health and Care Excellence (NICE) guidelines recommend
favoring chlortalidone and indapamide over hydrochlorothiazide.24
With regard to calcium channel antagonists, amlodipine undoubtedly has the highest level of proof, with the results of four
major therapeutic trials in the field of hypertension: VALUE,
described previously13; ALLHAT (Antihypertensive and LipidLowering treatment to prevent Heart Attack Trial), which did
not find any difference in the composite of fatal coronary heart
disease plus nonfatal myocardial infarction compared with
lisinopril (primary end point) and also found a decrease in
HYPERTENSION
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stroke of 23% (secondary end point)25; ASCOT, with a significant decrease in all end points including all-cause mortality in the amlodipine/perindopril group compared with the
atenolol/thiazide group10; and finally, the ACCOMPLISH trial
(Avoiding Cardiovascular events in COMbination therapy in
Patients LIving with Systolic Hypertension), which found that
amlodipine in combination with benazepril was superior to
the combination of benazepril plus hydrochlorothiazide in a
high-risk population.26
Conclusion
Poor blood pressure control at the population level motivates
promotion of new therapeutic strategies. Since the vast majority of hypertensive patients need more than one drug to control their blood pressure, the emphasis should be on combina-
ARE
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tion therapy evaluation rather than duplication of conventional
therapeutic trials evaluating monotherapies. Among the different possible combination therapies, there is one that has
been insufficiently evaluated and promoted: the CCB/thiazide
diuretic combination. This combination is considered as “preferred” by the ESH but just as “acceptable” by the ASH. Nevertheless, several therapeutic trials have shown that this combination is at least as effective as comparators, and sometimes
superior. Furthermore, in addition to a well-accepted systolic
blood pressure–lowering effect, this combination could also
have beneficial effects over and above blood pressure reduction; namely, its effects on central blood pressure and systolic blood pressure variability. Finally, therapeutic innovation
in hypertension will perhaps come more from the combination
of older drugs than from the discovery of new ones. n
References
1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217-223.
2. Danaei G, Finucane MM, Lin JK, et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Pressure). National, regional, and global trends in systolic blood pressure since 1980: systematic
analysis of health examination surveys and epidemiological studies with 786
country-years and 5.4 million participants. Lancet. 2011;377:568-577.
3. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart
disease. Part 2. Short-term reductions in blood pressure: overview of randomised
drug trials in their epidemiological context. Lancet. 1990;335:827-838.
4. Godet-Mardirossian H, Girerd X, Vernay M, Chamontin B, Castetbon K, de Peretti
C. Patterns of hypertension management in France (ENNS 2006-2007). Eur
J Prev Cardiol. 2012;19:213-220.
5. Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and
blood pressure control among United States adults with hypertension: the
National Health And Nutrition Examination Survey, 2001 to 2010. Circulation.
2012;126:2105-2114.
6. Czernichow S, Castetbon K, Salanave B, et al. Determinants of blood pressure
treatment and control in obese people: evidence from the general population.
J Hypertens. 2012;30:2338-2344.
7. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial
Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
8. Mancia G, Laurent S, Agabiti-Rosei E, et al; European Society of Hypertension.
Reappraisal of European guidelines on hypertension management: a European
Society of Hypertension Task Force document. J Hypertens. 2009;27:21212158.
9. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
10. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendoflumethiazide as required, in
(ASCOT-BPLA): a multicentre randomized controlled trial. Lancet. 2005;366:
895-906.
11. Blacher J, Halimi JM, Hanon O, et al; la Société Française d'Hypertension Artérielle Recommandation 2013 de la Société Française d’Hypertension Artérielle pour la prise en charge de l’hypertension artérielle de l’adulte. Press Med.
2013;42:819-825.
12. Gradman AH, Basile JN, Carter BL, Bakris GL; American Society of Hypertension Writing Group. Combination therapy in hypertension. J Am Soc Hyper.
2010;4:42-50.
13. Julius S, Kjeldsen SE, Weber M, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsar-
tan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022-2031.
14. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157-2172.
15. Zanchetti A, Bond GM, Hennig M, et al; ELSA Investigators. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis.
Principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a
randomized, double-blind, long-term trial. Circulation. 2002;106:2422-2427.
16. Matsuzaki M, Ogihara T, Umemoto S, et al; Combination Therapy of Hypertension to Prevent Cardiovascular Events Trial Group. Prevention of cardiovascular
events with calcium channel blocker-based combination therapies in patients
with hypertension: a randomized controlled trial. J Hypertens. 2011;29:16491659.
17. Protogerou AD, Papaioannou TG, Blacher J, Papamichael CM, Lekakis JP, Safar
ME. Central blood pressures: do we need them in the management of cardiovascular disease? Is it a feasible therapeutic target? J Hypertens. 2007;265-272.
18. Protogerou AD, Stergiou GS, Vlachopoulos C, Blacher J, Achimastos A. The
effect of antihypertensive drugs on central blood pressure beyond peripheral
blood pressure. Part II: evidence for specific class-effects of antihypertensive
drugs on pressure amplification. Curr Pharm Des. 2009;15:272-289.
19. Morgan T, Lauri J, Bertram D, Anderson A. Effect of different antihypertensive
drug classes on central aortic pressure. Am J Hypertens. 2004;17:118-123.
20. Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug
class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010;375:906-915.
21. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network
meta-analyses. Hypertension. 2012;59:1110-1117.
22. Beckett NS, Peters R, Fletcher AE, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:18871898.
23. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and
indapamide on macrovascular and microvascular outcomes in patients with
type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
24. NICE/National Clinical Guideline Centre 2011 hypertension guidelines. Available at: http://www.nice.org.uk/nicemedia/live/12167/53228/53228.pdf. Accessed April 16, 2013.
25. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic:
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT). JAMA. 2002;288:2981-2997.
26. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators.
Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk
patients. N Engl J Med. 2008;359:2417-2428.
Keywords: blood pressure variability; calcium channel blocker; central hemodynamics; combination therapy; thiazide diuretic
401
HYPERTENSION
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ASSOCIATIONS
ANTIHYPERTENSIVES
:
QUE MANQUE -T- IL
?
Toutes les études épidémiologiques montrent que l’hypertension reste insuffisamment dépistée, traitée et contrôlée.
Il a été montré que lorsqu’une monothérapie antihypertensive ne suffit pas à contrôler la pression artérielle, il est plus
efficace d’associer deux produits de deux classes différentes, quelles qu’elles soient, que de doubler la dose d’un
seul produit. La plupart des recommandations actuelles privilégient l’association d’un inhibiteur du système rénineangiotensine-aldostérone et d’un diurétique thiazidique ou d’un inhibiteur calcique. Les autres associations sont moins
encouragées, en particulier celle d’un diurétique thiazidique et d’un inhibiteur calcique, qui a été néanmoins utilisée
dans plusieurs essais thérapeutiques avec des bénéfices supérieurs ou équivalents à ceux des médicaments utilisés
comme comparateurs. Dans les études VALUE (Valsartan Antihypertensive Long-Term Use Evaluation), ELSA (European Lacidipine Study on Atherosclerosis), FEVER (Felodipine EVEnt Reduction) et COPE (COmbination therapy
of hypertension to Prevent cardiovascular Events), les associations inhibiteur calcique / diurétique thiazidique se sont
montrées efficaces à la fois pour diminuer la pression artérielle systolique et pour prévenir les complications cardiovasculaires. Outre son efficacité reconnue sur la pression systolique, cette association pourrait également se montrer bénéfique au-delà de la diminution de la pression artérielle, par son action sur la pression artérielle centrale et sur
la variabilité de la pression artérielle systolique. Finalement, l’innovation thérapeutique dans l’hypertension viendra
peut-être plus de l’association de médicaments plus anciens que de la découverte de nouvelles molécules.
402
‘‘
HYPERTENSION
AND
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Among those individuals
with known hypertension who are
receiving treatment, a significant
number have uncontrolled hypertension and are left unprotected
from adverse cardiovascular
events. Ultimately, many of these
individuals will succumb to premature cardiovascular death as a
direct consequence of this. National and international guidelines encourage aggressive blood pressure control and, in keeping with
trial data, support combination
regimens to achieve this.”
ARE
PREVENTION:
GOING?
When more than two drugs
are needed to further
decrease blood pressure
b y A . G re e n s t e i n , K . K h a va n d i ,
a n d T. H e a g e r t y, U n i t e d K i n g d o m
T
Adam GREENSTEIN
PhD, MRCP, FAHA
he risk conferred by high blood pressure is continuous, and follows a
linear association with all adverse cardiovascular events. Epidemiological studies inform us that hypertension is on the rise, driven by an increasingly unhealthy society and a pandemic of obesity. Unfortunately, a substantial number of individuals will be unaware of their condition, and therefore
left unprotected against multiple target organ insults. More frustrating still, a
very significant proportion of those being treated for high blood pressure fail
to achieve adequate control, and thereby remain subject to an unacceptably
high risk of cardiovascular morbidity and mortality. National and international
guidelines have consistently emphasized the importance of prompt and effective intervention to reduce blood pressure to recommended levels. Following trial data, combination therapies with multiple antihypertensive agents
have been advocated, and conscious efforts made to alert clinicians to the dangers of untreated hypertension, while simultaneously reducing prescriber anxiety when administering multiple antihypertensives. Sadly, we remain conservative in our approach to blood pressure management, and although a
fraction of individuals has genuine resistant hypertension, physician inertia
and patient nonadherence is responsible for the majority of cases of suboptimal control. Herein, we discuss these contributing factors in more detail, and
summarize society recommendations, the scientific rationale, and trial data
to support and guide clinicians in managing patients who require more than
two antihypertensive agents to control their blood pressure.
Tony HEAGERTY
MD, FRCP, FAHA, FMedSci
Kaivan KHAVANDI
MRes, MBChB
Institute of Cardiovascular
Sciences, University of
Manchester, Manchester
UNITED KINGDOM
Dr Adam Greenstein, Senior Lecturer
in Cardiovascular Medicine,
Institute of Cardiovascular Sciences,
Core Technology Facility (3rd floor),
University of Manchester, 46 Grafton
Street, Manchester M13 9NT,
United Kingdom (e-mail:
[email protected])
ypertension is now the world’s leading cause of death.1 Although the pharmacological tools to treat blood pressure successfully have been available
for many years, most patients are not well controlled. Evidence shows that
above a certain threshold (140/90 mm Hg), the risk of cardiovascular disease is
clear and merits treatment. However, despite vigorously published and publicized
guidelines, the majority of published studies show that only half of treated patients
achieve satisfactory control. Reasons underlying this phenomenon are multiple and
complex, but it is undeniable that a large proportion of patients have difficulty taking their medication due to side effects. This article briefly reviews the reasons underlying poor compliance and outlines some of the innovative new ideas for early
treatment with a single pill containing a triple combination of drugs. Evidence is now
emerging that this is a safe and effective way to treat hypertension which merits further consideration as guidelines evolve.
H
When more than two drugs are needed to further decrease blood pressure – Greenstein and others
403
HYPERTENSION
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Resistant or “resisting” hypertension?
It is an unfortunate reality for clinicians who treat hypertension
that one of the major obstacles to achieving satisfactory control of blood pressure in patients is compliance with medication. Hypertension is a very different disease to most other
chronic medical conditions. In heart failure, for example, treatSELECTED
ABBREVIATIONS
ACE
ARB
BHS
CCB
ESC
ESH
JNC 7
angiotensin II receptor 1 blocker
British Hypertension Society
The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure
National Institute for Health and Clinical Excellence
NICE
RAS
TRIALS
ACRONYMS
ACCELERATE Aliskiren and the Calcium ChannEL blockER
Amlodipine combination as an initial treatment strategy for hyperTEnsion
ADVANCE
Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled
Evaluation
ALLHAT
ANBP2
second Australian National Blood Pressure
Study
ASCOT
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm
HYVET
Hypertension in the Very Elderly Trial
LIFE
in hypertension
NHANES
National Health And Nutrition Examination
Survey
ONTARGET
ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial
PATHWAY
Prevention And Treatment of resistant Hypertension With Algorithm guided therapY
SHEP
Systolic Hypertension in the Elderly Program
STITCH
Simplified Therapeutic Intervention To Control
Hypertension
Syst-Eur
Systolic Hypertension in Europe
TRINITY
TRIple therapy with olmesartaN medoxomIl,
amlodipine besylaTe, and hYdrochlorothiazide in adult patients with hypertension
404
ment often rapidly improves debilitating symptoms such as
breathlessness. By contrast, hypertension is asymptomatic
for the majority of patients. Elevated blood pressure is usually
detected at a health-screening visit to a primary care or occupational physician and therapy is then started on the basis
of guidelines promoting primary prevention of cardiovascular
disease. Thus, hypertensive patients move quickly from selfperceived health to a position where they are worried about
their health and are taking a daily medicine for the first time in
their life. Based on current guidelines, the initial therapy is likely to be either an angiotensin-converting enzyme (ACE) inhibitor or a calcium channel blocker (CCB). The previously
asymptomatic patient may then variably experience cough,
swollen ankles, skin rashes, flushing, or chest pain while acclimatizing to a new therapy. Within the space of six months
or so, this patient is likely to be informed by their clinician that
their blood pressure is “not controlled” or is even “out of control.” A new medication will be added, and over the subsequent three to four years there will be changes and modifications to doses and regimens. Successful treatment is judged
by prevention of disease rather than amelioration of symptoms.
It is no wonder, then, that patients are often less enthusiastic
about their treatment than we would like.
Although perhaps overly bleak, this picture of routine hypertension care is strongly supported by study evidence. First,
and most importantly, there is overwhelming data to show
that higher blood pressure is associated with increased incidence of cardiovascular disease and that treatment can reverse this. Thus, a 20-mm Hg difference in systolic blood pressure is associated with a two-fold increase in cardiovascular
risk.2 Conversely, it is only necessary to achieve a 10-mm Hg
reduction in systolic blood pressure in 11 hypertensive patients to prevent one cardiovascular death.3 The initiative for
the motivated clinician is therefore both clear and compelling.
Furthermore, there are now clear guidelines from national bodies which consistently indicate that, in at risk individuals, blood
pressure should be reduced to below 140/90 mm Hg.4,5 Despite the availability of both medications and guidance, blood
pressure is still very poorly controlled in treated patients. In
the USA, data from NHANES (National Health And Nutrition
Examination Survey) show that only around 50% of treated
patients have blood pressures below 140/90 mm Hg.6 In Europe, the picture is possibly even worse, with up to two-thirds
of all patients inadequately controlled.7
There are several reasons why blood pressure tends to be
poorly controlled in treated patients. Drugs may be ineffective or the patient may have resistant hypertension. However, poor control is more likely to have resulted from drug side
effects, which lead to poor compliance, or—as is increasingly recognized—inadequate control of blood pressure is due
to a phenomenon known as “physician inertia.” Physician inertia is recognized but understudied, and is certainly underaddressed. It represents the apparent reluctance of a doctor
HYPERTENSION
AND
Thiazide diuretics
AT1-receptor
antagonists
β-Blockers
Calcium
antagonists
α-Blockers
ACE inhibitors
Figure 1. Recommended potential combinations proposed in the
ESH/ESC Guidelines.
Combinations recommended in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial
in controlled intervention trials.
Abbreviations: ACE, angiotensin-converting enzyme; ESC, European Society of
Cardiology; ESH, European Society of Hypertension.
After reference 5: Mancia G et al. J Hypertens. 2007;25(6):1105-1187. © 2007,
Lippincott Williams & Wilkins, Inc.
treating a hypertensive patient to escalate or maximize therapy when blood pressure remains above the recommended
threshold. The most notable study of physician inertia demonstrated that, in a cohort of over 7000 patients with hypertension, antihypertensive therapy was increased in only 13.1%
of clinic visits in patients where blood pressure was above
140/90 mm Hg.8 Furthermore, patients treated by clinicians
who did not show therapeutic inertia were 33 times more likely to achieve control of blood pressure than those patients
under the care of clinicians with high levels of therapeutic
inertia.8 A further important point, which may not always be
appreciated by the treating clinician, is that treatment with
only one drug is unlikely to achieve effective control of blood
pressure. For example, in elderly patients with previously untreated hypertension, monotherapy will control systolic blood
pressure to less than 140 mm Hg in only 15% of patients.9 Indeed, available evidence indicates that for the majority of
patients either two or three antihypertensive agents will be
needed to achieve satisfactory control.10,11
Guideline recommendations
Hypertension guidelines vary in their recommendations for firstline antihypertensive agents, and, therefore, combination therapies differ also. The 7th report of the JNC (JNC7 [The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure])
did not provide definitive recommendations for combination
therapy, but did suggest that thiazide diuretics were appropriate first-line agents and should form a component of initial combination therapy.4 JNC 7 also recommended that dual
antihypertensive therapy was appropriate in some patients
from the outset. This has since been supported by trial data
PREVENTION:
WHERE
ARE
GOING?
from ACCELERATE (Aliskiren and the Calcium ChannEL blockER Amlodipine combination as an initial treatment strategy for
hypertension),12 although a combination of aliskiren and a CCB
was used in this study. The European Society of Hypertension
(ESH) and European Society of Cardiology (ESC) guidelines
were published in 2007,5 and reappraised in 2009.13 There was
again no clear preference for a specific class of antihypertensive agent; instead, the recommendation was to select optimal agents based on the individual, taking into consideration
factors such as cardiovascular risk profile, target organ damage, and concomitant disease. Again, there was a strong emphasis on the use of multidrug combinations to achieve blood
pressure control, and five potential combinations were proposed for priority use, as illustrated in Figure 1.
Guidelines from the British Hypertension Society (BHS) and
National Institute for Health and Clinical Excellence (NICE)
were released in 2011, and form the most recent evidencebased recommendations available.14 The guideline was structured in a similar format to its predecessor, with a stepped
approach to achieving blood pressure control, and recommendations for specific agents determined by age and ethnicity of the individual (Figure 2). In those <55 years of age, an
ACE inhibitor is the preferred choice, or a low-cost angiotensin II receptor 1 blocker (ARB) if intolerant of ACE inhibitors
(eg, due to cough). Those ⱖ55 years of age or black people
Step 1
Aged under
55 years
Aged over 55 years or
black person of African
or Caribbean family origin
of any age
A
C
Step 2
A+C
Step 3
A+C+D
Step 4
Resistant hypertension
A + C + D + consider diuretic
or α-blocker or β-blocker
Consider seeking expert advice
Figure 2. Algorithm from the NICE/BHS guidelines in 2011, recommending calcium channel blocker + angiotensin blocking agent
as the only preferred combination, with sequential addition of a
thiazide-like diuretic, further diuretic (spironolactone), and/or 움- or
웁-blockade.
Abbreviations: BHS, British Hypertension Society; NICE, National Institute for
Health and Clinical Excellence. A = angiotensin-converting enzyme inhibitor or
angiotensin II receptor blocker; C = calcium channel blocker; D = thiazide-like
diuretic.
After reference 14: NICE Clinical Guideline 127. © 2011, National Institute for
Health and Clinical Excellence.
405
HYPERTENSION
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of African or Caribbean decent of any age should commence
treatment with a CCB, or if not suitable, a thiazide-like diuretic
such as chlorthalidone or indapamide. This is based on the
fact that younger patients (excluding black people) have higher renin levels, and therefore receive greater benefit from angiotensin blocking agents, whereas older people and people
of African and Caribbean origin tend to have lower renin levels and respond better to CCBs and diuretics. If blood pressure remains elevated, step 2 involves addition of a second
agent to give the combination of an ACE inhibitor (or ARB if
intolerant) and a CCB (or thiazide-like diuretic if intolerant, or in
heart failure). If a third agent is required, a thiazide-like diuretic
should be added. If clinic blood pressure remains >140/90
mm Hg after treatment with optimal or best-tolerated doses
of a CCB, angiotensin blocker, and thiazide-like diuretic, the
disorder is classified as resistant hypertension, and a fourth
antihypertensive agent should be considered and expert opinion sought. If potassium is not elevated, further diuretic therapy with low-dose spironolactone can be considered, or if
contraindicated/ineffective, an a- or b-blocker.
Scientific rationale
Combination therapies should be based on complementary
physiological mechanisms of action. The pathophysiology of
blood pressure is multifactorial, but the predominant factors
are an increased peripheral vascular resistance and elevated
cardiac output. A combination regimen should, therefore, aim
to target these pathways, for example with an angiotensin
blocker to reduce peripheral vascular resistance, a diuretic to
reduce excess fluid volume, and b-blockers to reduce the
heart rate. However, as peripheral vascular resistance is the
primary driver of increased blood pressure, additional benefit
may be conferred by vasodilating dihydropyridine CCBs over
b-blockers. Mechanistically, therefore, a rational choice might
be a renin-angiotensin system (RAS) blocker and a CCB. Thirdand fourth-line add-on agents should overcome any potential compensatory changes caused by previous medications,
which can trigger reflex elevations in blood pressure. For example, the RAS can be activated as a counter-regulatory response to diuretics or CCBs, as a maladaptive response to
restore the elevated blood pressure. An angiotensin blocking
agent, with a CCB and a thiazide diuretic may, therefore, provide synergistic benefits. Further, when blood pressure control is not achieved with two antihypertensive agents, subjects
are likely to have fluid retention,15,16 and treatment with diuretics is often necessary for that reason. Aldosterone excess may
also contribute to the development of resistant hypertension,
and spironolactone blocks the action of aldosterone at the
mineralocorticoid receptor, stimulating natriuresis and alleviating fluid overload. This can also address aldosterone rebound, which is seen with long-term angiotensin blockade,
where aldosterone escapes blockade and levels return to
baseline.17 Deriving rational pharmacological combinations
from such principles has, unsurprisingly, lead to discrepancies
in practice—for example with some promoting the combina-
406
tion of dihydropyridine and nondihydropyridine CCBs, while
others support the use of high-dose nitrates and direct vasodilators or a-agonists. It is therefore necessary to evaluate
trial evidence to confirm which combinations carry the best
evidence.
Current evidence
High blood pressure investigation is one of the most evidencerich areas in medical research, and patients have benefited
significantly from application of evidence-based recommendations. However, when taken collectively, the literature concerning combination therapies (with more than two drugs) is
not structured, with comparator trials including a mix of monotherapy and placebo, with a variety of different add-on agents,
and no definitive head-to-head comparisons for combination
regimens with two or more drugs. Data has, therefore, been
extrapolated from the efficacy of agents as monotherapy, or
as dual combinations.
Diuretics were prominent in early guideline recommendations.
This was based on evidence of their efficacy as monotherapy in trials such as SHEP18 (Systolic Hypertension in the Elderly Program) and Syst-Eur19 (Systolic Hypertension in Europe),
but primarily driven by their low cost. More recent comparator trials such as ACCOMPLISH20 (Avoiding Cardiovascular
events through COMbination therapy in Patients Living with
Systolic Hypertension), ASCOT-BPLA21 (Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm), and
ANBP222 (second Australian National Blood Pressure Study),
have shown thiazide diuretics as inferior to their comparators
in preventing adverse cardiovascular end points. Consequently, there has been a decline in the use of diuretic prescriptions
for the treatment of hypertension in recent years. If used, thiazide-like diuretics are preferred over true thiazides. Data from
ADVANCE23 (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) and HYVET 24
(Hypertension in the Very Elderly Trial) support the use of perindopril/indapamide combinations in high-risk diabetic patients and hypertensive individuals over 80 years of age, respectively.
The LIFE trial (Losartan Intervention For Endpoint reduction in
hypertension) 21 supported the use of an ARB over a b-blocker
in combination with a thiazide diuretic, with a reduced composite cardiovascular end point (driven by improvement in
rates of stroke). Now that ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) has unequivocally showed that perindopril plus amlodipine was superior to atenolol and thiazide
diuretic in normalizing blood pressure parameters and preventing cardiovascular events,21 b-blockers have fallen out of
favor, which is reflected by their exclusion as preferred agents
in the recent NICE guidance. The ASCOT and ACCOMPLISH20
trials (Avoiding Cardiovascular events through COMbination
therapy in Patients Living with Systolic Hypertension) support
the use of an angiotensin-blocking agent in combination with
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a CCB as superior in preventing cardiovascular end points.
There is some debate about class benefits independent of
blood pressure lowering, with some evidence that CCBs are
preferential in stroke, and ACE inhibitors in coronary heart disease,25 above and beyond blood pressure lowering. However, the general focus over recent years has been to prioritize blood pressure lowering, which ultimately remains the
absolute priority.26 A number of important secondary analyses
of ASCOT have, however, provided evidence of additional benefits for this combination, above and beyond greater blood
pressure control,27 including reduced incidence of diabetes,28
reduced blood pressure variability,29 superior reduction in central blood pressure,30 and indirect measures of improved arterial remodeling and peripheral vascular resistance.31 Additional RAS blockade achieved by combining an ACE inhibitor
with an ARB did not confer any additional cardiovascular benefit in ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), and produced
increased adverse renal outcomes,32 despite a slight reduction
in blood pressure.33 There is limited evidence for direct renin inhibition, although a recent trial of type 2 diabetic patients failed
to show any benefit from the addition of aliskiren to either an
ARB or ACE inhibitor, for cardiac or renal end points.32
There is no robust evidence to guide the selection of a third
antihypertensive agent.34,35 Chlorthalidone (ALLHAT [Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial] and SHEP) and spironolactone have particular efficacy in lowering blood pressure in resistant hypertension,36,37
although indapamide has a more favorable metabolic profile
and has demonstrated strong mortality reduction. In ASCOTBPLA, spironolactone38 was used as a fourth-line add-on
agent in resistant hypertension, which was well tolerated at
low doses and produced significant additive blood pressure–
lowering benefits. If side effects such as gynecomastia and
breast tenderness are experienced, consideration can be made
for the more selective mineralocorticoid receptor blocker eplerenone. Amiloride is another suitable substitute, although it
would require increased doses.34 Side effects with spironolactone are related to duration/dose, and are normally reversible upon discontinuation of treatment. Electrolytes and renal function must be monitored within two weeks of initiating
these agents, and with subsequent follow-up depending on
baseline values and dosage. If potassium is elevated, the dose
of the thiazide-like diuretic can be increased. In ASCOT-BPLA,
doxazosin gastrointestinal therapeutic system was used as
the third-line agent for both of the blood pressure–lowering
treatment regimens,39 and afforded sustained blood pressure–lowering effects without adverse effects on heart failure
(in contrast to ALLHAT) or lipids. The recent concept of sequential nephron blockade was proposed as a strategy in resistant hypertension.40 It is centered on countering intrarenal
compensatory sodium reabsorption at unblocked nephron
sites through stepped addition of low doses of four different diuretics, working at different sites. In those individuals unable to
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achieve blood pressure control on triple therapy with an ARB,
thiazide, and CCB, sequential nephron blockade achieved
blood pressure control in 58% of patients, compared with
20% in patients treated with sequential RAS blockade.
Nonadherence
When taken together, what is clear from the above data is
that a number of antihypertensive agents are available and
have proven efficacy in decreasing blood pressure and reducing cardiovascular risk. Even accounting for physician inertia,
it seems surprising that quite so many “treated” individuals
have uncontrolled hypertension. Of course, the bulk of responsibility for control of blood pressure lies with the patient.
If they are compliant with their medication, then it is far more
likely that they will achieve a satisfactory blood pressure. However, published studies indicate that compliance with prescribed antihypertensive medication may be as low as 25%
to 50%.41 Reasons for noncompliance are complex, but can
be divided into intentional and unintentional reasons. Intentional nonadherence is usually due to the side effects of medications and compounded by lack of communication between
the doctor and patient regarding the importance of good blood
pressure control. Unintentional nonadherence is more common in elderly patients, who are more likely to be on complex
medication regimens or may forget to take their tablets.
It is for all of these reasons that single-pill combination treatments (also known as fixed drug combinations) are increasingly used in patients with hypertension. Thiazide diuretics are
the most common components, usually combined with ACE
Inhibitors, ARBs, or b-blockers. Combinations including dihydropyridine CCBs are also available and increasingly popular.
These single-pill combination regimens are used much more
sparingly for hypertension management in the UK (2% of all
antihypertensive prescriptions) compared with the rest of Europe (40%-50% of prescriptions),42 despite evidence that their
use is associated with improved adherence and blood pressure control.5,43,44 Reluctance to prescribe fixed drug combinations is often due to concerns regarding cost. However, a
retrospective analysis of a UK primary care database of over
25 000 patients treated for hypertension has shown that patients on single-pill combination treatments attain significantly better blood pressure control than those on individual drug
regimens.42 Subsequently, although prescription costs were
higher in the group taking the single-pill combination treatments, cardiovascular event rates (and thus, overall management cost per patient) were higher for those on individual drug
regimens.
The use of single-pill combination treatments for initial therapy in hypertension therefore confers a number of important
advantages over starting treatment with a single drug. First, it
is a reality that most patients will need at least two drugs to
control their blood pressure. Thus, initiation with a combination treatment is more likely to achieve a rapid and effective re-
407
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duction in blood pressure compared with monotherapy. Second, judicious combination of therapies may actually reduce
side effects. For example, the side effect that most commonly limits the use of CCBs is ankle edema. However, when
CCBs are used in combination with an ACE inhibitor or an
ARB, the incidence of ankle edema is significantly reduced.45,46,47 Therefore, when used appropriately, the single-pill
combination approach has the potential to fundamentally alter the initial management of hypertension. It is interesting to
reflect on the Veterans Affairs Cooperative Study from the
1960s, which was the first clinical trial to show prevention of
adverse cardiovascular events with effective pharmacological treatment of hypertension. The study adopted a triple-drug
combination consisting of reserpine, hydralazine, and hydrochlorothiazide,48 which was highly effective but associated with
significant side effects. This prompted the paradigm change
to the now familiar stepped therapy approach, where practitioners start with a single therapy and then titrate this up to
the maximum tolerated dose. However, using the single-pill
combination approach, multiple drugs can be initiated at lower doses than those which might be expected to have an effect individually, and there is evidence that this is associated
with more effective blood pressure control.49 Furthermore,
because lower doses of the individual components of the
combination pill can be used, side effects are less likely to occur than when titrating a single agent up to a maximum.
More recently, commercially available single-pill combination
treatments have included three drugs: an ARB, a CCB, and a
thiazide diuretic. The use of these three drug classes reflects
the evidence from a number of clinical studies. STITCH (Simplified Therapeutic Intervention To Control Hypertension) compared a treat-to-goal protocol starting with an ARB or ACE
inhibitor combined with a thiazide diuretic, with subsequent
addition of a CCB against conventional care based on national guidelines. The study demonstrated that the triple combination therapy was well tolerated and achieved a greater
degree of blood pressure control compared with a guidelinebased approach within the study period of six months (intervention group, 64.7% vs control group, 52.4%; P=0.026).50
In the TRINITY study by Oparil and colleagues (TRIple therapy with olmesartaN medoxomIl, amlodipine besylaTe, and
hYdrochlorothiazide in adult patients with hypertension), initial
triple therapy with olmesartan, amlodipine, and hydrochlorothiazide was compared with dual combination or placebo in hypertensive patients. After three months, 69% of patients on
triple combination therapy had achieved target blood pressures of ⱕ140/90 mm Hg compared with only 41%-53% of
patients on dual combination therapy.51 Of the 2400 patients
treated, only 52 patients discontinued therapy due to adverse
effects (4% drop-out rate in the triple combination group vs
1%-2% in the dual combination group). In a study in a cohort
408
with diastolic hypertension, the fixed-dose combination of valsartan, amlodipine, and hydrochlorothiazide was shown to reduce blood pressure to a greater extent than any of the dual
therapy combinations of the same drugs, with a significantly
higher rate of blood pressure control (71% vs 45%-54%).52
A number of new fixed-dose combinations including triple therapies have been approved for the treatment of hypertension.
Aliskiren has been approved in combination with hydrochlorothiazide, amlodipine, or as a fixed-dose combination of the
three.
Conclusions
Reducing blood pressure has become an international priority. Hypertension is now the biggest killer in the world, and
its incidence is growing as a result of overweight and obesity. Among those individuals with known hypertension who
are receiving treatment, a significant number have uncontrolled hypertension and are left unprotected from adverse
cardiovascular events. Ultimately, many of these individuals
will succumb to premature cardiovascular death as a direct
consequence of this. National and international guidelines encourage aggressive blood pressure control and, in keeping
with trial data, support combination regimens to achieve this.
Current evidence supports the use of a CCB and an angiotensin-blocking agent for dual therapy. The evidence is less
robust for the choice of further agents, but a thiazide-like diuretic, followed by spironolactone and then doxazosin represent rational add-on agents with some supporting evidence.
The BHS Collaborative Research Working Party has initiated the PATHWAY studies (Prevention And Treatment of resistant Hypertension with Algorithm guided therapy) to investigate
the best approach to the treatment of resistant hypertension.34
Although it is interesting (and important) to dissect the data
and determine precise combination regimens with the most
evidence, in reality it is unlikely that there will be an optimal
three- to four-drug combination to suit everyone. Conversely,
it is probable that if patients were prescribed, and adhered to,
current recommended combination therapies based on complimentary pharmacology, the majority would achieve satisfactory blood pressure control. At the prescribers’ end, the promotion of the recent national guidelines issued by NICE/BHS
will encourage practitioners to comply with evidence-based
recommendations and the frequent need to adopt multi-combination therapies. As hypertension is a stealth condition, public health campaigns to raise awareness of the risks of high
blood pressure will increase adherence. Fixed-dose combinations will likely improve things at both ends of the stethoscope. These interventions should be combined with diet and
lifestyle campaigns, which will ultimately prevent hypertension
in most cases. We cannot afford to take a casual approach
to high blood pressure treatment, and the “conservative” approach, which is so often adopted, equates to delayed or failed
control, and a number of avoidable cardiovascular deaths. n
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24. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients
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27. Poulter NR, Wedel H, Dahlof B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA).
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28. Gupta AK, Dahlöf B, Dobson J, et al. Determinants of new-onset diabetes among
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29. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit
variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375(9718):895-905.
30. Williams B, Lacy PS, Cafe, the AI. Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function
Evaluation) study: CAFE-Heart Rate. J Am Coll Cardiol. 2009;54(8):705-713.
31. Manisty CH, Zambanini A, Parker KH, et al. Differences in the magnitude of
wave reflection account for differential effects of amlodipine- versus atenololbased regimens on central blood pressure: an Anglo-Scandinavian Cardiac
Outcome Trial substudy. Hypertension. 2009;54(4):724-730.
32. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-2213.
33. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan,
ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):
547-553.
34. Myat A, Redwood SR, Qureshi AC, Spertus JA, Williams B. Resistant hypertension. BMJ. 2012;345:e7473.
35. Williams B. Resistant hypertension: an unmet treatment need. Lancet. 2009;
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36. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510-526.
37. Vaclavik J, Sedlak R, Plachy M, et al. Addition of spironolactone in patients with
resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069-1075.
38. Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49(4):839-845.
39. Chapman N, Chang CL, Dahlof B, Sever PS, Wedel H, Poulter NR. Effect of
doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes
Trial. Circulation. 2008;118(1):42-48.
40. Bobrie G, Frank M, Azizi M, et al. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective,
randomized, open blinded endpoint study. J Hypertens. 2012;30(8):1656-1664.
41. Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood
pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med. 2004;164(7):722-732.
42. Belsey JD. Optimising adherence in hypertension: a comparison of outcomes
and costs using single tablet regimens vs individual component regimens. J Med
Econ. 2012 2012:1-9.
43. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120
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2010;55(2):399-407.
45. Jamerson KA, Nwose O, Jean-Louis L, Schofield L, Purkayastha D, Baron M.
Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension. Am
J Hypertens. 2004;17(6):495-501.
46. Fogari R, Zoppi A, Derosa G, et al. Effect of valsartan addition to amlodipine
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on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens. 2007;21(3):220-224.
47. Hatala, Pella D, Hatalová K, Šidlo R. Optimization of blood pressure treatment
with fixed-combination perindopril/amlodipine in patients with arterial hypertension. Clin Drug Investig. 2012; 32(9):603-612.
48. Black HR. Triple fixed-dose combination therapy: back to the past. Hypertension. 2009;54(1):19-22.
49. Mahmud A, Feely J. Low-dose quadruple antihypertensive combination: more
efficacious than individual agents—a preliminary report. Hypertension. 2007;
49(2):272-275.
50. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A
simplified approach to the treatment of uncomplicated hypertension: a cluster
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51. Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter, randomized, double-blind,
12-week, parallel-group study. Clin Ther. 2010;32(7):1252-1269.
52. Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD. Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical
trial. Hypertension. 2009;54(1):32-39.
Keywords: blood pressure control, combination; compliance; guidelines; hypertension; therapeutic inertia
QUAND PLUS DE DEUX MÉDICAMENTS SONT NÉCESSAIRES
POUR OBTENIR UNE RÉDUCTION SUPPLÉMENTAIRE DE LA PRESSION ARTÉRIELLE
Il existe une relation linéaire et continue entre une pression artérielle élevée et la survenue d’événements cardiovasculaires. D’après les études épidémiologiques, l’hypertension est en progression, notamment à cause de la pandémie d’obésité et de l’hygiène de vie de moins en moins bonne de nos sociétés actuelles. Malheureusement, de nombreuses personnes ne sont pas conscientes de leur pathologie et ne sont donc pas protégées contre les nombreuses
agressions que subissent les organes cibles. Encore plus frustrant, une proportion très significative d’hypertendus
sous traitement n’est pas contrôlée correctement et reste donc soumise à un risque inacceptable de morbimortalité
cardiovasculaire. Les recommandations nationales et internationales soulignent régulièrement l’importance d’une prise
en charge rapide et efficace pour réduire la pression artérielle aux niveaux souhaités. Suivant les données des études,
des associations de plusieurs antihypertenseurs ont été préconisées et des efforts délibérés ont été faits pour alerter les médecins des dangers d’une hypertension non traitée, tout en les rassurant sur la prescription de plusieurs antihypertenseurs. Malheureusement, notre approche de la prise en charge de la pression artérielle reste frileuse. Même
si une partie des patients souffre véritablement d’hypertension résistante, c’est bien l’inertie des médecins et la mauvaise observance des patients qui sont responsables de la majorité des cas de contrôle insuffisant. Nous analysons
ici plus en détail certains de ces facteurs et nous résumons les recommandations des sociétés, les arguments scientifiques et les données des études afin d’aider et de guider les médecins dans la prise en charge des patients nécessitant plus de deux antihypertenseurs pour contrôler leur pression artérielle.
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Since raised BP and dyslipidemia frequently coexist to impart
a multiplicative impact on CV risk
(…), a combined approach of lowering BP and improving lipid profiles is a logical one. The best currently available evidence from
clinical trials supports the routine
use of such an approach, and consequently several sets of guidelines
for the management of hypertension also recommend the routine
use of statins for a large proportion of hypertensive patients.”
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Treating both hypertension
and dyslipidemia:
a synergistic approach
b y N . R . Po u l t e r, U n i t e d K i n g d o m
T
Neil POULTER, MB, MSc
FRCP, FMed Sci
International Centre for
Circulatory Health
Imperial College London
London, UK
he cardiovascular benefits of lowering blood pressure have been clearly established for decades. More recently, the cardiovascular benefits
of lipid lowering with statins among subgroups of hypertensive patients
and in specific trials of hypertensive patients have also become clear. Because raised blood pressure and dyslipidemia coexist more frequently than
chance would predict, a combined approach to improve both blood pressure
and lipid levels in patients with hypertension appears logical. ASCOT-LLA,
the lipid-lowering arm of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) confirmed the logic of such an approach by showing not only the
independent and superior benefits of the “A + C” (angiotensin-converting enzyme inhibitor plus calcium channel blocker) combination of antihypertensive
agents over the then-standard 웁-blocker +/- thiazide (“B + D”) combination in
terms of cardiovascular prevention, but also the benefits of atorvastatin versus
placebo. The combined effects of amlodipine +/- perindopril plus atorvastatin
in ASCOT-LLA were large and compelling with some suggestion of a real synergy between these two regimens in preventing coronary events. Meanwhile,
guidelines for hypertension management based on best current trial data increasingly recommend an “A + C” regimen for optimizing cardiovascular prevention among hypertensive patients and the use of statins for a significant
proportion of the hypertensive population. Urgent steps must be taken to implement best practice before the anticipated global increase in the prevalence
and absolute numbers affected by hypertension translates into an ever greater
cardiovascular burden than that which currently prevails.
he cardiovascular (CV) benefits of treating severe, moderate, and more mild
hypertension were clearly established by the mid-1990s.1,2,3 Several years later, subgroup analyses of the large statin trials confirmed that those patients
with hypertension who were allocated to statins rather than placebo experienced a
similar relative risk reduction in CV events as those who were normotensive (Table I,
page 412).4-10 Because those with hypertension are at higher absolute risk of suffering CV events than those who are normotensive, these relative risk reductions
translate into greater absolute CV benefits. Furthermore, because CV risk factors
tend to cluster in individuals, such that dyslipidemia is more prevalent among hypertensive than normotensive people,11 there appeared to be a reasonable rationale for
using lipid-lowering agents—specifically statins, given their proven efficacy—as part
of the routine treatment strategy for those with hypertension, to optimize the reduction of CV events.
T
Professor Neil R. Poulter,
International Centre for Circulatory
Health, Imperial College London,
59-61 North Wharf Road,
Paddington, London W2 1LA, UK
Treating both hypertension and dyslipidemia: a synergistic approach – Poulter
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Total population
n
n
% reduction*
Trial
1°/2°
4S4
2°
1154
37
4444
34
CARE5
2°
1774
23
4159
24
LIPID
2°
3758
15
9014
24
GREACE7
2°
686
48
1600
51
6
% reduction*
HPS†8
1°+ 2°
10594
20
20536
24
PROSPER†9
1°+ 2°
2212
15
5804
15
1°
1445
39
6605
37
AF/TexCAPS10
Table I. Cardiovascular end point reduction by
hypertension status in statin trials.
“Hypertensive”
sive population of 10 305 patients who had
a baseline total cholesterol of ⱕ6.5 mmol/L.14
This lipid-lowering component of the trial
(ASCOT-LLA) was stopped prematurely after a median follow-up period of 3.3 years
due to a highly significant reduction (36%;
P=0.0005) in the primary end point of nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD).
* All CHD except (†) – CHD+ stroke
Risk ratio
Hazard ratio
Primary
0.64 (0.50-0.83)
Secondary
Total CV events and procedures
0.79 (0.69-0.90)
0.71 (0.59-0.86)
0.62 (0.47-0.81)
All-cause mortality
0.87 (0.71-1.06)
0.90 (0.66-1.23)
0.73 (0.56-0.96)
Fatal and nonfatal heart failure
1.13 (0.73-1.78)
Abbreviations: 4S, Scandinavian Simvastatin Survival Study;
AF/TexCAPS, Air Force/Texas Coronary Atherosclerosis
Prevention Study; CARE, Cholesterol And Recurrent Events
trial; CHD, coronary heart disease; LIPID, Long-term Intervention with Pravastatin in Ischemic heart Disease; GREACE,
GREek Atorvastatin and Coronary-heart-disease Evaluation
(GREACE) study; HPS, Heart Protection Study; PROSPER,
Pravastatin in elderly individuals at risk of vascular disease
study.
The ASCOT trial: combining lipid
lowering and blood pressure
lowering
0.5
1.0
1.5
Atorvastatin better Placebo better
Area of squares is proportional to the amount of statistical information
Figure 1. Effects of atorvastatin and placebo on primary and secondary end points
in ASCOT-LLA.
Abbreviations: ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CHD,
coronary heart disease; CV, cardiovascular; MI, myocardial infarction.
After reference 14: Sever PS et al. Lancet. 2003;361:1149-1158. © 2003, Elsevier Ltd.
The blood pressure (BP)–lowering arm of the
trial (ASCOT-BPLA), which included 19 257
hypertensive patients at baseline, continued
for a further 2 years after the end of ASCOTLLA. This arm of the trial was also stopped
prematurely because of the significantly reduced rates of all-cause mortality and other
CV events (notably stroke) among those randomized to receive amlodipine with perindopril added as required to reach BP targets (amlodipine +/– perindopril) compared
with those randomized to receive atenolol
with bendroflumethiazide added as required
(atenolol +/– thiazide).15
Trials of lipid lowering in hypertensive patients
With that background, two trials were designed to incorporate an evaluation of lipid lowering specifically among hypertensive patients.12,13 Unfortunately, the first trial—ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart
Attack Trial)12—was designed to compare the effects of pravastatin (a relatively ineffective statin) with usual care, which
in the context of the ALLHAT trial population involved significant use of other, and possibly stronger, statins. The net effect was a limited differential effect on low-density lipoprotein
(LDL)–cholesterol with a consequently limited effect on CV
events between treatment groups.
In contrast, the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial)13 included as part of a 2 × 2 factorial design, a
placebo-controlled evaluation of atorvastatin 10 mg once daily on major CV events. Figure 1 shows the benefits of atorvastatin on primary and secondary end points in this hyperten-
412
SELECTED
ALLHAT
ASCOT
ASCOT-BPLA
ASCOT-LLA
BP
CCB
CHD
CV
GREACE
LDL
MI
Anglo-Scandinavian Cardiac Outcomes Trial–
Blood Pressure Lowering Arm
Lipid Lowering Arm
blood pressure
coronary heart disease
cardiovascular
GREek Atorvastatin and Coronary-heartdisease Evaluation study
low-density lipoprotein
HYPERTENSION
AND
Amlodipine-based treatment
Placebo
Atorvastatin
53%
2.0
1.0
HR=0.47 (0.32-0.69); P<0.01
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Cumulative incidence (%)
Cumulative incidence (%)
4.0
3.0
0.0
ARE
Atenolol-based treatment
4.0
Placebo
Atorvastatin
3.0
HR=0.84 (0.60-1.17); P=0.30
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
One of the tertiary objectives of the ASCOT trial was to evaluate whether there was any interaction between the BP-lowering and lipid-lowering therapies used in the trial in terms of
impact on three specified CV events.13 Consequently, the relevant and appropriate analyses were carried out to evaluate this question and revealed that there was indeed a statistically significant interaction (P=0.025) between the use of
atorvastatin in the amlodipine +/– perindopril and atenolol +/–
thiazide groups in terms of impact on the primary end point
of the trial (nonfatal MI and fatal CHD).16 As shown in Figure 2,
allocation to atorvastatin was associated with a 53% reduction (P<0.001) in the primary end point of the trial among
those also allocated to amlodipine +/– perindopril, whereas
the equivalent effect on those randomized to atenolol +/– thiazide was a 16% reduction (P=0.30). The other two CV end
points that were prespecified for evaluation as to whether the
impact of statins and the BP-lowering agents in ASCOT would
Atorvastatin
GOING?
Figure 2. Cumulative incidence for
nonfatal myocardial infarction and
fatal coronary
heart disease in
ASCOT-LLA.
Abbreviations:
ASCOT-LLA, AngloScandinavian Cardiac
Outcomes Trial–Lipid
Lowering Arm;
HR, hazard ratio.
After reference 16:
Sever P et al. Eur
Heart J. 2006;27:
2982-2988. © 2006,
European Society of
Cardiology.
1.0
Years
End point and blood
pressure regimen
16%
2.0
0.0
PREVENTION:
WHERE
show any sign of interaction in terms of differential effects were
nonfatal or fatal stroke (total stroke) and total CV events and
procedures (CV mortality, nonfatal MI [symptomatic and silent],
unstable angina, chronic stable angina, life-threatening arrhythmias, nonfatal heart failure, nonfatal stroke, peripheral arterial disease, revascularization procedures, and retinal vascular thrombosis).13 No such significant effect was observed
for either of these two end points (P=0.728 and P=0.253, respectively) (Table II).
The differential effect of statins on coronary events when stratified by BP-lowering regimen was of modest statistical significance given that this was a tertiary objective of the trial.13 Furthermore, the difference between BP-lowering regimens was
to an extent driven by a less-than-expected impact of atorvastatin among those allocated to atenolol +/– thiazide. The
possibility that this difference occurred by chance should
Placebo
n (%)
Rate*
Unadjusted HR
95% CI
P-value
Nonfatal myocardial infarction + fatal CHD
Amlodipine-based
38 (1.5%)
4.6
Atenolol-based
62 (2.4%)
7.5
80 (3.1%)
74 (2.9%)
9.8
9.0
0.47 (0.32-0.69)
0.84 (0.60-1.17)
0.00007
0.295
0.025
Totalcardiovascular events and procedures
Amlodipine-based
173 (6.7%) 21.3
Atenolol-based
216 (8.4%) 27.0
233 (9.1%)
253 (9.8%)
29.4
31.7
0.73 (0.60-0.88)
0.85 (0.71-1.02)
0.001
0.079
0.253
50 (2.0%)
71 (2.7%)
6.1
8.6
0.69 (0.45-1.06)
0.76 (0.53-1.08)
0.088
0.129
0.728
End point
Amlodipine-based
Atenolol-based
n (%)
35 (1.4%)
54 (2.1%)
Rate*
4.2
6.5
Interaction
P-value
* Per 1000 patient years.
Table II. The effects of atorvastatin vs placebo for amlodipine-based and atenolol-based treatment for fatal coronary heart disease and
nonfatal myocardial infarction, total cardiovascular events and procedures, and fatal and nonfatal stroke.
Abbreviations: CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio.
After reference 16: Sever P et al. Eur Heart J. 2006;27:2982-2988. © 2006, European Society of Cardiology.
413
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
also not be ignored. Nevertheless, the 53% reduction in coronary events (95% confidence interval, 31-68) observed among
those allocated to atorvastatin 10 mg daily and amlodipine
+/– perindopril compared with those allocated to placebo and
amlodipine +/– perindopril was large and greater than might,
on average, have been expected with atorvastatin 10 mg daily.
ASCOT-LLA: impact on guidelines
The large relative reductions in risk among those randomized
to atorvastatin compared with placebo are clear (Figure 1) and
argue forcibly for the routine use of statins among the hypertensive population. Indeed, hypertension guidelines17,18 produced after the results of ASCOT-LLA were published14 supported such a position, including the following statement for
patients with hypertension in the context of primary prevention:
“In view of the results of the ASCOT trial and other currently available trial data, it seems reasonable, in the interests of simplicity,
to treat with a statin, all those patients at least up to the age of
80 years with a total cholesterol >3.5mmol/L who have an estimated 10-year cardiovascular disease risk of 20% or more. In reality, this would mean considering statin therapy in most hypertensive patients (especially men) over the age of 50 years. As
resources allow, a rationale for lowering this threshold could be
made on the basis of trial evidence.” 17,18
Furthermore, support for the use of statins in the context of
hypertensive patients arose from cost-effectiveness analyses
based on the ASCOT-LLA data.19 These data showed that the
cost per life-year gained using atorvastatin 10 mg daily in hypertensive adults was about €10 000, and based on these
findings, it was concluded that the use of atorvastatin in hypertensive patients at modest CV risk but who have not suffered a prior MI was a cost-effective strategy. It is important
to add that since these health economic analyses were performed, atorvastatin has become generic and so any residual
cost-based reservations regarding the use of atorvastatin in
hypertensive patients appear to have no basis. Finally, the CV
benefits of lipid lowering with atorvastatin 10 mg in ASCOTLLA would reasonably be expected to be enhanced by higher doses of atorvastatin and by use among those with more
adverse lipid profiles (inclusion in ASCOT-LLA was restricted to those with a total cholesterol of ⱕ6.5 mmol/L [ⱕ250
mg/dL]).
cholesterol, and triglycerides was essentially the same once
stratified by BP-lowering group,16 and if anything, what minor differences that did exist favored the atenolol +/– thiazide
group.
More generally, angiotensin-converting enzyme (ACE) inhibition has been reportedly associated with reductions in CHD
events beyond BP-associated benefits21,22 and in both experimental23 and clinical situations,24,25 dihydropyridine calcium
channel blockers (CCBs) have been reported to have antiatherosclerotic actions. Furthermore, a hypothesis based on studies of a cellular and molecular interaction between amlodipine
and atorvastatin has been proposed.26,27 Based on Mason’s
report that electrochemical bonding between amlodipine and
atorvastatin occurs in the lipid bilayer of vascular smooth muscle membranes,27 it is hypothesized that, while the functionality of L-type calcium channels in vascular smooth muscle
cells is normally lost during the migration of these cells in the
atherosclerotic process, the effect of atorvastatin is to induce
arrest of growth and differentiation of the smooth muscle cells
and restoration of their responsiveness to CCBs.
In addition, it is argued that atherosclerotic plaques are stabilized due to the reduced apoptosis and destruction of vascular smooth muscle cells, a reduction in the release of matrix
metalloproteinases, and preservation of the intracellular matrix.
The findings of bonding between amlodipine and atorvastatin
have not been replicated using other statins and other antihypertensive agents and hence makes any such interaction,
if true, product-specific.
Statin/CCB interaction: supportive data
Statistical synergy between lipid-lowering and
blood pressure lowering in ASCOT: possible
mechanisms
u Internal consistency from ASCOT
The possible mechanisms underlying the superiority of amlodipine +/– perindopril over atenolol +/– thiazide in ASCOTBPLA were evaluated and published along with the main final
results.28 The authors concluded that it was likely that some
as-yet-unidentified mechanisms—other than those identified
in this publication, and certainly beyond the mean BP differences achieved—might have contributed to the differential CV
event rates. One such possibility might involve a positive interaction between atorvastatin and amlodipine among those in
the amlodipine +/– perindopril group (half of whom were on
atorvastatin). However, more recently, the differential effects of
the two BP-lowering regimens on BP variability appear to have
explained away most of the CV differences observed.29,30
The apparently greater preventive effect on coronary events of
atorvastatin when used in combination with amlodipine +/–
perindopril compared with atenolol +/– thiazide (Figure 2) may
have occurred as a result of differential BP-lowering or lipidlowering effects induced by atorvastatin in the two BP treatment groups. While statins do cause a small BP-lowering effect,20 no differential effect was noted in ASCOT (unpublished
data). Furthermore, the effect of atorvastatin compared with
placebo on LDL-cholesterol, high-density lipoprotein (HDL)–
Other examples of synergy between atorvastatin and amlodipine +/– perindopril have also been observed in analyses of two
subgroups from among the ASCOT participants. In the first
one, Manisty and colleagues described a statistically significant interaction between the lipid-lowering and BP-lowering
regimens in terms of their impact on carotid systolic BP in a
subgroup of ASCOT patients.31 Systolic BP was found to be
significantly lower among those randomized to atorvastatin
414
HYPERTENSION
AND
WHERE
and the amlodipine +/– perindopril combination than in those
treated with atorvastatin and atenolol +/– thiazide. In the second example, analysis of the subgroup of diabetic patients in
ASCOT demonstrated a significant interaction favoring the
atorvastatin, amlodipine +/– perindopril combination in terms
of a beneficial effect on estimated glomerular filtration rate
(eGFR), which was not observed between the two BP-lowering groups randomized to placebo.32
u External consistency from other studies
In the GREACE trial (GREek Atorvastatin and Coronary-heartdisease Evaluation) a synergistic effect between atorvastatin
and ACE inhibitors was reported among patients with established CHD.33
Statin/CCB interaction: conflicting data
In the Prospective Pravastatin Pooling Project, the impact of
pravastatin on CHD events among hypertensive patients was
significantly less than among nonhypertensives (14% vs 33%,
heterogeneity; P=0.003).34 However, the authors were unable
to attribute this apparent difference to any specific antihypertensive agents. To be compatible with the ASCOT-BPLA findings, a predominance of b-blocker use and limited CCB use
among the hypertensive population of the pooling project
would have been required.
In the Heart Protection Study,35 the effect of simvastatin on CHD
events did not differ between those receiving or not receiving
antihypertensive medication. Furthermore, no differential CCBspecific effect on events was apparent in this large trial.35
In the meta-analysis carried out on behalf of the Cholesterol
Treatment Trialists (CTT) collaboration,36 the presence or absence of hypertension at baseline in the 14 trials included did
not affect the impact of statins on CHD event rates, or indeed
any other event rates.
Conclusion
Whether the apparent synergy between atorvastatin and the
amlodipine +/– perindopril regimen shown in Figure 2 was the
result of chance or not, when the results of ASCOT-BPLA
and ASCOT-LLA are viewed together, it is quite clear that of
the four possible means of preventing CV events incorporated in the ASCOT trial design (Table III), those allocated to
the newer antihypertensive regimen (amlodipine +/– perindopril) and atorvastatin (a) were less likely to suffer any of the major CV end points evaluated in this trial than those allocated
to any of the other three possible treatment combinations (b,
c, or d). By contrast, those allocated to receive atenolol +/–
thiazide and placebo (d) were more like to suffer any of the
major CV end points evaluated than those allocated to any
of the other possible treatment combinations (a, b, or c). Those
allocated to either of the other two possible combinations (b
and c in Table III) were neither ‘best’ nor ‘worst’ in terms of
prevention of whatever CV end point was considered.
ARE
PREVENTION:
GOING?
BPLA
Amlodipine
± perindopril
Atenolol
± thiazide
Atorvastatin
a
b
Placebo
c
d
LLA
Table III. ASCOT trial design: blood pressure–lowering arm and
lipid-lowering arm combined.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; BPLA,
blood pressure–lowering arm; LLA, lipid-lowering arm.
Data from reference 16: Sever P et al. Eur Heart J. 2006;27:2982-2988.
Amlodipine
± perindopril
+ atorvastatin
Atenolol
± thiazide
+ placebo
Relative
risk
reduction
Nonfatal MI and
fatal CHD
4.8
9.2
48%
Fatal and nonfatal
stroke
4.6
8.2
44%
End point
Table IV. ASCOT blood pressure–lowering arm and lipid-lowering
arm combined: insight into optimal cardiovascular prevention.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; CHD,
coronary heart disease; MI, myocardial infarction.
Data from reference 16: Sever P et al. Eur Heart J. 2006;27:2982-2988.
The absolute event rates of the primary end point of the trial
(nonfatal MI and fatal CHD) and all strokes (fatal and nonfatal)
suffered by those allocated to the “best” and “worst” therapy
combination (respectively, a and d in Table III) are shown in
Table IV.
Summary
As recently stated in the most recent NICE guidelines on hypertension management, “The prime motivation for treatment
in hypertension, as an asymptomatic condition, is the prevention of mortality and morbidity.”37 Similarly, the purpose of
using statins is to reduce the huge burden to global health
that CV disease currently causes.
Since raised BP and dyslipidemia frequently coexist to impart
a multiplicative impact on CV risk (ie, if for example, raised BP
doubles CV risk and abnormal lipids trebles risk, the combined effect is to increase risk six-fold), a combined approach
of lowering BP and improving lipid profiles is a logical one.
The best currently available evidence from clinical trials supports the routine use of such an approach, and consequently
several sets of guidelines for the management of hypertension
also recommend the routine use of statins for a large proportion of hypertensive patients.17,18
Some data suggest that specific combinations of BP-lowering drugs and statins may interact to generate synergistic benefit on CHD events,16 but even without synergy, the ASCOT
trial clearly shows large beneficial effects on all CV events as-
415
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
sociated with the use of amlodipine +/– perindopril with atorvastatin (Table IV). It seems likely that, for patients with hypertension, the routine use of the combination of an “A” drug
(ACE-inhibitor or ARB) plus a “C” drug (CCB) as recommended in the NICE guidelines of 2011,37 along with a cost-effec-
tive statin (eg, atorvastatin), would result in a dramatic reduction in the dreadful CV burden currently caused by raised
BP and, on the basis of best currently available evidence,
should probably form the cornerstone of standard hypertension management. n
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HYPERTENSION
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PREVENTION:
GOING?
Keywords: blood pressure; cardiovascular risk; coronary heart disease; dyslipidemia; hypertension; statin; synergy
UNE
APPROCHE SYNERGIQUE POUR TRAITER À LA FOIS L’ HYPERTENSION ET LA DYSLIPIDÉMIE
Les bénéfices sur le plan cardiovasculaire d’une diminution de la pression artérielle sont clairement établis depuis
des années. Plus récemment, c’est également devenu le cas pour les bénéfices cardiovasculaires d’une diminution
des lipides par les statines dans le cadre d’études spécifiques menées chez des patients hypertendus et dans des
sous-groupes de patients hypertendus. Etant donné qu’une pression artérielle élevée et une dyslipidémie sont plus
fréquemment concomitantes que ne le voudrait le hasard, il semble logique d’associer chez les patients hypertendus l’amélioration de la pression artérielle à celle des taux de lipides sanguins. L’étude ASCOT-LLA, le bras hypolipémiant de l’étude ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) a confirmé la logique d’une telle approche :
non seulement l’association d’antihypertenseurs A+C (inhibiteur de l’enzyme de conversion + inhibiteur calcique) s’est
montrée indépendante et supérieure en termes de bénéfices sur la prévention cardiovasculaire à l’association standard B+D (bêtabloquant +/- diurétique thiazidique), mais les effets supérieurs de l’atorvastatine par rapport au placebo ont également été démontrés. Les effets combinés de l’amlodipine +/-périndopril plus atorvastatine dans l’étude
ASCOT-LLA sont importants et incontestables et suggèrent une réelle synergie entre ces deux traitements dans la
prévention des événements coronaires. Par ailleurs, les recommandations dans la prise en charge de l’hypertension,
basées sur les meilleures données actuelles, sont de plus en plus en faveur d’une association A+C, afin d’optimiser
la prévention cardiovasculaire chez les hypertendus, et de l’utilisation des statines pour une proportion significative
des hypertendus. Il est urgent de prendre des mesures pour mettre en œuvre de meilleures pratiques, avant que l’augmentation globale et attendue de la prévalence et du nombre absolu d’hypertendus ne se traduise par un fardeau
cardiovasculaire encore plus lourd qu’il ne l’est actuellement.
417
‘‘
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Hypertension accelerates the
development and progression of
atherosclerosis, and stable blood
pressure elevation can lead to destabilization of the coronary plaque
and development of acute coronary syndrome… The pathophysiological association of hypertension with IHD is probably due to
two main mechanisms: endothelial dysfunction, which is an early
stage of atherosclerosis, and increased afterload leading to myocardial hypertrophy.”
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Antihypertensive treatment
in ischemic heart disease:
is there an ideal pill?
b y E . V. S h l ya k h t o , R u s s i a
T
Evgeny V. SHLYAKHTO
MD, PhD, FESC, FACC
Almazov Federal Heart, Blood
and Endocrinology Centre
Saint Petersburg
RUSSIA
he coexistence of arterial hypertension and ischemic heart disease results in more than a simple summation of their clinical features. Mutual activation of common pathophysiological mechanisms leads to increased levels of morbidity and mortality in this group of high-risk patients.
This is characterized not only by progression of atherosclerosis and stabilization of high blood pressure, but also by the occurrence of a number of concomitant problems such as arrhythmias and heart failure. All of this places additional demands on the choice of treatment for hypertensive patients with
ischemic heart disease. When choosing a treatment for these patients the
whole complexity of the problem should be considered: atherosclerosis, angina, fibrosis, arrhythmia, dyslipidemia, and other metabolic disorders. Drug
therapy should be individualized and take into account the heightened risk
for cardiovascular events. Recent data suggest that the use of certain groups
of medication raises many questions, but administration of ACE inhibitors,
statins, and acetylsalicylic acid seems to have undeniable benefits.
espite the significant progress made by medical science in the last several
decades, ischemic heart disease (IHD) is still the leading cause of death in the
majority of countries worldwide. With improvement of technology, the availability of invasive treatment methods, and extension of pharmacological treatment
options, the IHD mortality rate has decreased, but the incidence of cardiovascular
risk factors—particularly obesity, hypertension, and hyperlipidemia—is rapidly increasing. Statistics from 2010 revealed that hypertension was present in 34% of the adult
population, with obesity found in 33%, the metabolic syndrome in 34%, and 59%
having no daily physical activity.1
D
Hypertension as a risk factor for ischemic heart disease
Prof Evgeny V. Shlyakhto,
Director of Almazov Federal Heart,
Blood, and Endocrinology Centre,
Akkuratova Street 2,
Saint Petersburg 197341, Russia
418
In 2002-2003, Khot et al analyzed the incidence of traditional risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking) among 122 458 patients
with evident IHD. They reported the absence of risk factors in only 10% to 15% of
patients; in all others, at least one of the risk factors was present.2 The presence of
hypertension ranged from 21% to 60% across different age groups.2,3 There is no
doubt that risk factors significantly affect the course of atherosclerosis, including
the state of coronary plaques, and that the risk of complications is increased with the
presence of risk factors. Hypertension is known to be not only the major risk factor
for stroke and heart failure, but also for IHD. According to the results of the INTER-
Antihypertensive treatment in ischemic heart disease: is there an ideal pill? – Shlyakhto
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HEART study, which involved participants in 52 countries, hypertension is a more significant additional risk factor for myocardial infarction than diabetes. In patients aged 40 to 90
years, for every 20/10-mm Hg elevation in blood pressure, the
risk of fatal coronary events doubles.4 Hypertension accelerates the development and progression of atherosclerosis, and
stable blood pressure elevation can lead to destabilization of
the coronary plaque and development of acute coronary syndrome. Hypertension can lead to myocardial ischemia even in
the absence of coronary atherosclerosis.
Pathophysiological mechanisms in arterial
hypertension and ischemic heart disease
The pathophysiological association of hypertension with IHD
is probably due to two main mechanisms: endothelial dysfunction, which is an early stage of atherosclerosis, and increased
afterload leading to myocardial hypertrophy.
Early atherogenesis is characterized by endothelial damage
caused by high arterial pressure leading to impairment of nitric oxide production and release, and simultaneous accumulation of free radicals and mediators of inflammation in the
vascular wall. Inflammation and activation of the renin-angiotensin-aldosterone (RAS) system and sympathetic nervous
system are common pathophysiological processes for arterial
hypertension and IHD. In particular, angiotensin II maintains
elevated blood pressure and leads to atherosclerosis progression due to vasoconstriction and vascular remodeling. It is
also known to stimulate hypertrophy of cardiomyocytes and
smooth muscle cells by the direct activation of type 1 receptors, and to increase expression of inflammatory factors and
cytokines. Aside from this, RAS activation leads to the accumulation of low-density lipoproteins in the vascular wall.5
SELECTED
atrial fibrillation
angiotensin receptor blocker
Candesartan in Heart failure Assessment of moRtality
and Morbidity (trial)
HOPE Heart Outcomes Prevention Evaluation
IHD
ischemic heart disease
IPC
ischemic preconditioning
LIFE
Losartan Intervention For Endpoint reduction in hypertension (trial)
LVH
left ventricular hypertrophy
RAS
renin-angiotensin-aldosterone
REACH Reduction of Atherothrombosis for Continued Health
(registry)
SCOPE Study on COgnition and Prognosis in the Elderly
VALUE Valsartan Antihypertensive Long-term Use Evaluation
(trial)
ACE
AF
ARB
ASCOT
CHARM
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The metabolic syndrome
Hypertension is one of the components of the metabolic syndrome, which affects about one-third of the population and
is becoming increasingly prevalent. Several studies report a
correlation between the metabolic syndrome and atherosclerosis. The clustering of abdominal obesity with other components in the metabolic syndrome results in a significantly higher
incidence of elevated carotid intima-media thickness. In addition to increased incidence of IHD, the metabolic syndrome is
associated with a more severe disease course, and the presence of a higher number of components from the metabolic
syndrome is correlated with worse IHD on coronary angiography. Patients with the metabolic syndrome are approximately
four times more likely to die of IHD.6-8
u Adiponectin
The increased cardiovascular risk arising from the metabolic
syndrome is the result of a complex interaction of individual
risk factors that is not completely understood. One of the possible explanations is oxidative stress. Increased oxidative stress
is known to be strongly associated with atherosclerosis development and progression. Furthermore, visceral adipose tissue is a source of a large number of biologically active substances, including RAS components, inflammatory factors,
interleukins, adiponectin, and others. Obesity is characterized
by low serum adiponectin levels (hypoadiponectinemia). The
severity of hypoadiponectinemia correlates with coronary lesions, and plasma adiponectin levels can be used to identify
patients prone to coronary artery disease. It is of interest that
adiponectin can limit the damage from myocardial infarction
during acute injury. In ischemia-reperfusion mice, adiponectin
deficiency was found to increase myocardial infarct size by
up to 78%, and changes were also found in tumor necrosis
factor–a levels resulting in increased apoptosis of myocytes
and stromal cells. Treatment of these mice with adiponectin
led to a reduction in the infarcted zone.9,10 In humans, adhesion of monocytes to aortic endothelial cells is inhibited by
adiponectin through reduction of the expression of vascular
cell adhesion molecule 1, E-selectin, and intercellular adhesion
molecule 1 on the surface of endothelial cells.11 Adiponectin inhibits the transformation of human macrophages into foam
cells by inhibiting the class A macrophage scavenger receptor.
One possible role of adiponectin in atherosclerosis may relate
to its ability to decrease lipid accumulation in the subendothelial space, which is the earliest step in atherosclerotic plaque
formation. In addition, a single nucleotide polymorphism at
position +276 in the adiponectin gene is known to be linked
with IHD. T/T polymorphism is associated with a lower risk
of developing coronary artery disease than G/G or G/T variants of the genes. Adiponectin has been shown to activate
the peroxisome proliferator-activated receptor–a pathway
and to increase expression of AdipoR1 in IHD. Expression of
adiponectin receptors is 30% lower than normal in the subcutaneous fat of obese patients, and expression normalizes
419
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following weight loss. It is well established that adiponectin
plays an important role in type 2 diabetes, hypertension, multiple sclerosis, and dyslipidemia, the most significant of which
is its insulin-sensitizing effect. Adiponectin blood levels are
lower in diabetic patients than in nondiabetic individuals, and
higher plasma levels of adiponectin minimize the risk of developing type 2 diabetes. Adiponectin is negatively related to
blood glucose and insulin levels.10,12
Left ventricular hypertrophy
Another important link between hypertension and IHD has
been attributed to left ventricular hypertrophy (LVH), one of
the forms of myocardial remodeling. Myocardial hypertrophy
impairs myocardial relaxation and coronary perfusion during
diastole. LVH is known to be an independent strong predictor
of adverse cardiovascular events, including death from IHD,
congestive heart failure, sudden cardiac death, and stroke.13
Data from the Framingham Heart Study showed that males
with electrocardiographic signs of LVH had an eightfold increase in cardiovascular mortality and a sixfold increase in the
rate of sudden death compared with those who did not have
LVH.14
So far, there is no clear opinion as to the reasons for the close
association between hypertension, LVH, and IHD. Both experimental and clinical evidence confirms that high blood pressure stimulates the development of atherosclerosis.15,16 In addition, LVH is associated with changes in the density, structure,
and tone of coronary arteries. Despite the fact that absolute
coronary blood flow is elevated in the hypertrophied heart, a
decrease in capillary density and coronary reserve is observed,
even in the absence of coronary atherosclerosis.17,18
In accordance with experimental data, hypertrophied myocardium is more susceptible to electrical instability during ischemia/reperfusion. During reperfusion after global ischemia,
the ability to restore contractility is impaired in hypertrophied
hearts, and levels of lactate dehydrogenase and creatine kinase are increased. A number of hypotheses have been put
forward to explain the high sensitivity of the hypertrophied
myocardium to ischemia/reperfusion injury, which include mitochondrial damage, lactate accumulation, disturbance of glycolysis, as well as oxidative stress and an increase in oxygen
free radicals.16
Elevated systemic blood pressure is one reason for the development of endothelial dysfunction and degenerative changes
of the peripheral arteries associated with elasticity loss and
an increase in vascular stiffness. Such changes lead to elevation of central blood pressure, causing additional strain and
further remodeling of the left ventricle. These changes are especially significant in patients with isolated systolic hypertension, as a simultaneous decrease in diastolic blood pressure
can worsen perfusion pressure in the coronary arteries. Both
structural and functional changes in the peripheral arteries
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make a significant contribution to the phenomenon of blood
pressure variability, which, in turn, leads to further hypertrophy
and coronary flow impairment.19,20
LVH is also associated with an increased risk of sudden cardiac death, which is usually due to fatal ventricular arrhythmias.
The electrophysiological mechanisms are not fully understood,
but experimental data suggest a prolongation of the action
potential and changes in the ionic fluxes in hypertrophied cardiomyocytes. The presence of fibrosis foci is typical of LVH in
arterial hypertension, and leads to the appearance of zones
of impaired conductivity.21 Fibrosis also contributes to the dispersion of the duration of action potentials and to the formation of reentry. The frequency and severity of tachyarrhythmia
is probably increased in the presence of LVH. Belichard et al
demonstrated in 1987 that the duration of ventricular tachycardia paroxysms caused by coronary occlusion was significantly higher in spontaneously hypertensive rats than in control
normotensive animals.22 This phenomenon was due exclusively to myocardial hypertrophy and not to elevated blood
pressure. Similar results confirming the high rate of ventricular fibrillation in ischemia in hypertrophied myocardium were
produced by other authors.16 Fibrosis of the myocardium and
the phenomenon of high blood pressure variability probably
contribute to the occurrence of another form of arrhythmia;
namely, atrial fibrillation (AF), which is the most prevalent type
of rhythm disturbance. At present, hypertension is the most
frequent independent modifiable risk factor for AF. The relative risk of AF in hypertension is lower than in other diseases
(eg, heart failure or valvular heart diseases), but because of
the high worldwide prevalence of arterial hypertension, it is
the main risk factor for AF.23 Investigations into the pathogenesis of AF have confirmed a strong association between AF
and RAS activation.24
Treatment of arterial hypertension and
concomitant ischemic heart disease
The close association between arterial hypertension and IHD,
the presence of common pathophysiological mechanisms,
and the widespread prevalence of a number of concomitant
problems (systolic and/or diastolic myocardial dysfunction,
AF, ventricular arrhythmia) demand special attention with regard to choice of antihypertensive medication. Modern risk
stratification criteria refer patients with arterial hypertension
and concomitant cardiovascular disease to the very-high-risk
group. It is well known that achievement of goal blood pressure levels in this particular category of patients is a serious
problem. The debate concerning appropriate blood pressure lowering (“the lower, the better”) in this category of patients has been going on for more than 30 years. At the end
of the 1970s, Steward demonstrated a fivefold increase in the
relative risk of myocardial infarction in patients with diastolic
blood pressure below 90 mm Hg compared with those in
whom it remained within the 100-109 mm Hg range.25 There
is still no definitive explanation for this “J-curve” phenomenon.
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It is believed that excessive diastolic blood pressure reduction leads to the worsening of coronary perfusion and thus induces adverse coronary events. Most experts do not recommend diastolic blood pressure lowering to below 60 mm Hg.
According to the majority of the current guidelines, the target
blood pressure level in hypertensive patients with concomitant cardiovascular diseases is 130/80 mm Hg; this demands
more aggressive treatment and early administration of combination therapy. The presence of coexisting IHD requires medications with the following effects: (i) a decrease in the severity
of symptoms (eg, angina pectoris); (ii) prevention of atherosclerosis progression; and (iii) modification of other factors
that induce or worsen ischemia.
The general principles of nonpharmacological treatment in
patients with arterial hypertension and IHD do not differ significantly from those in the general population of hypertensives. Regular physical activity improves inotropic function,
decreases blood pressure, afterload, and arterial stiffness, and
leads to an increase in coronary reserve.26
u 웁-Blockers
b-Blockers have been used in cardiology for more than 40
years, and according to many reports, they contribute significantly to blood pressure lowering, decrease cardiovascular
morbidity and mortality, and positively affect clinical manifestations in patients with IHD. So at first glance, b-blockers
could be an optimal treatment for this particular group of patients. However, it is well known that the use of b-blockers
may be limited by a number of adverse events and poor tolerability: fatigue, weakness, sexual dysfunction, cold in the
extremities, etc. Moreover, a large pool of data has demonstrated the negative effects of b-blockers on metabolism—
first and foremost, on glycemic control. Finally, the results of
an analysis of data from the REACH registry (Reduction of
Atherothrombosis for Continued Health) published at the end
of 2012 produced a strong response.27 Having analyzed data
from 44 708 patients (31% with a history of myocardial infarction, 27% with other forms of IHD, and 42% with only risk factors for coronary artery disease), the authors of this study
suggested that b-blocker administration was not associated
with a decrease in cardiovascular event rates within a followup period of 44 months in the myocardial infarction group.
Moreover, in some subgroups of patients, use of b-blockers
was associated with a higher rate of cardiovascular events.
These data are not currently supported by randomized clinical trials, but they do suggest that the rapid progress of medical science and the emergence of new drugs and therapies
have resulted in a change in the established views on the treatment of such patients. Nevertheless, current guidelines state
that patients with stable angina pectoris, a history of myocardial infarction, and systolic dysfunction of the left ventricle
should receive b-blockers as part of their complex treatment
regimen.
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u Calcium channel blockers
Another well-studied group of medications is the calcium
channel blockers. They appear to be good substitutes for
b-blockers in the treatment of angina in hypertensive patients;
however, they are not recommended for secondary prevention because of their inability to prevent ventricular dilatation
and heart failure. Nondihydropyridine agents should not be
used in patients with systolic heart failure, and short-acting
dihydropyridine calcium channel blockers should be avoided
in patients with acute myocardial infarction, pulmonary edema, or significant left ventricular dysfunction.26
u RAS blockade
As mentioned, the RAS system plays a key role in the pathogenesis of arterial hypertension, atherosclerosis, type 2 diabetes, heart failure, and kidney damage. Thus, the groups of
drugs that block RAS activity, namely angiotensin-converting
enzyme (ACE) inhibitors and angiotensin receptor blockers
(ARBs), attract much attention. The level of RAS activity is believed to be a strong predictor of cardiovascular complications
and death. For example, in untreated hypertensive patients,
high plasma renin levels are associated with a more than twofold increase in cardiovascular morbidity, and in patients with
severe IHD, they are associated with a high mortality level.28,29
Aside from its potent vasoconstrictor effect, angiotensin II affects cell growth and sodium and water metabolism, and modulates sympathetic activity. It also promotes endothelial dysfunction, inflammation, oxidative stress, and insulin resistance,
and decreases the reactivity of pancreatic b-cells.30
The pressor effect of angiotensin II is predominantly due to
its binding to type 1 receptors in the heart, peripheral arteries,
kidneys, adrenal glands, brain, and adipocytes. The angiotensin II/type 1 receptor complex suppresses renin production, stimulates aldosterone release, enhances cardiomyocyte
contractility, hypertrophy, and fibrosis, and increases vascular
tone and sodium reabsorption. It is thought that binding of
angiotensin II to type 2 receptors promotes cardioprotection
and nephroprotection due to vasodilation caused by nitric oxide release and antiproliferative and anti-apoptotic activity
mediated by kinins.31 Both ACE inhibitors and ARBs are effective antihypertensive medications. Both classes prevent
cardiovascular complications, which makes them the basic
drugs for the treatment of high-risk patients. Leading European and American experts recommend these medications
for patients with concomitant cardiovascular diseases.
u Angiotensin receptor blockers
In 2006, the results of a meta-analysis were published suggesting that ARBs can increase the risk of myocardial infarction. In the LIFE trial (Losartan Intervention For Endpoint reduction in hypertension) involving more than 9000 patients,
losartan therapy was associated with a 5% increased rate of
myocardial infarction (statistically insignificant) compared with
atenolol-based therapy, despite the lower levels of blood pres-
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sure obtained in the losartan group.32 In SCOPE (Study on
COgnition and Prognosis in the Elderly), compared with the
control group, candesartan treatment was associated with
a 10% increased incidence of fatal and nonfatal myocardial
infarction, which also did not achieve statistical significance.33
The results of VALUE (Valsartan Antihypertensive Long-term
Use Evaluation) in 15 245 patients demonstrated a significant 19% increase (P=0.02) in the rate of myocardial infarction in patients receiving valsartan 160 mg compared with
those receiving amlodipine 10 mg.34
cardiomyocytes to avoid damage during ischemia, decreases
the size of infarction, and prevents ventricular arrhythmia. ACE
inhibitors have been shown to improve endothelial function in
peripheral and coronary arteries. One of the suggested mechanisms for this is their effect on gene expression, which leads
to the enhanced activity of cyclo-oxygenase-2, and consequently to prostacyclin and prostaglandin E2 production, without increasing thromboxane A2.35 In contrast, ARBs have
practically no effect on endothelial dysfunction, which is known
to be an early marker of atherosclerosis.
It should be noted that all of the aforementioned trials included hypertensive patients at very high risk, 80% of whom had
evident cardiovascular disease. In total, 9 of the 11 major clinical trials on ARBs reported an increased rate of myocardial
infarction, and in 2 of these (VALUE and CHARM [Candesartan in Heart failure Assessment of moRtality and Morbidity]),
the difference was statistically significant.
Although the beneficial effects of ACE inhibitors on postinfarct
left ventricular remodeling have been unequivocally demonstrated in both animal models and clinical trials, the acute
infarct–limiting effect of these drugs has been controversial.
Recent evidence suggests that a genetically-determined decrease in ACE activity is associated with a significant reduction in infarct size.42 By contrast, increased ACE activity in mice
was found to be associated with a trend toward increased infarct size and blunted preconditioning-mediated infarct limitation. Oral administration of ramiprilat at a dose of 50 mg/kg
during 1, 4, and 10 weeks resulted in a significantly reduced
infarct size in a rat model of myocardial ischemia-reperfusion.43
It should be noted, however, that the infarct-limiting effect of
ACE inhibitors has been called into question by other investigators. This controversy could stem from the use of different
routes of drug administration in different studies and differences in the doses of drugs and their pharmacokinetic profiles.
This paradox can be explained by the excessive stimulation
and overexpression of angiotensin type 2 receptors.35 As a result of angiotensin type 1 receptor blockade, ARBs can cause
an increase in angiotensin II levels that leads to the excessive
stimulation of type 2 receptors. It is thought that such stimulation has adverse effects due to enhanced cell growth, fibrosis, hypertrophy, a proinflammatory effect, and stimulation
of atherogenesis.13,36-38 Experimental data report that excessive stimulation of type 2 receptors leads to cardiomyocyte
contractile dysfunction, and in humans, this phenomenon is
associated with hypertrophy. It was also demonstrated that
activation of type 2 receptors inhibits hypoxia-induced neovascularization, which is an important compensatory mechanism in chronic myocardial ischemia.13 In 2005, Alfakih et al
in the UK revealed an association between increased expression of angiotensin type 2 receptors and early development
of IHD.39 These data suggest that ARBs can cause plaque
injury and rupture.35
u ACE inhibitors
ACE inhibitors are not associated with increased levels of angiotensin II. Besides ACE inhibition, the drugs are accompanied by increased levels of some ACE-dependent substrates;
eg, bradykinin, substance P, and enkephalins. This phenomenon provides ACE inhibitors with additional physiological and
clinical properties: increased vasodilation, decreased thrombogenesis, and the slowing down of atherogenesis and tissue proliferation. Bradykinin suppresses platelet aggregation
and decreases the level of plasminogen activator inhibitor-1,
which is a potent fibrinolysis inhibitor and can independently
predict the mortality rate after myocardial infarction.40 Thus,
long-term use of ACE inhibitors improves peripheral vasodilatation mediated by bradykinin and stimulates the release of
tissue plasminogen activator to levels achieved during systemic thrombolysis.41 Bradykinin is also the main mediator of
ischemic preconditioning, a unique phenomenon that allows
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In our own experiments, we investigated the infarct-limiting
and antiarrhythmic effects of captopril and zofenopril in the rat
model of myocardial ischemia-reperfusion in vivo.44 Both ACE
inhibitors were administered intravenously and the mean blood
pressure and heart rate were monitored throughout the experiments. Baseline blood pressure and heart rate values were
no different among the groups. Intravenous administration of
ACE inhibitors at a dose of 2.5 mg/kg resulted in a significant blood pressure decrease (by 40% to 45% from baseline).
The ACE inhibitor–induced decrease in blood pressure persisted throughout the entire experiment. No changes in heart
rate were observed after ACE inhibitor infusion. The anatomical area at risk was no different between the groups. In comparison with controls, infarct size was significantly smaller in
the group of animals treated with zofenopril, and there also
tended to be a decrease in the captopril group. These data
indicate that zofenopril significantly limited the infarct size
when administered 30 minutes prior to ischemia. The enhanced
infarct-limiting effect could be explained by the presence of
an SH group in the chemical structure of zofenopril, as well
as by its greater ability to inhibit tissue ACE.45
u Ischemic preconditioning
Ischemic preconditioning (IPC) is a phenomenon of increased
myocardial tolerance to ischemia-reperfusion injury occurring after single or multiple brief episodes of ischemia-reper-
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fusion.46 We were interested in investigating whether a subthreshold preconditioning stimulus could be strengthened by
the concomitant administration of the ACE inhibitor spirapril.
IPC was elicited by a single 5-minute episode of ischemia followed by 5 minutes of reperfusion. IPC significantly reduced
infarct size, but spirapril alone failed to limit the infarct size.
However, a combination of the preconditioning stimulus and
a nonhypotensive dose of spirapril resulted in significant attenuation of infarct size compared with IPC alone, which is
suggestive of a potentiation of the protective effect of IPC by
the ACE inhibitor. These data are in agreement with the findings of Miki et al, who showed that captopril could enhance
the infarct-limiting effect of a single 2-minute IPC stimulus in
rabbits.47 This effect was abolished by the concomitant administration of the B2-receptor blocker HOE 140, which indicates that ACE inhibitor–induced potentiation of IPC is bradykinin dependent.
u Metabolic effects
Another important issue with regard to RAS blockade concerns the beneficial metabolic effects of RAS blockers. A number of clinical trials have observed beneficial effects of RAS
blockade on cardiovascular morbidity and mortality in both
hypertensive and normotensive patients with the metabolic
syndrome. RAS blockade is known to have positive effects
on insulin resistance, glucose tolerance, lipid profiles, and oxidative state. In an animal model of insulin resistance and RAS
overactivity, administration of RAS blockers improved insulin
sensitivity, stimulated glucose transport into muscle, and reduced oxidative stress. Similar results were shown in other
experimental studies in which RAS blockade was associated
with increased numbers of GLUT-4 transporters and increased
glucose uptake.6,48 Moreover, analysis of HOPE (Heart Outcomes Prevention Evaluation) demonstrated a 32% reduction in the incidence of new-onset diabetes in patients treated with an ACE inhibitor.
u Statins
When discussing the treatment of hypertensive patients with
IHD, one cannot avoid mentioning the statin group of drugs.
The addition of lipid-lowering medications to RAS inhibitors is
a widely-accepted treatment strategy in this category of patients. There are several possible interactions between cholesterol and angiotensin II: (i) as they affect endothelial function,
they may interact to promote the development and progression of atherosclerosis; (ii) hypercholesterolemia, particularly
high levels of low-density lipoprotein, leads to the upregulation
of vascular ACE and angiotensin II type 1 receptors; and (iii)
angiotensin II promotes oxidation and vascular uptake of lowdensity lipoprotein cholesterol.
Aside from lowering cholesterol levels, statins are known to
modify endothelial function and atherogenesis, stabilize atherosclerotic plaques, and reduce inflammation and thrombus
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formation. These pleiotropic properties of statins may have
important clinical implications in addition to their lowering of
serum cholesterol levels.49
Important data on statins came from ASCOT-LLA (the lipidlowering arm of the Anglo-Scandinavian Cardiac Outcomes
Trial), which was a double-blind placebo-controlled trial of
atorvastatin in 10 305 hypertensive patients originally enrolled
in the blood pressure–lowering arm of ASCOT and with baseline total cholesterol concentrations of below 6.5 mmol/L.
ASCOT-LLA was stopped prematurely after a 3.3-year follow-up because of a 36% relative risk reduction in nonfatal
myocardial infarction and fatal coronary heart disease (the
primary outcome) in favor of atorvastatin and a nonsignificant
reduction in cardiovascular death (16%) and all-cause mortality (13%). In the 11 years after initial randomization and 8
years after closure of the lipid-lowering arm, all-cause mortality remained significantly lower in patients assigned to atorvastatin. Cardiovascular deaths were also fewer, although not
significantly, and noncardiovascular deaths were significantly
lower, which was attributed to a reduction in deaths from infection and respiratory illness. The study authors concluded
that the pleiotropic effects of statins may play a role in these
protective effects.50
Clinical data suggest that hypertensive diabetic patients who
experience an acute myocardial infarction have a smaller infarct size, better global systolic function, and less hospital
morbidity and mortality if they were receiving combined ACE
inhibitor and statin therapy prior to the event. Thus, prior combination therapy with an ACE inhibitor and a statin has cardioprotective effects in hypertensive diabetic patients with acute
myocardial infarction.51 The combination of an ACE inhibitor
and a statin stops proteinuria and protects against renal dysfunction and structure impairment. Statins reduce cholesterol,
are antiatherosclerotic, and improve endothelial function. ACE
inhibitors are effective in controlling hypertension and cardiovascular disease, not only because of their blood pressure–
lowering effect, but also as a result of their ability to block the
production of angiotensin II. Further studies are warranted to
confirm the beneficial impact of ACE inhibitors and statins
and their potentially synergistic mode of action, as this could
represent a potent and effective combination in high-risk patient populations.
u Future therapies
In terms of the development of new drugs and therapeutic approaches, one attractive option is the newly-discovered class
of intracellular regulators, microRNAs (miRNAs). Their small
size and known conserved sequences make them promising
candidates in the development of new drugs. Currently, there
are two major approaches in microRNA therapeutics—activation of existing miRNAs (miRNA mimetics) and blockage
of miRNAs with the help of complementary oligonucleotides
(antimiRs).52 The latter approach is easier and currently much
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more advanced; however, there are no cardiology clinical trials presently in progress using antimiRs, despite the development of many approaches and intracellular targets in this
area.53 In the field of arterial hypertension and coronary artery
disease, protection of the target organs—in particular, prevention of left ventricular hypertrophy—is an important task.
To this end, miR-208a, the only cardiac-specific microRNA
encoded in the a-MYH7 gene, is known to block cardiac hypertrophy.54 At the same time, it has been shown to have a
protective effect against development of cardiac fibrosis and
cardiac remodeling after ischemia and development of diastolic heart failure, as well as the ability to improve tissue and
systemic energy metabolism. Other potential options are miR21 and miR-29,52,55 which specifically target cardiac fibrosis.
Conclusion
In general, the choice of treatment for a hypertensive patient
with a serious comorbidity such as IHD should take into account the whole complexity of the problem: atherosclerosis,
angina, fibrosis, arrhythmia, dyslipidemia, and other metabolic
disorders. Drug therapy should be individualized and should
take into account the heightened risk for cardiovascular events.
Recent data suggest that the use of certain groups of medication raises many questions, but administration of ACE inhibitors, statins, and acetylsalicylic acid seems undeniably beneficial. It is of note that hypertensive patients with concomitant
IHD belong to the very-high-risk group, and as such, should all
receive combination therapy as a first step in their treatment
regimen. n
References
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Influence of ramiprilat and losartan on ischemia reperfusion injury in rat hearts.
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effect of angiotensin-converting enzyme inhibitor zofenopril in acute myocardial
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47. Miki T, Miura T, Ura N. Captopril potentiates the myocardial infarct size-limiting effect of ischemic preconditioning through bradykinin B2 receptor activation. J Am Coll Cardiol. 1996;28:1616-1622.
48. Henriksen EJ. Improvement of insulin sensitivity by antagonism of the renin-angiotensin system. Am J Physiol. 2007;293:R974-R980.
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Keywords: cardiovascular risk; ischemic heart disease; hypertension; metabolic syndrome; renin-angiotensin system
LE
TRAITEMENT ANTIHYPERTENSEUR DANS LA MALADIE CORONAIRE
LE COMPRIMÉ IDÉAL EXISTE -T- IL ?
:
Les conséquences de la coexistence d’une hypertension artérielle et d’une maladie coronaire sont supérieures à la
simple addition de leurs tableaux cliniques. L’activation mutuelle des mécanismes physiopathologiques communs
augmente la morbidité et la mortalité dans ce groupe de patients à haut risque. Ceci se caractérise par une progression de l’athérosclérose, une pression artérielle élevée et de nombreux problèmes concomitants comme des arythmies et une insuffisance cardiaque. Tout ceci impose des contraintes supplémentaires lors du choix du traitement des
patients hypertendus souffrant de maladie coronaire. Lorsque l’on choisit un traitement pour ces patients, il faut envisager le problème dans toute sa complexité: athérosclérose, angor, fibrose, arythmie, dyslipidémie et autres désordres métaboliques. Les traitements médicamenteux doivent être individualisés et prendre en compte le risque accru d’événements cardiovasculaires. D’après des données récentes, l’utilisation de certains groupes médicamenteux soulève de nombreuses questions mais les bénéfices des IEC, des statines et de l’acide acétylsalicylique sont
indéniables.
425
‘‘
HYPERTENSION
AND
WHERE
… the combination of perindopril and indapamide is the one
specific combination that has been
rigorously tested and found to be
truly effective for the prevention of
recurrent stroke. The absolute risk
reductions observed with the combination of perindopril and indapamide suggest that 5 years’ treatment with this combination would
avoid one major vascular event,
fatal or nonfatal, for every 11 patients treated.”
ARE
PREVENTION:
GOING?
Is fixed-combination
antihypertensive therapy
needed in post-stroke
patients?
b y J . C h a l m e r s a n d H . A r i m a , A u s t ra l i a
C
▲
John CHALMERS, AC, FAA, FRACP
Hisatomi ARIMA, MD, PhD
The George Institute for Global
Health, University of Sydney
and the Royal Prince Alfred
Hospital, Sydney
AUSTRALIA
ombination antihypertensive therapy is now recommended for the
vast majority of patients who need blood pressure–lowering therapy.
Patients with previous stroke form a particularly important group for
whom combination therapy has been shown to be both beneficial and superior. The best evidence for this comes from the PROGRESS trial (Perindopril
pROtection aGainst REcurrent Stroke Study), which clearly demonstrated that
a regimen based on the angiotensin-converting enzyme inhibitor perindopril,
with additional use of the diuretic indapamide, as required, reduced the incidence of recurrent stroke by around one quarter. In the PROGRESS trial, combination therapy with perindopril and indapamide produced an even larger
reduction in the risk of stroke (relative risk reduction, 43%), which is consistent
with the larger blood pressure reduction obtained with combination therapy
compared with single drug therapy (12.3/5.0 mm Hg vs 4.9/2.8 mm Hg). Similar trends toward greater reductions associated with combination therapy were
also observed for all other outcomes including major vascular events, coronary
heart events, heart failure, disability, dependency, cognitive decline, and death.
Therefore, the combination of perindopril and indapamide can be recommended for the prevention of recurrent stroke and associated cardiovascular events
in all patients with cerebrovascular disease.
ombination antihypertensive therapy is now recommended for the vast majority of patients who need blood pressure–lowering therapy, including those
with hypertension (defined as systolic blood pressure ≥140 mm Hg), and
also patients with high cardiovascular risk, whether hypertensive or not.1-5 Furthermore, in the past 10 years, these recommendations have broadened to cover the
use of combination therapy to initiate drug treatment for patients with more severe hypertension (systolic blood pressure ⱖ160 mm Hg) or patients at high cardiovascular risk.1-4 In addition, many guidelines now recommend that fixed-dose (or
“single pill”) combinations may be used, as they may facilitate adherence and improve blood pressure control.1-5
C
Professor John Chalmers, PO Box
M201, Missenden Rd, NSW 2050,
Australia
(e-mail:
[email protected])
426
Patients with previous stroke form a particularly important group for whom combination therapy has been shown to be both beneficial and superior. The best evidence for this comes from the PROGRESS trial (Perindopril pROtection aGainst
REcurrent Stroke Study), which clearly demonstrated that a regimen based on the
angiotensin-converting enzyme inhibitor perindopril, with additional use of the di-
Fixed-combination antihypertensive therapy in post-stroke patients – Chalmers and Arima
HYPERTENSION
AND
WHERE
uretic indapamide, as required, reduced the incidence of recurrent stroke, major vascular events, coronary heart events,
and heart failure by around one quarter.6,7 Even more important, the main analysis and all subsequent analyses have
confirmed that the greatest reductions in stroke and all other
major cardiovascular events were obtained in the subgroup
treated with both perindopril and indapamide.6-9
Since then, a number of other studies have reported the effects of blood pressure–lowering after stroke, using a variety
of other regimens.10,11 Some of these studies compared active
treatment with placebo,11 while others compared two active
treatments.10 None of these studies involved combination therapy either in the trial as a whole, or in a specific subset of patients. In this article, we examine the results of PROGRESS
and of the more recent trials and present analyses based both
on PROGRESS and on a meta-regression of numerous studies. The particular focus of this article will be on the evidence
regarding the use of combination blood pressure–lowering
therapy in patients with cerebrovascular disease and on the
possible benefits observed with the combinations that have
been tested.
The PROGRESS trial – results and implications
u Background
Stroke kills over 5 million people every year, so that it now constitutes the second largest cause of death across the world.12
Many more people have a stroke and survive it—well over 15
million annually—but around one-third of survivors are disabled. Recurrent stroke is also common in survivors and prevention of recurrence is a major challenge. While aspirin therapy has been shown to be effective for reducing recurrence
after ischemic stroke, prior to PROGRESS no strategies were
available to prevent stroke recurrence after a hemorrhagic
stroke.13
The PROGRESS trial was launched as an investigator-initiated study to test the hypothesis that routine blood pressure
lowering in patients who had suffered a stroke or a transient
ischemic attack, would be both safe and effective in reducing the incidence of recurrent stroke. A number of small trials
had been conducted before PROGRESS with mixed results,
and there was continuing uncertainty regarding the wisdom
and safety of lowering blood pressure in patients who had survived a stroke.14
As there was good evidence from observational studies that
the association between blood pressure and both primary
and secondary stroke was positive and continuous, well into
the normal range of blood pressure,15,16 all patients with previous stroke or transient ischemic attack could be enrolled in
PROGRESS, whether they were hypertensive or normotensive.6,14 Furthermore, PROGRESS was deliberately planned to
include patients from China and Japan, where stroke is particularly common.
ARE
PREVENTION:
GOING?
u Brief description of the PROGRESS trial
Patients were eligible for PROGRESS if they had a stroke or a
transient ischemic attack in the past five years. They also had
to have no definite indication or contraindication to treatment
with an angiotensin converting-enzyme inhibitor. There were
no blood pressure entry criteria and both hypertensive and
normotensive individuals were eligible. Potentially eligible individuals entered a 4-week run-in period during which they
received open-label perindopril, 2 mg daily for 2 weeks followed by 4 mg daily for another 2 weeks. Participants who
tolerated this treatment were randomly assigned on a double
blind basis to either continuing active therapy or matching placebo. Active therapy consisted of a flexible regimen whereby
all participants received perindopril 4 mg daily, with addition
of the diuretic indapamide 2.5 mg daily (2 mg in Japan), in patients without definite indication or contraindication to treatment
with a diuretic. The purpose of allowing combination therapy
was to maximize the magnitude of blood pressure reduction
achieved; and physicians were asked, prior to randomization,
to determine whether the individual participants should be randomized to single therapy with perindopril (or matching placebo) or to combination therapy with both perindopril and indapamide (or double placebo). After the first few months,
patients were seen every six months, and blood pressure was
measured with a mercury sphygmomanometer.
The primary study outcome was stroke (fatal or nonfatal), and
secondary outcomes included stroke subtypes, major vascular events (nonfatal stroke, nonfatal myocardial infarction,
or death due to any vascular cause), disability, dementia, and
cognitive decline. Prespecified subgroup analyses included
comparison of treatment effects among participants randomized to combination therapy or to single therapy.
u Patient enrolment, follow-up, and baseline characteristics
A total of 7121 patients entered the 4-week run-in phase and
1016 were found ineligible or withdrew during that time, so that
6105 were randomized. Of those randomized, 3051 were assigned active treatment, with 1770 stratified to the combination of perindopril 4 mg and indapamide 2.5 mg and 1281
stratified to perindopril alone. A total of 3054 patients were
assigned placebo treatment, with 1774 on double placebo
and 1280 on single placebo. The mean duration of follow-up
was 3.9 years. Only 3 patients were lost to follow-up and had
unknown vital status at the end of the study, 2 on active treatment and 1 on placebo.
The baseline characteristics of all randomized participants are
summarized in Table I (page 428). There was a good balance
between those on active treatment and those on placebo.
There was also a good balance between those stratified to
combination therapy or to single therapy, though as expected, those on combination therapy or double placebo, were
younger, had higher baseline blood pressures, and were more
likely to be hypertensive or to have coronary disease (Table I).
427
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
Randomized treatment
Prespecified regimen*
Active
(n=3051)
Placebo
(n=3054)
Combination
(n=3544)
Single
(n=2561)
64 (10)
30
39
64 (10)
30
39
63 (9)
29
38
65 (10)
32
39
71
11
4
22
71
11
5
22
71
11
4
22
70
11
6
23
8 (2 to 21)
8 (2 to 22)
7 (2 to 21)
9 (3 to 23)
Other medical history, %
Current smoker
Diabetes
CHD‡
Carotid disease§
20
13
16
7
20
12
16
7
20
12
18
7
19
13
14
7
Blood pressure
Mean SBP, mm Hg (SD)
Mean DBP, mm Hg (SD)
Hypertension||
147 (19)
86 (11)
48
147 (19)
86 (11)
48
149 (19)
87 (11)
54
144 (19)
84 (11)
40
Demographics
Mean age, years (SD)
Women, %
Asian†, %
Cerebrovascular disease history
Ischemic stroke, %
Hemorrhagic stroke, %
Stroke of unknown type, %
TIA, %
Median time since qualifying event,
months (interquartile range)
Medication, %
Antiplatelet therapy
Oral anticoagulants
Antihypertensive therapy¶
Lipid-lowering therapy
73
9
49
13
72
10
51
15
72
8
50
14
Table I. Baseline
characteristics
of PROGRESS
participants.
Abbreviations: CHD,
coronary heart disease;
DBP, diastolic blood
pressure; PROGRESS,
Perindopril pROtection
aGainst REcurrent
Stroke Study; SD,standard deviation; SBP,
systolic blood pressure;
TIA, transient ischemic
attack.
Adapted and expanded from reference 6:
PROGRESS Collaborative Group. Lancet.
2001;358:1033-1041.
© 2001, Elsevier.
73
10
51
14
* Combination=perindopril + indapamide, or double placebo; single= perindopril alone or single placebo.
† Participants recruited from the People’s Republic of China or Japan.
‡History of myocardial infarction or coronary revascularization, or angina (supported by documented electrocardiographic or angio-
graphic evidence).
§ Previous carotid endarterectomy, previous carotid angioplasty or carotid stenosis > 50% (confirmed by angiogram or Doppler).
|| Systolic ≥160mm Hg and/or diastolic blood pressure ≥90mm Hg.
¶ Currently treated hypertension.
Proportion with stroke (%)
20
B
Placebo
Active
20
Proportion with stroke (%)
A
Relative risk reduction 28%
P<0.0001
10
0
Placebo
Active
Relative risk reduction 43%
P<0.0001
10
0
0
1
2
3
4
0
Follow-up (years)
1
2
3
4
Follow-up (years)
Figure 1. PROGRESS trial: Cumulative incidence of stroke among 3051 participants assigned active treatment and 3054 participants
assigned placebo (A) and among 1770 participants assigned combination therapy and 1774 assigned double placebo (B).
Abbreviation: PROGRESS, Perindopril pROtection aGainst REcurrent Stroke Study.
After reference 6: PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041. © 2001, Elsevier.
428
HYPERTENSION
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u Effects on blood pressure
Overall, across the whole 4 years of follow up, blood pressure was reduced by an average of 9.0/4.0 mm Hg among
those randomized to active treatment compared with those
assigned placebo.6 The reduction was considerably greater
among those treated with combination therapy (12.3/5.0
mm Hg), and was actually twice that observed in participants
treated with single therapy (4.9/2.8 mm Hg).6
u Effects on stroke
Active treatment reduced the risk of stroke by 28% overall
(P<0.0001).6 The Kaplan-Meier curves diverged early and continued to separate during follow-up (Figure 1). Among participants treated with combination therapy, perindopril plus indapamide, the greater reduction in blood pressure was matched
by a greater 43% reduction in stroke risk, compared with those
receiving single therapy with perindopril alone (Figure 2, panel A).6 The reductions in stroke subtypes, particularly hemorrhagic stroke and ischemic stroke, were also markedly accentuated in patients on combination therapy, not only compared
with those on single therapy,6 but also compared with the overall reduction for those on any active treatment, whether sin-
A
Number of events
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PREVENTION:
GOING?
gle or dual (Figure 3, page 430). Thus, combination therapy
achieved a 76% reduction in hemorrhagic stroke, a 36% reduction in ischemic stroke (Figure 3), and a 46% reduction in
fatal or disabling stroke.6
A subsidiary analysis of PROGRESS data examined the effects of randomized blood pressure–lowering treatment on
the risk of stroke by strata of baseline blood pressure. Combination therapy with perindopril and indapamide provided
consistently greater benefits, which were significant across a
range of subgroups defined by baseline systolic and diastolic
blood pressures ranging from ⱖ160/100 mm Hg to <120/80
mm Hg (Figure 2, panel B).17,18
u Effects on major vascular events
Out of the 6105 randomized patients, 1062 participants experienced a major vascular event, fatal or nonfatal, 458 in the
active treatment group and 604 in the placebo group, a reduction of 26% with active treatment (Figure 3).6 The reduction in major vascular events was much greater in participants
receiving the combination of perindopril plus indapamide (40%;
P<0.001)
Favors
active
Favors
placebo
Risk reduction
(95% CI)
Active
Placebo
BP
reduction
Combination therapy
150
255
12/5 mm Hg
Single-drug therapy
157
165
5/3 mm Hg
5% (–19 to 23%)
Total
307
420
9/4 mm Hg
28% (17 to 38%)
Combination therapy
231
367
12/5 mm Hg
40% (29 to 49%)
Single-drug therapy
227
237
5/3 mm Hg
4% (–15 to 20%)
Total
458
604
9/4 mm Hg
26% (16 to 34%)
Stroke
43% (30 to 54%)
Major vascular events
0.25
B
Number of events
0.5
1
2
Hazard ratio (95% CI)
Favors
active
Favors
placebo
Risk reduction
(95% CI)
Active
Placebo
≥160 mm Hg
57
106
47% (27-62%)
140 to 159 mm Hg
54
87
41% (16-58%)
120 to 139 mm Hg
37
58
41% (11-61%)
2
4
≥100 mm Hg
16
40
64% (35-80%)
90 to 99 mm Hg
53
84
41% (17-58%)
89 to 90 mm Hg
52
85
39% (14-57%)
<80 mm Hg
49
46
38% (1-61%)
P
homogeneity
Systolic blood pressure
<120 mm Hg
0.5
36% (–249-88%)
Diastolic blood pressure
0.25
0.5
1
2
Hazard ratio (95% CI)
0.2
Figure 2. (A) Effects
of combination and
single drug therapy
on stroke and major
vascular events and
(B) effects of combination therapy on
stroke by baseline
blood pressure in
the PROGRESS trial.
Solid boxes represent
estimates of hazard ratio
of outcomes; the areas of
the boxes are proportional
to the inverse variance
of the estimates; vertical
lines represent 95% CI;
diamonds represent estimates and 95% CI for
overall effects.
Abbreviations:
CI, confidence interval;
PROGRESS, Perindopril
pROtection aGainst
REcurrent Stroke Study.
Panel A: modified from
reference 6: PROGRESS
Collaborative Group.
Lancet. 2001;358:10331041. © 2001, Elsevier.
Panel B: after reference
18: Arima and Chalmers.
J Clin Hypertens
(Greenwich). 2011;13:
693-702. © 2011, Wiley
Periodicals, Inc.
429
HYPERTENSION
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PREVENTION:
GOING?
Participants on combination therapy
(n=3544)
All participants (n=6105)
Favors Favors Risk reduction
active placebo
(95% CI)
Favors Favors Risk reduction
active placebo
(95% CI)
28 (17 to 38)
43 (30 to 54)
Ischemic stroke
24 (10 to 35)
36 (19 to 49)
Intracerebral hemorrhage
50 (26 to 67)
76 (55 to 87)
stroke of unknown type
18 (-24 to 45)
29 (–22 to 58)
Major coronary events
26 (6 to 42)
35 (12 to 52)
Heart failure
26 (5 to 42)
26 (–12 to 52)
Major vascular events
26 (16 to 34)
40 (29 to 49)
Disability
24 (11 to 35)
30 (14 to 43)
Dependency
16 (1 to 29)
22 (3 to 37)
Stroke
Vascular death
Total death
9 (–12 to 25)
28 (5 to 45)
4 (–12 to 18)
17 (–2 to 33)
Dementia
12 (–8 to 28)
23 (0 to 41)
Cognitive decline
19 (4 to 32)
22 (2 to 38)
0.25
0.5
1
Relative risk (95% CI)
2
0.25
0.5
1
2
Figure 3. Effects of blood
pressure lowering on serious
clinical outcomes in the
PROGRESS trial.
Solid boxes represent estimates of
relative risk of outcomes (hazard
ratio for stroke, major coronary
events, heart failure, major vascular
events, vascular death and total
death, and odds ratio for disability,
dependency, dementia and cognitive decline). Other conventions
as for Figure 2.
Abbreviations: CI, confidence
interval; PROGRESS, Perindopril
pROtection aGainst REcurrent
Stroke Study.
Based on data from reference 6:
PROGRESS Collaborative Group.
Lancet. 2001;358:1033-1041;
reference 7: PROGRESS Collaborative Group. Eur Heart J. 2003;24:
475-484; reference 8: PROGRESS
Collaborative Group. Stroke.
2003;34:2333-2338; reference 9:
PROGRESS Collaborative Group.
Arch Intern Med. 2003;163:10691075; and reference 18: Arima H
and Chalmers J. J Clin Hypertens
(Greenwich). 2011;13:693-702.
u Effects on other outcomes
Active treatment resulted in significant reductions in many secondary outcomes including major coronary events, heart failure, disability and dependency, and cognitive decline (Figure 3,
left panel).6-9 Once again, these effects were substantially magnified in the group receiving combination treatment (Figure 3,
right panel), where, for example, the reduction in the risk of dementia reached 23% (P<0.05) in those who receiving perindopril and indapamide (Figure 3).9
of patients who achieved the lowest follow-up blood pressure
levels (with a median of 112/72 mm Hg), with no excess of serious complications.17 Similar relationships were observed for
both ischemic and hemorrhagic stroke (Figure 4),17 both in patients with and without chronic kidney disease.19 These observational data are supported by the evidence shown in Figure 2 (panel B), demonstrating the efficacy of combination
therapy across subgroups, defined by baseline systolic and
diastolic blood pressures down to <120/80 mm Hg.17,18
Association between the risk of stroke and
achieved blood pressure in clinical trials
u Randomized trials after PROGRESS
Several randomized trials completed after PROGRESS have
reported the effects of blood pressure lowering on recurrent
stroke, though none has looked specifically at the effects of
combination therapy.10,11,20-23 A meta-regression of these and
u The PROGRESS trial
An observational analysis of PROGRESS revealed that the
lowest risk of recurrent stroke was observed in the one quarter
Figure 4. Annual rates of ischemic
stroke and intracerebral hemorrhage
according to achieved follow-up
systolic blood pressure levels in the
PROGRESS trial.
430
Ischemic stroke
Intracerebral hemorrhage
0.32
Annual rate (%)
0.16
Annual rate (%)
Annual incidence rates and P values were controlled for age, sex, smoking, diabetes, study
treatment, and combination therapy. Solid boxes
represent estimates of annual incidence rates of
stroke. The centers of the boxes are placed at
the estimates of annual incidence rates and at
median values of systolic blood pressure; the
areas of the boxes are proportional to the number
of events. Vertical lines represent 95% confidence
intervals. P trend=0.0005 for ischemic stroke,
<0.0001 for intracerebral hemorrhage.
PROGRESS, Perindopril pROtection aGainst
REcurrent Stroke Study.
After reference 17: Arima et al. J Hypertens.
2006;24:1201-1208. © 2006, Lippincott
Williams & Wilkins.
8
4
2
0.08
0.04
0.02
1
0.01
100
120
140
160
180
Systolic blood pressure (mm Hg)
100
120
140
160
180
Systolic blood pressure (mm Hg)
HYPERTENSION
AND
WHERE
Figure 5. Meta-regression analysis of 9 randomized
controlled trials of blood pressure lowering to investigate association of reduction in systolic blood
pressure with risk reduction for recurrent stroke.
PREVENTION:
GOING?
Reduction in risk for each 10-mm Hg reduction
33% (95% CI, 9 to 5%), P=0.04
2
A total of 9 randomized controlled trials for secondary prevention
of stroke published after 1990 with information on reduction in
systolic blood pressure were included. The area of each circle
is proportional to the inverse variance of the log of relative risk.
The fitted line represents summary meta-regressions for recurrent stroke.
Abbreviations: CI, confidence interval; Dutch TIA, Dutch Transient Ischemic Attack trial; FEVER, Felodipine EVEnt Reduction;
HOPE, Heart Outcomes Prevention Evaluation; MOSES, MOrbidity and mortality after Stroke, Eprosartan compared with
nitrendipine for Secondary prevention; PATS, Post-stroke antihypertensive treatment study; PRoFESS, Prevention Regimen for
efFEctively avoiding Second Strokes; PROGRESS, Perindopril
pROtection aGainst REcurrent Stroke Study; SCOPE, Study on
COgnition and Prognosis in the Elderly; TEST, Timolol, Encainide,
Sotalol Trial.
After reference 18: Arima and Chalmers. J Clin Hypertens
(Greenwich). 2011;13:693-702. © 2011, Wiley Periodicals, Inc.
ARE
PRoFESS
TEST
MOSES
1
HOPE
DutchTIA
FEVER
PROGRESS
PATS
0.5
SCOPE
0.25
–15
–10
–5
0
5
Reduction in systolic blood pressure (mm Hg)
a few small earlier trials is shown in Figure 5, and this suggests that each 10-mm Hg reduction in systolic blood pressure is associated with a 33% reduction in the risk of recurrent
stroke.18 This is consistent with analyses from other observational studies reporting that every 10-mm Hg reduction in
systolic blood pressure was associated with a 28% lower risk
of recurrent stroke.16
tial in order to achieve sufficient reduction in blood pressure
for this to translate into effective reduction in the risk of stroke.
The specificity of this message is absolutely in line with the results of numerous national and international studies on the
need for combination therapy for effective reduction in the burden of cardiovascular disease, as reflected in all major guidelines.1-5,24
Implications and conclusions
It is also abundantly clear that the combination of perindopril and indapamide is the one specific combination that has
been rigorously tested and found to be truly effective for the
prevention of recurrent stroke. The absolute risk reductions observed with the combination of perindopril and indapamide
suggest that 5 years’ treatment with this combination would
avoid one major vascular event, fatal or nonfatal, for every 11
patients treated. Therefore, this combination can be recommended for the prevention of recurrent stroke and associated cardiovascular events in all patients with cerebrovascular
disease. n
The totality of the studies and analyses reported here make
it clear that reduction in the risk of recurrent stroke in patients
with cerebrovascular disease is closely tied to the magnitude
of reduction in blood pressure, as well as to the level of blood
pressure achieved, at least to below 130/80 mm Hg when
this is well tolerated in the individual patient. It is also abundantly clear from the PROGRESS trial, which conducted a rigorous comparison of the effect of combination therapy with
the angiotensin-converting enzyme inhibitor perindopril and
the diuretic indapamide, that combination therapy is essen-
References
1. World Health Organization International Society of Hypertension Writing Group.
2003 World Health Organization (WHO)/International Society of Hypertension
(ISH) statement on management of hypertension. J Hypertens. 2003;21:19831992.
2. Chobanian AV, Bakris GL, Black HR, et al; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High
Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
3. Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial
document. J Hypertens. 2009;27:2121-2158.
5. Ogihara T, Kikuchi K, Matsuoka H, et al; Japanese Society of Hypertension
Committee. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res. 2009;32:3-107.
6. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood
pressure lowering regimen among 6,105 individuals with previous stroke or tran-
sient ischaemic attack. Lancet. 2001;358:1033-1041.
7. PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur Heart J. 2003;24:475-484.
8. PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure-lowering regimen on disability and dependency in 6105 patients with cerebrovascular disease: a randomized controlled trial. Stroke. 2003;34:2333-2338.
9. PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163:1069-1075.
10. Schrader J, Luders S, Kulschewski A, et al; MOSES Study Group. Morbidity and
mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomised controlled study (MOSES).
Stroke. 2005;36:1218-1226.
11. Yusuf S, Diener HC, Sacco RL, et al; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:
1225-1237.
12. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235
causes of death for 20 age groups in 1990 and 2010: a systematic analysis for
the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-2128.
431
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
13. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials
of antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke
by prolonged antiplatelet therapy in various categories of patients. Antiplatelet
Trialists' Collaboration. BMJ. 1994;308:81-106.
14. MacMahon S, Rodgers A, Neal B, Chalmers J. Blood pressure lowering for
the secondary prevention of myocardial infarction and stroke. Hypertension.
1997;29:537-538.
15. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart
disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765774.
16. Rodgers A, MacMahon S, Gamble G, Slattery J, Sandercock P, Warlow C; United Kingdom Transient Ischaemic Attack Collaborative Group. Blood pressure
and risk of stroke in patients with cerebrovascular disease. BMJ. 1996;313:147.
17. Arima H, Chalmers J, Woodward M, et al; PROGRESS Collaborative Group.
Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens. 2006;24:1201-1208.
18. Arima H, Chalmers J. PROGRESS: prevention of recurrent stroke. J Clin Hyper-
tens (Greenwich). 2011;13:693-702.
19. Ninomiya T, Perkovic V, Gallagher M, et al; PROGRESS Collaborative Group.
Lower blood pressure and risk of recurrent stroke in patients with chronic kidney disease: PROGRESS trial. Kidney Int. 2008;73:963-970.
20. PATS Collaborating Group. Post-stroke antihypertensive treatment study: a
preliminary result. Chin Med J. 1995;108:710-717.
21. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an
angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. N Engl J Med. 2000;342:145-153.
22. Lithell H, Hansson L, Skogg I, Elmfeldt D, Hofman A, Olofsson B; SCOPE Study
Group. The Study on Cognition and Prognosis in the Elderly (SCOPE). Principal results of a randomised double-blind intervention trial. J Hypertens. 2003;21:
875-886.
23. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A; FEVER Study Group. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157-2172.
24. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management
of hypertension: summary of NICE guidance. BMJ. 2011;343:d4891.
Keywords: combination therapy; hypertension; indapamide; perindopril; PROGRESS; stroke
L’ASSOCIATION
FIXE D ’ANTIHYPERTENSEURS EST- ELLE NÉCESSAIRE EN POST-AVC
?
Il est désormais recommandé d’utiliser une association antihypertensive pour la plupart des patients nécessitant un
traitement antihypertenseur. Les patients ayant subi un accident vasculaire cérébral (AVC) forment un groupe particulièrement important pour lequel une association médicamenteuse s’est montrée bénéfique et supérieure. L’étude
PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study) en est la meilleure preuve car elle a clairement
montré qu’un traitement basé sur le périndopril, un inhibiteur de l’enzyme de conversion, auquel est associé un diurétique, l’indapamide, utilisé en fonction des besoins, diminue l’incidence des récidives d’AVC d’environ 25 %. Selon
cette étude, l’association thérapeutique périndopril et indapamide diminue encore plus le risque d’AVC (diminution
de 43 % du risque relatif), ce qui concorde avec l’importante diminution de la pression artérielle obtenue avec cette
association médicamenteuse comparée à celle obtenue avec un seul médicament (12,3/5 mm Hg vs 4,9/2,8 mm Hg).
Une tendance similaire (diminution plus importante avec cette même association médicamenteuse) a été observée
pour tous les autres résultats comme les événements vasculaires majeurs, les événements coronariens, l’insuffisance
cardiaque, l’incapacité, la dépendance, le déclin cognitif et le décès. L’association périndopril et indapamide peut donc
être recommandée pour la prévention des AVC récidivants et des événements cardiovasculaires associés pour tous
les patients atteints de maladie cérébrovasculaire.
432
‘‘
HYPERTENSION
AND
WHERE
Candidates that will best benefit from the combination of an ACE
inhibitor (first line) and a b-blocker
are hypertensive patients with concomitant coronary artery disease.
Patients that have relatively recently had a myocardial infarction and
those with chronic heart failure
and low ejection fraction are likely
to obtain beneficial outcomes that
are predominantly independent of
BP lowering. Patients with angina will also benefit from a symptomatic improvement on top of a
BP-dependent improvement in
prognosis.”
ARE
PREVENTION:
GOING?
W hich patients should
benefit from ACE inhibitor–
b-blocker therapy?
b y K . A m o s ova , U k ra i n e
C
Kateryna AMOSOVA, MD, PhD
Department of Internal Medicine
O. Bogomolets National Medical
University, Kyiv, UKRAINE
andidates that will best benefit from the combination of an angiotensinconverting enzyme (ACE) inhibitor (first line) and a 웁-blocker are hypertensive patients with concomitant coronary artery disease. Patients
with a relatively recent myocardial infarction and those with chronic heart
failure and low ejection fraction are likely to obtain beneficial outcomes with
this combination — predominantly independent of blood pressure lowering —
while patients with angina will gain symptomatic benefits on top of the blood
pressure–dependent improvement in prognosis. The improvement in prognosis, however, is likely to be inferior to that achieved with the use of an ACE inhibitor–dihydropyridine calcium channel blocker combination, due to the inferior central blood pressure reduction that is inherent with heart rate lowering.
Although the combination of an ACE inhibitor and a 웁-blocker appears pathophysiologically to be a sound choice for use in a subset of younger patients
with uncomplicated hypertension, hyperkinetic circulation, and probable hyperreninemia, its hemodynamic effectiveness in such patients is questionable. Moreover, the probability of obtaining a modification in outcomes that is
comparable to that achieved in the ASCOT trial (Anglo-Scandinavian Cardiac
Outcomes Trial) does not appear very high with the use of this combination
because of the heart rate reduction that is inherent with its use. This particular combination approach is only likely to be preferable in hypertensive patients with palpitations and certain arrhythmias who will gain a symptomatic
benefit, and heart rate should not be considered as a therapeutic goal. The
optimal choice of ACE inhibitor–웁-blocker combination is likely to rely on perindopril, which has the largest body of evidence showing outcome benefits in
hypertensive and coronary artery disease patients, and long-acting 웁-blockers such as bisoprolol and nebivolol.
ore than 50% of patients with uncomplicated hypertension require more
than one drug to achieve adequate blood pressure (BP) control.1 This is because of the limited antihypertensive effect of monotherapy, which, on
average, results in reductions of 9.1 mm Hg for systolic BP, and 5.5 mm Hg for
diastolic BP.2 Multiple randomized controlled trials using placebo and active controls, and the majority of meta-analyses, have shown no significant differences in BP
lowering and clinical efficacy between the five main classes of antihypertensive drugs
when used at adequate doses. For this reason, the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) 2007 guidelines stressed that the
M
Prof Kateryna Amosova, Department
of Internal Medicine, O. Bogomolets
National Medical University,
13 Shevchenko Boulevard,
Kyiv 01004, Ukraine (e-mail:
[email protected])
Which patients should benefit from ACE inhibitor–b-blocker therapy? – Amosova
433
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
effect of BP-lowering drugs in reducing the risk of serious
cardiovascular events and all-cause death is virtually entirely
due to BP reduction, and diuretics, b-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE)
inhibitors, and angiotensin receptor blockers (ARBs) should
all be considered as equivalent first-line choices for monotherapy and add-on therapy.3
Are all combinations of first-line drugs equal in
their effectiveness?
In contrast with the arbitrary choices made in many earlier randomized controlled trials using a varied assortment of addon drugs, the design of more recent trials has strictly specified the add-on treatment regimens in all treatment arms. Such
an approach has allowed evidence to be obtained that can be
used to make claims about the comparable efficacy of particular drug combinations. The results of these trials have enabled the ESH and ESC in the 2009 reappraisal of their guidelines to recommend specific combinations for priority use and
to specify certain undesirable or unacceptable combinations
(Figure 1).4 The former includes combinations of renin-angiotensin system (RAS) inhibitors (ACE inhibitors and ARBs) with
a dihydropyridine CCB or diuretic, or a CCB with diuretic, and
the latter would be combination of a b-blocker with diuretic
(undesirable) or an ACE inhibitor with an ARB (unacceptable).
Importantly, the inferiority of the b-blocker/diuretic and ACE
inhibitor/ARB combinations in the landmark trials (LIFE [Losartan Intervention For Endpoint reduction in hypertension study],5
ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial],6 and
Diuretics
AT1-receptor
antagonists
β-Blockers
?
?
α-Blockers
CCBs
?
ACE inhibitors
?
Combinations recommended for priority use
Undesirable combinations
Unproven, yet utilized in “real life” combinations
Unacceptable combinations
Figure 1. Recommendations of the 2009 reappraisal of the European Society of Hypertension (ESH) and European Society of
Cardiology (ESC) regarding optimal drug combinations in patients
with uncomplicated hypertension.
Abbreviations: ACE, angiotensin-converting enzyme; AT1 , angiotensin II type 1;
CCB, calcium channel blocker.
After data from reference 4: Mancia G et al. J Hypertens. 2009;27:2121-2158.
434
ONTARGET [ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial]) was marked not only by
an increased frequency of serious side effects (for the b-blocker/diuretic combination this was mainly new-onset diabetes
and sexual dysfunction; for the ACE inhibitor–ARB combination it was hard renal end points), but also suboptimal clinical efficacy regarding particular BP reduction targets. In LIFE,
combined therapy with a b-blocker and diuretic in high-risk
hypertensive patients was associated with a higher incidence
of stroke compared with an ARB–diuretic combination, despite identical BP control. ASCOT was stopped prematurely
SELECTED
Action in Diabetes and VAscular disease:
Preterax and DiamicroN MR Controlled
Evaluation
ARB
ASCOT
BP
blood pressure
CAFE
Conduit Artery Function Evaluation (substudy
of ASCOT)
CAMIs
Carvedilol Acute Myocardial Infarction Study
CAPRICORN CArvedilol Post-infaRct survIval COntrol in left
ventRicular dysfuNction (trial)
CCB
CIBIS
Cardiac Insufficiency BIsoprolol Study
COMET
Carvedilol Or Metoprolol European Trial
COMMIT
ClOpidogrel and Metoprolol in Myocardial
Infarction Trial
COPERNICUS CarvedilOl ProspEctive RaNdomIzed
CUmulative Survival
ESC
ESH
EUROPA
EURopean trial On reduction of cardiac
events with Perindopril in stable coronary
Artery disease
GEMINI
Glycemic Effects in diabetes Mellitus:
carvedIlol-metoprolol comparisoN In hypertensives (trial)
HOPE
Heart Outcomes Prevention Evaluation
HYVET
LIFE
in hypertension study
MERIT HF
MEtoprolol CR/XL Randomised Intervention
Trial in congestive Heart Failure
NICE
National Institute for Health and Care
Excellence
ONTARGET
ONgoing Telmisartan Alone and in combination
with Ramipril Global Endpoint Trial
RAS
SENIORS
Study of the Effects of Nebivolol Intervention
on Outcomes and Rehospitalisation in
Seniors with heart failure (trial)
ACE
ADVANCE
HYPERTENSION
AND
WHERE
because of significantly higher all-cause mortality in the group
of uncomplicated high-risk hypertension patients treated with
the atenolol–diuretic combination compared with the amlodipine–perindopril combination. This was associated with a higher incidence of coronary events, stroke, and cardiovascular
mortality, which, according to the results of the multivariate
analysis, could only partly be explained by the small average
difference in BP reduction of 2.7/1.9 mm Hg.7
Inferior cardiovascular protection with b-blockers
in hypertension: evidence and reasons
ARE
PREVENTION:
GOING?
shift of its reflection sites in small resistance arteries, absolute
or relative to other therapies. The lack of a positive effect of
b-blockers on artery compliance, and the structural remodeling of small arteries that b-blockers produce—in contrast
with treatment with dihydro-pyridine CCBs and RAS inhibitors
with the same brachial BP-lowering effect—has been demonstrated in several studies.15,16 An important factor influencing
the timing of the retrograde pulse wave return to the thoracic
aorta and central BP is pulse wave velocity, which increases
with aortic wall stiffening in the course of both physiological
and premature vascular aging (eg, in hypertension and diabetes). This forms the theoretical background for the inferior
clinical effectiveness of b-blockers in older hypertensive patients compared with younger ones.
The results of LIFE and ASCOT correspond with the results
of several meta-analyses that have reassessed the cardiovascular protection and safety of b-blockers as a first-line therapy for hypertension.8-10 These have demonstrated that despite antihypertensive therapy based on a b-blocker (mainly Position of the guidelines on the use of b-blockers
atenolol) achieving effective BP reduction compared with plain uncomplicated hypertension
cebo, the b-blocker has no impact on all-cause mortality, coro- Taking into account the suboptimal cardiovascular protecnary events, and stroke. b-Blocker therapy was also shown tion afforded by b-blockers shown in the aforementioned ranto be inferior to therapy with other first-line drugs when taken
domized controlled trials and meta-analyses, as well as the
together, including diuretics, for all-cause mortality and stroke physiological background, the UK National Institute for Health
prevention.8-9 One meta-analysis comparing specific drug and Care Excellence (NICE) and British Hypertension Sociclasses found that b-blockers were inferior
to CCBs for all-cause mortality, stroke, and
Atenolol
Peripheral SBP
total cardiovascular events, and inferior to
Diff mean (AUC) = 0.7 (–0.4,1.7) mm Hg
Amlodipine
10
RAS inhibitors for stroke.
140
135
mm Hg
According to the results of a meta-analysis
by Khan and McAlister that took into account patient age, b-blockers reduced major cardiovascular outcomes in placebocontrolled trials in younger patients but not
in older patients.11 The observed benefits,
however, were less than might be expected given the results of epidemiological studies.12 In active comparator trials, b-blockers were inferior to other therapies for the
composite outcome of stroke, myocardial
infarction, and death, and particularly inferior for stroke in elderly patients, although
not in younger patients.
133.9
133.2
130
125
125.5
120
121.2
Central SBP
Diff mean (AUC) = 4.3 (3.3, 5.4) mm Hg
115
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
AUC
Time (years)
Figure 2. Differences in brachial (peripheral) and aortic (central) systolic blood pressure with use of atenolol/bendroflumethiazide and amlodipine/perindopril combinations in the CAFE substudy of the ASCOT trial.
The principal explanation for the subopti- Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; AUC, area under the curve;
CAFE, Conduit Artery Function Evaluation; SBP, systolic blood pressure.
mal cardiovascular protection afforded by After reference 14: Williams B et al. Circulation. 2006;113:1213-1225. © 2006, Wolters Kluwer Health.
b-blockers compared with other drug classes is the inferiority of their BP-lowering effect on central sys- ety disregarded the 2007 EHS/ESC recommendations3 and
tolic BP despite producing a similar reduction in brachial BP downgraded b-blockers from first-line to fourth-line drugs; eg,
to other antihypertensive drug classes; this has been shown
for use as add-on drugs in patients requiring multiple therain several small studies and was confirmed in the large CAFE
pies.17 Similar recommendations were issued by the South
13,14
trial (Conduit Artery Function Evaluation) (Figure 2).
Ac- African and Australian national hypertension societies,18,19
cording to the results of the multifactorial analysis of the CAFE
while the Canadian Hypertension Society excluded b-blockdata, this inferiority is mainly due to their heart rate–reducing
ers from the list of first-line drugs for patients with diastolic or
effect, which enables reflected pulse waves to return to the systolo-diastolic hypertension aged less than 60 years and
thoracic aorta well before the end of left ventricular systole. for all patients with isolated systolic hypertension.20 These disSuch pulse wave dyssynchrony is facilitated by a proximal crepancies between the opinions of leading experts regarding
435
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
the role of b-blockers in therapy for uncomplicated hypertension highlight their disagreement on how to interpret the available data and the need for new, specially planned, randomized controlled trials.
Combination of ACE inhibitors and b-blockers in
uncomplicated hypertension: expected benefits
and risks
Are there grounds for speculating that combining b-blockers
with drug classes other than diuretics (primarily ACE inhibitors) as a cornerstone of cardiovascular prevention may have
potential benefits, at least in certain subgroups of patients,
eg, younger patients? The combination of b-blocker with ACE
inhibitor is very often used empirically in clinical practice for
younger patients with a tendency toward a higher heart rate;
eg, obese patients with the metabolic syndrome.
reduction in systolic BP to that of CCBs (–16 mm Hg versus
–18.5 mm Hg), and tended to be more effective than therapy with ARBs. However, diastolic BP reduction with ACE inhibitors was inferior to that with CCBs (–4.9 mm Hg versus
–9.3 mm Hg; P<0.05) and similar to that with ARBs. The small
sample size did not allow for analysis of the results in subpopulations; eg, younger or older patients. Thus, the question of
the existence of additive antihypertensive effects with the ACE
inhibitor–b-blocker combination in younger hypertensive patients remains open to debate.
A separate comment deserves to be made on the appropriateness of heart rate control as one of the possible therapeutic goals of add-on treatment with b-blockers in younger
patients with uncomplicated hypertension. It has become a
clinical convention to consider heart rate as a universal risk
factor, whose pharmacological slowing, eg, with b-blockers,
invariably produces an improvement in outcome. Yet, in contrast with post–myocardial infarction or chronic heart failure
patients (ejection fraction <40%),25,26 this contention appears
to be wrong for the hypertensive patient; this is despite a multitude of observational data showing a tight association between heart rate and the cardiovascular and all-cause mortality rate in this patient population, similar to that observed
in patients with coronary artery disease or chronic heart fail-
The pathophysiology of hypertension in younger people, especially those with short anamnesis, is different from that in
older people. Sympathetic activation plays an important role
in its development, causing high cardiac output and hyperdynamic circulation, as well as mediation of higher renin release via b receptors on the kidney juxtaglomerular cells. It
is reasonable to speculate that treating such a subset of patients who have hyperkinetic circulation (and probably also
normokinetic circulation) with an ACE inhibitor–b-blocker combination could produce
No. events/patients
additive antihypertensive effects: the lowHeart
Atenolol
Amlodipine
rate
categories
ering of cardiac output and inhibition of renin
release produced by the b-blocker would
110/678
<60 bpm
116/640
combine with the ACE inhibitor neutraliza203/1596
60 to <70 bpm
277/1689
tion of the undesirable vasoconstrictive ef245/1847
287/1799
70 to <80 bpm
fects and insulin resistance amplification pro21
166/1115
80
to
<90
bpm
185/1080
duced by the b-blocker. Yoneda et al and
22
69/552
90+ bpm
91/544
Holmer et al demonstrated that the reactive increase in renin blood concentrations
in hypertensive patients starting treatment
793/5788
Overall
956/5732
with ACE inhibitors was largely prevented
Interaction
by concomitant treatment with b-blockers.
P value = 0.91
0.5
0.8 1 1.2
The hemodynamic effectiveness and clinical
Amlodipine better
Atenolol better
implications of such an interaction remain
Hazard ratio and 95% CI (log scale)
to be demonstrated.
Figure 3. Relationship between cardiovascular events and baseline heart rate in the
One small prospective study in patients with ASCOT trial.
mild to severe hypertension found that the Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; bpm, beats per minute; CI, conficombination of a b-blocker with an ACE in- dence interval.
After reference 29: Poulter NR et al. J Am Coll Cardiol. 2009;54:1154-1161. © 2009, Elsevier.
hibitor lowered diastolic BP significantly more
than monotherapy (–20 mm Hg versus –10 mm Hg), while the ure.27,28 However, the fallacy of this contention can be seen in
lowering of cardiac output and elevation of vascular resistance
the results of ASCOT, wherein amlodipine–perindopril treatproduced by the b-blockers was attenuated by addition of the ment was superior to atenolol–diuretic therapy for modificaACE inhibitor.23 A more recent retrospective database analytion of outcomes, despite a higher mean on-treatment heart
sis by Bisognano et al24 in patients treated with b-blockers rate in the amlodipine–perindopril group. The magnitude of
who were matched for baseline characteristics (n=660; mean this positive effect did not differ in the subgroups with a basal
age 66 years; basal BP 156/88 mm Hg) showed that add-on heart rate ranging from <60 beats per minute to >90 beats per
minute (Figure 3).29
therapy with ACE inhibitors produced a more-or-less similar
436
HYPERTENSION
AND
WHERE
ARE
PREVENTION:
GOING?
Based on this reasoning, I consider it inappropriate to use an ACE inhibitor–b-blocker combination in older patients with uncontrolled uncomplicated hypertension, and
Figure 5. Risk of nonfatal myocardial
infarction as a function of heart rate.
Relative risk of nonfatal myocardial infarction as a function
of heart rate achieved at the end of the study in the
웁-blocker group. The diameter of the circles represents
the weight of each individual trial.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; bpm, beats per minute; ELSA, European
Lacidipine Study on Atherosclerosis; HAPPHY, Heart
Attack Primary Prevention in Hypertension; INVEST, International Verapamil SR and Trandolapril study; IPPSH,
International Prospective Primary Prevention Study in
Hypertension; LIFE, Losartan Intervention for End point
Reduction trial; VACS, Veterans Administration
Cooperative Study Group on Antihypertensive Agents.
After reference 30: Bangalore S et al. J Am Coll Cardiol.
2008;52:1482-1489. © 2008, Elsevier.
0.4
0.2
Yurenev
0.0
60
62
64
66
68
70
72
74
Heart rate at trial end-beta blocker group (bpm)
Figure 4. Cardiovascular mortality risk as a function of heart rate.
Relative risk of cardiovascular mortality as a function of heart rate achieved at the end of the study in
the 웁-blocker group. The diameter of the circles represents the weight of each individual trial.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; bpm, beats per minute; ELSA,
European Lacidipine Study on Atherosclerosis; HAPPHY, Heart Attack Primary Prevention in Hypertension; INVEST, International Verapamil SR and Trandolapril study; IPPSH, International Prospective Primary Prevention Study in Hypertension; LIFE, Losartan Intervention for End point Reduction trial.
After reference 30: Bangalore S et al. J Am Coll Cardiol. 2008;52:1482-1489. © 2008, Elsevier.
1.5
r= –0.8486, P=0.00001
y= 2.5794 – 0.0235 x
VACS (1982)
Relative risk of myocardial infarction
This finding can be explained by the important negative impact of central systolic and
pulse BP elevation that occurs with pharmacological heart rate lowering, even in patients younger than age 60 years with systolo-diastolic hypertension, and probably in
the absence of significant aorta stiffening.
Thus, in hypertensive patients without recent
myocardial infarction or chronic heart failure
with low ejection fraction, even in younger
patients, heart rate control should not be
considered a therapeutic goal.
Relative risk of cardiovascular death
The negative impact on the prognosis of hypertensive pa- think that we should be careful when adding b-blockers to
tients of heart rate reduction with b-blockers used as first- ACE inhibitors (particularly regarding dosing) in younger paline therapy was convincingly shown by the results of a meta- tients (in whom it would probably be for hyperreninemia corregression analysis performed by Bangalore et al.30 Exclusion rection). In my opinion, the safest candidates are patients with
concomitant symptomatic tachycardia, and on-treatment restcriteria were previous acute myocardial infarction and chronic heart failure, but not chronic coronary artery disease. Par- ing heart rate should be as high as tolerated, in no case less
adoxically, the heart rate lowering attained in the b-blocker than 70 beats per minute (better, 75 beats per minute). The
group at study end was associated with a proportionate use of nonpharmacological approaches should strongly be
recommended as a priority for heart rate reduction in such parise in all-cause mortality (r= –0.51), cardiovascular mortality
(r=–0.61) (Figure 4), and myocardial infarction rates (r=–0.85; tients with inappropriate tachycardia; ie, regular aerobic trainall P<0.0001) (Figure 5). The same was true when the differing and correction of excessive body mass.
ence in heart rate at study end between
the two treatment modalities was compared
2.2
with the relative risk reduction for these
ELSA
r= –0.6133, P=0.00001
2.0
events. Importantly, the average age of the
y= 3.5913 – 0.0375 x
patients was 58 years and the mean basal
1.8
diastolic BP was 100 mm Hg. One can thus
1.6
ASCOT
conclude that contrary to the situation in
1.4
LIFE
post–myocardial infarction and chronic heart
INVEST
1.2
failure patients with low ejection fraction, in
1.0
hypertensive patients, heart rate elevation
HAPPHY
can be considered a risk marker but not a
0.8
IPPPSH
risk factor.
0.6
1.4
1.3
Yurenev
ASCOT
1.2
HAPPHY
1.1
INVEST
1.0
LIFE
ELSA
0.9
IPPPSH
0.8
60
62
64
66
68
70
72
74
Heart rate at trial end-beta blocker group (bpm)
437
HYPERTENSION
WHERE
ARE
AND
PREVENTION:
GOING?
Clinical situations favoring ACE inhibitor–b-blocker
combination therapy
In hypertensive patients, the principal indication for combined
ACE inhibitor–b-blocker therapy is concomitant coronary artery disease. According to the results of a recent meta-analysis by Law et al,2 compared with placebo or no treatment,
b-blocker–based antihypertensive therapy was highly effective in reducing coronary events, chiefly when given within 4
months of an acute myocardial infarction (29% relative risk
reduction; P<0.001). However, in hypertensive coronary artery disease patients without recent myocardial infarction or
any myocardial infarction, it was only associated with a tendency toward risk reduction compared with placebo (relative
risk 0.87; 95% confidence interval, 0.71-1.06) and did not
show any benefits in terms of coronary event prevention compared with the other drug classes. Clearly, the pronounced
relatively short-term preventive effect of b-blockers in hypertensive patients with recent myocardial infarction (up to 2 years
after myocardial infarction) goes mostly beyond BP lowering
and is due to their postinfarction protective effect, because
in this particular clinical situation, the very high cardiovascular
risk is mainly associated with the recent myocardial infarction. The same presumably holds true for the modification of
prognosis seen in hypertensive patients with concomitant
chronic heart failure and low ejection fraction who are treated with b-blockers. Aside from these situations, it is appropriate to consider the ACE inhibitor–b-blocker combination
as the combination of choice for hypertensive patients with
angina, or certain arrhythmias, for symptomatic improvement,
if not modification of prognosis.31 However, for patients with
angina, dihydropyridine CCB add-on therapy would be a
better alternative for improvement of outcomes.
Choosing ACE inhibitors and b-blockers
Let us elaborate on which particular ACE inhibitor and b-blocker molecules might be considered as the optimal choices in
a fixed-dose combination that could be a useful addition to
the existing arsenal of fixed-dose combination antihypertensive drugs.
u Trial-based evidence of improvement in outcomes
with certain drugs in certain clinical situations (possible
“drug effects”)
In the ACE inhibitor drug class, perindopril has the largest
body of evidence for prognosis modification in hypertensive
patients, both from randomized placebo-controlled trials
(ADVANCE [Action in Diabetes and VAscular disease: Preterax
and DiamicroN MR Controlled Evaluation], HYVET [HYpertension in the Very Elderly Trial], etc) and active comparator
trials (ASCOT).
Perindopril and ramipril are the only ACE inhibitors to have
demonstrated a cardioprotective effect, in the landmark placebo-controlled EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease)
438
and HOPE trials (Heart Outcomes Prevention Evaluation). Participants in these trials were chronic coronary artery disease
patients, including those post–myocardial infarction, more
than half of whom had concomitant hypertension with satisfactory, but not optimal, BP control.
In the modern reperfusion era, the evidence-based b-blockers for the post–myocardial infarction patient are carvedilol
(CAPRICORN [CArvedilol Post-infaRct survIval COntrol in
left ventRicular dysfuNction]) and metoprolol succinate XL
(COMMIT [ClOpidogrel and Metoprolol in Myocardial Infarction Trial]). For patients with chronic heart failure with low
ejection fraction, in addition to carvedilol and metoprolol XL
(COPERNICUS [CarvedilOl ProspEctive RaNdomIzed CUmulative Survival] and MERIT HF [MEtoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure]), there
is also bisoprolol (CIBIS-II [Cardiac Insufficiency BIsoprolol
Study]). Nebivolol demonstrated a benefit versus placebo in
the SENIORS study (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with
heart failure),32 which recruited elderly chronic heart failure patients with any level of ejection fraction—low as well as preserved—but nebivolol did not reduce mortality. For patients
with uncomplicated coronary artery disease, we do not yet
have evidence that any b-blocker treatment can improve
prognosis. Although claims have been made that the pharmacodynamic advantages of the third-generation b-blockers
(carvedilol and nebivolol) might transform into certain benefits in outcomes,9 as occurred for carvedilol versus metoprolol tartrate in chronic heart failure patients in the COMET trial (Carvedilol Or Metoprolol European Trial),33 this is not very
likely. The CAMIS trial (Carvedilol Acute Myocardial Infarction
Study)34 did not show any superiority for carvedilol over atenolol
in patients with acute coronary syndrome and a mean ejection fraction of 54%; moreover, the aforementioned COMET
trial was subjected to serious criticism.
u Evidence of pharmacodynamic advantages
Considering the importance of optimal dual RAS inhibition
and nitric oxide production for an ACE inhibitor, at least in
terms of coronary event prevention, perindopril might be considered a drug of choice owing to it having the highest selectivity for bradykinin versus angiotensin I binding sites in its
drug class.35
In terms of b-blockers, two small studies in hypertensive patients found that, for an equivalent lowering of brachial BP,
therapy with nebivolol was associated with a greater reduction in aortic pulse pressure and a superior impact on the
augmentation index than atenolol treatment. This was probably due to the reduction of wave reflection with nebivolol as
a result of vasodilation of resistant arteries, as well as higher
on-treatment heart rates.36,37 One might expect the same from
carvedilol. I share the opinion of Sever and Messerli,38 however, that this complimentary effect of the newer b-blockers
HYPERTENSION
AND
WHERE
is unlikely to significantly improve clinical outcomes with fulldose b-blocker therapy in hypertensive patients, because
heart rate reduction per se is the cornerstone of the suboptimal effect of b-blockers on central BP, as well as on BP variability.39 The latter, in addition to central BP, is considered to be
a strong predictor of both stroke and myocardial infarction
in hypertensive patients,40 and there is no evidence that the
newer generation of b-blockers improves BP variability.41
u Evidence of advantages in tolerability
In hypertensive patients with diabetes, the GEMINI trial (Glycemic Effects in diabetes Mellitus: carvedIlol-metoprolol comparisoN In hypertensives) showed a decrease in insulin resistance after treatment with carvedilol, but not metoprolol.42
The latter produced an increase in glycosylated hemoglobin
levels from baseline, whereas the levels did not change over
the course of therapy with carvedilol.42 A similar advantage regarding metabolic control in hypertensive patients without con-
ARE
PREVENTION:
GOING?
comitant diabetes was shown for nebivolol versus atenolol in
a study by Poirier et al.43 This can be at least partly explained
by the peripheral vasodilatory properties that are unique to
both of these third-generation b-blockers.
u Evidence of pharmacokinetic advantages
In terms of pharmacokinetic advantages, perindopril is preferable to several other ACE inhibitors, including ramipril, and
bisoprolol and nebivolol are preferable to carvedilol.
In conclusion, the optimal choice of drugs is likely to be: (i)
perindopril, as it has the largest body of evidence showing
beneficial outcomes in hypertensive and coronary artery disease patients; and (ii) long-acting b-blockers such as bisoprolol that have evidence of mortality reduction in post–myocardial infarction and heart failure patients. Nebivolol could also be
considered due to its advantages in terms of metabolic control and pulse wave reflection, which is associated with relatively mild heart rate lowering and peripheral vasodilation. n
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24. Bisognano JD, McLaughlin T, Roberts CS, Tang SS. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: effectiveness in combination with diuretics or b-blockers for treating
hypertension. Vasc Health Risk Manag. 2007:3:579-585.
25. Cucherat M. Quantitative relationship between resting heart rate reduction and
magnitude of clinical benefits in post-myocardial infarction: a meta-regression of randomized clinical trials. Eur Heart J. 2007;28:3012-3019.
26. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers.
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PREVENTION:
GOING?
Am J Cardiol. 2008;101:865-869.
27. Gillman MW, Kannel WB, Belanger A, D'Agostino RB. Influence of heart rate
on mortality among persons with hypertension: the Framingham Study. Am
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mortality in a French population: role of age, gender, and blood pressure. Hypertension. 1999;33:44-52.
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30. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker induced heart
rate lowering and cardioprotection in hypertension. J Am Coll Cardiol. 2008;
52:1482-1489.
31. Fox K, Garcia MA, Ardissino D, at al; Task Force on the Management of Stable
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32. Flather MD, Shibata MC, Coats AJ; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital
admission in elderly patients with heart failure (SENIORS). Eur Heart J.
2005;26: 215-225.
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metoprolol on clinical outcomes in patients with chronic heart failure in the
Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.
Lancet. 2003;362:7-13.
34. Jonsson G, Abdelnoor M, Muller C, Kjeldsen SE, Os I. A comparison of the two
beta-blockers carvedilol and atenolol on left ventricular ejection fraction and clinical end points after myocardial infarction: a single-centre, randomized study
of 232 patients. Cardiology. 2005;103:148-155.
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sites of human somatic ACE. Eur J Pharmacol. 2007;577:1-6.
36. Dhakam Z, McEniery YC, Burton T, et al. A comparison of atenolol and nebivolol
in isolated systolic hypertension. J Hypertens. 2008;26:351-356.
37. Mahmud A, Feely J. Beta-blockers reduce aortic stiffness in hypertension, but
nebivolol, not atenolol, reduces wave reflection. Am J Hypertens.
2008;21:663-667.
38. Sever PS, Messerli FH. Hypertension management 2011: optimal combination
therapy. Eur Heart J. 2011;32:2499-2506.
39. Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug
class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010;375:906-915.
variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895-905.
41. Dolan E, O’Brien E. Blood pressure variability: clarity for clinical practice. Hypertension. 2010;56:179-181.
42. Bakris GL, Fonseca V, Katholi RE, et al; GEMINI Investigators. Metabolic effects
of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004;292:2227-2236.
43. Poirier L, Cleroux J, Nadeau A, Lacourcière Y. Effects of nebivolol and atenolol
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Keywords: ACE inhibitor; 웁-blocker; cardiovascular outcome; combination therapy; hypertension
POUR
QUELS PATIENTS UN TRAITEMENT
IEC-b-BLOQUANT
PEUT- IL ÊTRE BÉNÉFIQUE
?
Les patients qui sont à la fois hypertendus et coronariens sont les meilleurs candidats pour recevoir l’association d’un
inhibiteur de l’enzyme de conversion de l’angiotensine (IEC) (en première intention) et d’un 웁-bloquant. Les patients
ayant eu récemment un infarctus du myocarde et ceux atteints d’insuffisance cardiaque chronique et ayant une fraction d’éjection ventriculaire basse devraient bénéficier de cette association (indépendamment de l’abaissement de
la pression artérielle). Les patients angineux auront, eux, des bénéfices symptomatiques en plus de l’amélioration du
pronostic lié à la pression artérielle. Cependant, cette amélioration est probablement moindre que celle obtenue avec
une association IEC-antagoniste calcique dihydropyridinique, la réduction de la pression centrale étant inférieure,
ce qui est inhérent au ralentissement de la fréquence cardiaque. Bien que l’association IEC-웁-bloquant semble un
choix physiopathologiquement pertinent dans le cas d’un sous-groupe de patients jeunes ayant une hypertension
non compliquée, une circulation hypercinétique et une éventuelle hyperréninémie, son efficacité hémodynamique
chez de tels patients reste discutable. De plus, la probabilité d’obtenir des résultats comparables à ceux obtenus
dans l’étude ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) ne semble pas très élevée avec cette association
étant donné la réduction de la fréquence cardiaque inhérente à son utilisation. Il semble que cette association particulière ne soit préférable que chez des hypertendus ayant des palpitations et certaines arythmies, qui en tireront
des bénéfices symptomatiques. La fréquence cardiaque ne doit pas être considérée comme un but thérapeutique
en soi. Il est probable que l’association optimale IEC-웁-bloquant repose, d’une part, sur le périndopril, l’IEC pour
lequel il existe le plus grand nombre de preuves d’effets bénéfiques chez les hypertendus et les coronariens, et
d’autre part, sur les 웁-bloquants d’action prolongée comme le bisoprolol et le nébivolol.
440
THE QUESTION
ypertension guidelines have
been increasingly recommending fixed-dose multiple-drug combinations to achieve
adequate blood pressure control
and cardiovascular prevention.
These combinations are more effective due to their complementary
and synergistic effects, and safer
since they are associated with fewer side effects due to the reduced
dosages of individual agents. Are
such combinations restricted to
secondary prevention, or are there
situations in which they should
also be used in primary prevention?
CONTROVERSIAL
QUESTION
H
Multiple-drug combinations
in hypertension and
cardiovascular prevention:
should they be used in primary
or secondary prevention?
1.
M. Alami, Morocco
2.
C. Amodeo, Brazil
3.
I. Attia, Egypt
4.
M. Bastos, Portugal
5.
A. Bhagwat, India
6.
K. J. Filipiak, Poland
7.
R. O’Hanlon, Ireland
8.
E. J. Ramos, Philippines
9.
H. A. Remah Mohammed, Saudi Arabia
10 .
M. Rizzo, Italy
11.
R. S. Tan, Singapore
12 .
S. L. Tokgozoglu, Turkey
13 .
M. Vrablik, Czech Republic
Multiple-drug combinations for primary or secondary prevention in hypertension?
441
CONTROVERSIAL
QUESTION
1. M. Alami, Morocco
Mohamed ALAMI, MD
Professor of Cardiology
Ghandi Cardiology Center
264 Boulevard Ghandi
Residence Jawhara, Apartment 9
Casablanca, BP 20200
MOROCCO
C
ardiovascular prevention is “sick” and the prognosis
is bad in developing countries: by 2020, 80% of cardiovascular mortality will occur in low- and middle-income countries. One optimistic solution is the multiple-drug
combination or polypill. Combining two or three blood pressure–lowering drugs and a statin and aspirin in the same pill
should improve adherence and reduce cost. In terms of primary prevention, the initial concept was “a polypill for all, starting at age 55,” with no screening and no monitoring. In theory, this strategy would reduce heart attacks and strokes by
more than 80%.1 In practice, putting apparently healthy people on a polypill with the risk of adverse events (from four to five
drugs) and no proven benefit on mortality is not at all convincing at this time. In addition, it seems wiser to advise people to
improve their diet and exercise than to rely on pills. Several trials have used a polypill in people without cardiovascular disease but with moderate to high risk. The TIPS study (The Indian Polycap Study) evaluated the use of a polypill in people with
one risk factor.2 The effect of simvastatin was lower than expected, but the polypill formulation reduced multiple risk factors and the global cardiovascular risk. A feasibility study by the
World Health Organization showed a reduction in systolic blood
pressure, total cholesterol, and 10-year risk of cardiovascular
disease with use of a multiple-drug combination, which was
highly accepted by physicians and study individuals.3 The PILL
pilot trial (Program to Improve Life and Longevity) used a polypill with aspirin (75 mg), lisinopril (10 mg), hydrochlorothiazide
(12.5 mg), and simvastatin (20 mg) in individuals with a Framingham score of more than 7.5% at 5 years. There was a significant reduction in blood pressure and cholesterol, but side
effects were present in about 1 in 6 people. TIPS-3 is evaluating the polypill without aspirin versus placebo in 5000 individuals without cardiovascular disease over 5 years.
In secondary prevention, proven therapies are underused (80%
of patients in developing countries do not receive any preventive drug),4 and long-term adherence to treatment is low (of-
442
ten less than 50% in developed countries). A combination of
four drugs—aspirin, 웁-blocker, statin, and angiotensin-converting enzyme (ACE) inhibitor—should, in theory, reduce vascular events by 75% in those with prior vascular disease. This
approach has been established as being cost-effective in developing countries. However, in practice, is there any level of
evidence of a reduction in events in patients with vascular disease with the use of such a polypill? TIPS-2 compared the
use of high doses with low doses (used in TIPS) of the polypill components in patients with previous vascular disease. The
study showed a more effective reduction in blood pressure
and cholesterol with the high doses. The ongoing FOCUS trial (Fixed-dOse Combination drUg for Secondary cardiovascular prevention) is assessing adherence and access to the
polypill (aspirin, ACE inhibitor, statin) in 4000 post–myocardial infarction patients. SPACE (Single Pill to Avert Cardiovascular Events) is a collaboration of ongoing trials assessing the
role of multiple-drug combinations mainly in patients with
vascular disease: UMPIRE (Use of a Multidrug Pill In Reducing cardiovascular Events), IMPACT (IMProving Adherence
using Combination Therapy), KANYINI-GAP (Kanyini Guidelines Adherence with the Polypill) and similar studies will collectively enroll around 7000 people. Data on safety and adherence, blood pressure– and cholesterol-lowering efficacy,
and mortality, will be decisive.
In conclusion, multiple-drug combination will probably get its
“approval” soon in secondary prevention. For primary prevention, the debate will last longer and has already raised a
crucial question for the medical community. “Firefighting” cardiovascular diseases: should we add more water (pills) or stop
the fuel (risk factors)? Please, answer…and act! ■
References
1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than
80%. BMJ. 2003;326:1419-1424.
2. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS). Effects of a polypill
(Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373:13411351.
3. Soliman EZ, Mendis S, Dissanayake WP, et al. A polypill for primary prevention
of cardiovascular disease: a feasibility study of the World Health Organization.
Trials. 2011;12:3.
4. Yusuf S, Islam S, Chow CK, et al; Prospective Urban Rural Epidemiology (PURE)
Study Investigators. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE study): a prospective epidemiological survey. Lancet. 2011;
378:1231-1243.
CONTROVERSIAL
QUESTION
2. C. Amodeo, Brazil
Celso AMODEO, MD
Head of Hypertension and
Nephrology Division
Institute Dante Pazzanese of Cardiology
São Paulo, BRAZIL
H
ypertension is a major independent risk factor for the
development of coronary artery disease, stroke, and
renal failure. Systolic blood pressure (BP) above 115
mm Hg explains 60% of the population-attributable stroke
risk.1 Cardiovascular risk in hypertension can be diminished
with multidrug antihypertensive therapy. The major reductions in cardiovascular morbidity and mortality over the past
50 years have been attributed mainly to increased availability and combined utilization of various antihypertensive drugs.
Randomized trials have shown that BP lowering produces
rapid reductions in cardiovascular risk.2 Moreover, it appears
that some drug classes may have additional cardiovascular
protective effects beyond BP reduction. Studies such as HOPE
(Heart Outcomes Prevention Evaluation)3 and EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril
in stable coronary Artery disease)4 have shown a beneficial
effect of angiotensin-converting enzyme (ACE) inhibitors on
cardiovascular risk in hypertensives and nonhypertensives,
indicating that the protective effect of ACE inhibition could be,
in part, independent of BP reduction. Antihypertensive medications should thus be selected not only for their potential
to reduce BP, but also for potential effects on concomitant
diseases and other cardiovascular risk factors.
Hypertension treatment aims to prevent associated morbidity and mortality through reduction of BP and cardiovascular
risk status. Multiple-drug therapy implies the use of lower doses of several antihypertensive classes. This not only offers the
possibility of greater therapeutic efficacy, but also a reduced
incidence of side effects.
Stroke is the most serious complication of hypertension and
better BP control is the only way to avoid stroke. A reduction
of 5 to 6 mm Hg in diastolic BP maintained over 5 years was
shown to reduce the incidence of stroke by 40%.5 In the Chinese PATS study (Post-stroke Antihypertensive Treatment
Study), patients with previous stroke history were treated with
2.5 mg/day of indapamide or placebo. After 2 years, indapamide decreased BP by 5 mm Hg systolic and 2 mm Hg diastolic and reduced stroke recurrence by 29% ( P=0.0009).6
In the PROGRESS study (Perindopril pROtection aGainst REcurrent Stroke Study), patients in the active treatment group
received perindopril (4 mg/day) alone or together with inda-
pamide (2.5 mg/day). Combination therapy lowered systolic
and diastolic BP by 12.3 mm Hg and 5.0 mm Hg, respectively, and reduced stroke recurrence by 43% (P<0.001). Perindopril monotherapy lowered BP by 5.0 mm Hg systolic and
2.0 mm Hg diastolic, but the relative risk reduction was only
4% (95% confidence interval, 19% to 23%).
Because hypertension control generally requires more than
one medication, particularly in patients with comorbid conditions, choosing a “first-line” agent may be less important than
identifying beneficial combinations for an individual patient. The
presence of “compelling indications” may necessitate treatment with antihypertensive agents that have demonstrated a
particular benefit in primary or secondary prevention. The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure
recommends diuretics and ACE inhibitors for secondary stroke
prevention. In a study evaluating angiotensin receptor blockers (ARBs) versus calcium channel blockers for secondary
stroke prevention, two-thirds of patients in both treatment arms
required at least one additional agent to achieve adequate BP
lowering. Despite equivalent BP lowering in both groups, patients in the ARB-based treatment group had lower stroke
incidence (absolute risk reduction, 8%; number needed to
treat, 12.5).
Multiple-drug combination has the added advantage of less
need to switch medications. Initial management with combination therapy should be considered in patients whose BP is
>20 mm Hg above systolic goal or >10 mm Hg above diastolic goal. The optimal choice of multiple antihypertensives remains controversial as doubts remain regarding the mechanisms of beneficial treatment effects: are they simply a function
of BP-lowering, or do certain drug classes exert protective effects in addition to lowering BP? ■
References
1. Lawes CM, Vander HS, Law MR, Elliott P, MacMahon S, Rodgers A. Blood
pressure and the global burden of disease 2000. Part II: estimates of attributable
burden. J Hypertens. 2006;24:423-430.
2. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists’
Collaboration. Effects of ACE inhibitors, calcium antagonists, and other bloodpressure-lowering drugs: results of prospectively designed overviews of randomized trials. Lancet. 2000;356:1955-1964.
3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in highrisk patients: the Heart Outcomes Prevention Evaluation Study. N Engl J Med.
2000;342:145-153. [Published correction in N Engl J Med. 2000;342:1376].
4. Fox KM; European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of
cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet. 2003;362:782-788.
5. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and
the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272-298.
6. PATS Collaborative Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J. 1995;108:710-717.
443
CONTROVERSIAL
QUESTION
3. I. Attia, Egypt
Ihab ATTIA, MD, FSCAI
92 El Tahrir Street
Dokki, Giza
EGYPT
A
lthough primary prevention measures are a key component of any public health strategy to reduce the burden of cardiovascular disease, a large proportion of
potential candidates do not receive adequate treatment. Defective prescription of medication, noncompliance with treatment, side effects, and unaffordable costs are some of the
causes of this treatment gap. Fixed-dose combination therapy
can overcome most of these issues. Poor compliance with
drug treatment is related to social, psychological, economic,
and clinical factors. Advanced age, psychiatric disorders, and
complexity of treatment have been repeatedly identified as
predictors of poor compliance, and there is a clear correlation
with the number of pills a patient needs to take daily.1
These factors led to the concept of a multidrug combination
with the potential to improve the management of cardiovascular risk factors. However, arguments against multidrug combinations have been that the estimated risk reduction could
be too optimistic, that many patients will remain undertreated,
and that patient and doctor acceptability will be less than expected. An additional source of concern is the potential adverse effects related to some of the components of cardiovascular multidrug combinations such as aspirin (gastrointestinal
complications). Adverse effects from one or more of the drugs
could lead to discontinuation of treatment and, therefore, loss
of the benefit of all the other drugs included in the formulation.
Furthermore, the need for the efficacy of a multidrug combination in primary prevention remains to be proven in large,
randomized trials before it can be accepted in clinical practice.
In addition, the pharmaceutical development of a cardiovascular multidrug combination presents several unique challenges, including the selection of components and doses, the
444
type of pharmaceutical formulation, and regulatory problems.
From a formulation development standpoint, an almost linear relationship exists between the number of active components in a multidrug combination and the technical problems
of formulation development. The association of different drugs
in a single pharmaceutical dosage form may have an effect
on the physicochemical properties of each and every individual component. In fact, increasing the number of active
components in a multidrug combination also increases the
likelihood of interactions between them.2
On the other hand, when it comes to secondary prevention in
hypertension, a meta-analysis of four hypertension trials published in 2007 by Bangalore et al showed that fixed-dose
combination therapy decreased the risk of medication noncompliance by 24% compared with conventional treatment.3
Pan et al have also shown a 29% improvement in treatment
adherence with a fixed-dose combination treatment in patients
with hypertension.4
Thus, it appears that combination therapy for primary cardiovascular prevention is not yet ready for widespread use; but
for secondary prevention in hypertension, combination therapy with two or more agents in a fixed-dose combination pill
will help most patients with hypertension to reach their target
blood pressure and reduce morbidity. In many cases, combination therapy improves rates of blood pressure control and
requires less time to achieve target blood pressure, with equivalent or better tolerability than higher-dose monotherapy. Additional benefits may include cost savings and better compliance. ■
References
1. Bosworth HB. Medication treatment adherence. In: Bosworth HB, Oddone EZ,
Weinberger M, eds. Patient Treatment Adherence. New York, NY: Routledge;
2006:147-194.
2. Sleight P, Pouleur H, Zannad F. Benefits, challenges, and registerability of the polypill. Eur Heart J. 2006;27:1651-1656.
3. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120:
713-719.
4. Pan F, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on
adherence to prescription medications. J Gen Intern Med. 2008;23:611-614.
CONTROVERSIAL
QUESTION
4. M. Bastos, Portugal
Mesquita BASTOS, MD
Department of Cardiology
Escola Superior de Saúde da
Universidade de Aveiro
Aveiro, PORTUGAL
A
rterial hypertension is the most prevalent risk factor
for cardiovascular (CV) disease in developed countries.1 With the exception of the USA and Canada,
arterial hypertension is characterized by a low percentage of
controlled patients. A recent observational study carried out
by the Portuguese Society of Hypertension, the PHYSA study
(Portuguese HYpertension and SAlt), concluded that 42.2%
of the adult Portuguese population has arterial hypertension
and that 55.7% of these patients have uncontrolled hypertension.2 When the Portuguese population was analyzed for
CV risk, 43.9% had moderate-to-high risk. Polońia et al analyzed the CV risk of Portuguese hypertensive patients using
the criteria of the European Society of Hypertension (ESH)/European Society of Cardiology (ESC),1 and found that 73.4%
of hypertensive patients attending primary care centers and
83.9% of hypertensive patients attending hospitals had moderate-to-very-high CV risk.3 According to the 2007 ESH/ESC
hypertension guidelines,1 those who are at least at moderate
CV risk should commence antihypertensive treatment, possibly with a low fixed-dose combined medication. In PHYSA,
56.4% of controlled patients were treated with two or more antihypertensive medications. Of these, 65% were fixed combinations.2
Fixed combinations enhance treatment compliance, as shown
by a meta-analysis of nine studies using fixed combinations,
which demonstrated a 24% reduction in noncompliance compared with the use of free drug combinations.4 Another advantage of fixed combinations is better blood pressure control,
as shown in the open-label AVANT’AGE study (Age VAsculaire
et risque résiduel chez l’hyperteNdu TrAité vu en médicine
GénéralE), which analyzed 7032 patients with hypertension
whose blood pressure was not at goal and for whom general practitioners had the intention of modifying their treatment.5
A fixed combination of perindopril plus amlodipine was added
for 6256 patients, which resulted in the majority of patients
meeting the criteria for controlled hypertension (74.4% for
systolic or diastolic values, 63.3% for both). Since the sooner
blood pressure control is reached, the better in terms of CV
prognosis,6 fixed combinations can have added value. A posthoc analysis of the VALUE study (Valsartan Antihypertensive
Long-term Use Evaluation) suggested that the earlier blood
pressure control was achieved, the lower the incidence of CV
events.6 If drugs that act through different pathways are used
simultaneously, the probability of achieving hypertension control is higher. With fixed combinations, classes of drugs with
complementary mechanisms of action can be used (eg, reninangiotensin system inhibitors and calcium antagonists).
Multiple-drug combinations are indicated in primary prevention, as shown by the trials ACCOMPLISH (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with
Systolic Hypertension), ASCOT (Anglo-Scandinavian Cardiac
Outcomes Trial), and HYVET (HYpertension in the Very Elderly
Trial) (reviewed in reference 6). HYVET showed that a combination of an angiotensin-converting enzyme (ACE) inhibitor
with indapamide decreased stroke and heart failure incidence
and overall mortality in the elderly.
Also, in secondary prevention, ADVANCE (Action in Diabetes
and cardioVAscular disease: Preterax and DiamicroN MR Controlled Evaluation) and PROGRESS (Perindopril pROtection
aGainst REcurrent Stroke Study) showed clear benefits for CV
outcomes with use of the same combination (reviewed in reference 6). Overall mortality and CV mortality, and stroke incidence and major vascular events, respectively, were decreased
in these two studies.
In conclusion, according to the present state of the art, multiple-drug combinations appear to be superior to monotherapy for both primary and secondary prevention of CV events. ■
References
1. Mancia G, de Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension. The Task Force for the Management of Arterial
2. Polońia J, Martins M, Pinto F, Nazare J. Salt intake, and prevalence awareness,
treatment and control of hypertension in Portugal. Changes over a 10-year period. J Hypertens. 2013;31:e-suppl A:e140.
3. Polońia J, Mesquita-Bastos J, Pessanha P, et al. Estratificação do risco cardiovascular global de doentes hipertensos seguidos em Portugal nos Cuidados
de Saúde Primários ou Hospitalar e segundo as orientações ESH/ESC [in Portuguese]. Rev Port Cardiol. 2010;29:1685-1696.
2010;55:399-407.
5. Zhang Y, Ly C, Yannoutsos A, et al. Effect of a fixed combination of perindopril
and amlodipine on blood pressure control in 6256 patients with not-at-goal hypertension: the AVANT'AGE study. J Am Soc Hypertens. 2013;7:163-169.
6. Cowart JB, Taylor AA. Should two-drug initial therapy for hypertension be recommended for all patients? Curr Hypertens Rep. 2012;14:324-332.
445
CONTROVERSIAL
QUESTION
5. A. Bhagwat, India
inhibitors—may be a reduction in BP variability, a risk factor
associated with myocardial infarction and stroke. The key issue then is selecting the best combination for most patients.
Ajit BHAGWAT, MD, DM
Head of Cardiology Department
Kamalnayan Bajaj Hospital
Aurangabad
INDIA
Renin-angiotensin-aldosterone system inhibitors
plus calcium channel blockers
T
he World Health Organization estimates that 70% of
patients do not take their prescribed antihypertensive
medication. One reason for this poor compliance is the
occurrence of side effects. In antihypertensive drug trials, compliance is at best 78%. In a meta-analysis of 38 antihypertensive drug trials, of all the strategies examined, use of oncedaily instead of twice-daily therapy improved adherence by
8% to 20%.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure recommends initiation of antihypertensive treatment
with a two-drug combination in patients with systolic blood
pressure (BP) ⱖ160 mm Hg and/or diastolic BP ⱖ100 mm Hg,
and in patients who are 20/10 mm Hg above their BP goal.
In fact, most patients require more than one medication to
achieve target BP. One method to simplify treatment is to
use fixed-dose combinations.
Combination treatment allows synergistic use of drugs with
complementary actions. In a meta-analysis of 42 trials, combination antihypertensive treatment was fivefold more effective in lowering BP than doubling the dose of single agents.
Moreover, the lower dose of each individual agent reduces the
risk of side effects, thereby improving compliance. Multiple
dosing decreases compliance. Use of a fixed-dose combination (FDC) overcomes this. In a meta-analysis of four hypertension studies, FDC treatment improved compliance by 24%
compared with individual agents given separately. A more recent meta-analysis confirmed this finding, and also reported a 50% increase in persistence with treatment with the use
of FDCs. However, FDCs have some limitations: loss of flexibility in adjusting the dose of each agent, ineligibility for medical insurance plans, as well as some formulations possibly not
being safe or practical for first-line treatment. Another benefit
of combination treatment—particularly with calcium channel
blockers (CCBs), diuretics, and angiotensin-converting enzyme
446
The ACCOMPLISH trial (Avoiding Cardiovascular events in
COMbination therapy in Patients LIving with Systolic Hypertension) showed that a FDC of benazepril and amlodipine was
superior to benazepril and hydrochlorothiazide in reducing cardiovascular events and death in patients with hypertension.
In the ACCELERATE trial (Aliskiren and the Calcium ChannEL
BlockER Amlodipine combination as an initial Treatment Strategy for HyperTEnsion), patients who took aliskiren and amlodipine achieved greater reduction in systolic BP than patients
taking either drug as monotherapy. It should be noted that
there are no outcome studies with angiotensin receptor blocker/CCB or direct renin inhibitor/CCB combinations. However,
the combination of a renin-angiotensin-aldosterone system
(RAAS) inhibitor with a CCB is a rational and effective choice.
In this regard, the only randomized trial evidence comparing
separate drug regimens comes from the ASCOT trial (AngloScandinavian Cardiac Outcomes Trial), which found that the
combination of the newer agents, perindopril plus amlodipine, was significantly better in reducing cardiovascular risk than
the older combination of 웁-blocker plus diuretic.
Renin-angiotensin-aldosterone system inhibitors
plus diuretics
Diuretics decrease volume, which in turn activates RAAS. This
activation leads to vasoconstriction, salt and water retention,
and increased BP. When added to a thiazide-like diuretic, an
inhibitor of RAAS overcomes these untoward effects and provides additional BP lowering. Furthermore, hypokalemia and
glucose intolerance—both commonly associated with diuretic use—are alleviated with the addition of a RAAS inhibitor,
making this a rational combination for hypertensive patients.
In the HYVET trial (HYpertension in the Very Elderly Trial), the
combination of perindopril and indapamide significantly reduced stroke and heart failure in an elderly population, compared with placebo.
In conclusion, use of a fixed-dose combination or selection of
complementary drug classes in the management of hypertension allows patients to achieve their BP goal quickly, reduces
adverse drug reactions, and improves compliance. ■
CONTROVERSIAL
QUESTION
6. K. J. Filipiak, Poland
Krzysztof J. FILIPIAK, MD, PhD, FESC
Medical University of Warsaw
POLAND
A
dherence to medical treatment is universally poor, with
estimates indicating that less than half of patients prescribed an antihypertensive, lipid-lowering, or antidiabetic drug continue treatment beyond 1 year.1 Smith et al
postulated that including key medications necessary to reduce
cardiovascular risk in a single pill could increase the use of
effective and inexpensive medications, improving treatment
adherence.2
What more can be done to speed up incorporation of multiple-drug combinations (MDCs) into everyday practice and clinical guidelines? We have still not defined proper target groups
for the different MDCs in “primary” and “secondary” prevention. Thus, I would like to propose at least four stages of prevention: (i) zero-order prevention; (ii) primary prevention; (iii)
secondary prevention; and (iv) tertiary prevention (Figure).
“Zero-order prevention” would be for those without hypertension but with high normal arterial blood pressure, and/or without hypercholesterolemia, but with slightly elevated serum C-reactive protein concentrations. Such patients benefited from
receiving renin-angiotensin blockers (reducing the probability of hypertension) in TROPHY (TRial Of Preventing HYperten-
Pill A
Pill B
Pill C
Pill D
Population cardiovascular risk
Single risk factors
ie, hypertension,
dyslipidemia
“Zero order”prevention/
risk factor prevention
Tested in trials:
TROPHY/
PHARAO/
JUPITER
Coronary artery
disease or
equivalent
Primary
prevention
(new
definition)
Cardiovascular event:
myocardial infarction,
stroke or
revascularization
Secondary
prevention
(new
definition)
Tertiary
prevention
(new
definition)
Figure. The four stages of cardiovascular risk prevention.
Pill A: aspirin + ACE inhibitor + statin; Pill B: aspirin + ACE inhibitor + second antihypertensive drug (amlodipine?) + statin; Pill C: aspirin + ACE inhibitor + 웁-blocker
+ statin; Pill D: aspirin 75 mg or aspirin/clopidogrel 75/75 mg + ACE inhibitor
(full dose) + 웁-blocker (full dose) + statin (full dose) + diuretic (indapamide).
Abbreviations: ACE, angiotensin-converting enzyme; JUPITER, Justification for
the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin; PHARAO, Prevention of Hypertension with the Angiotensin-converting
enzyme inhibitor RAmipril in patients with high nOrmal Blood Pressure;
TROPHY, TRial Of Preventing Hypertension.
sion) and PHARAO (Prevention of Hypertension with the Angiotensin-converting enzyme inhibitor RAmipril in patients with
high nOrmal Blood Pressure) or statins (reducing the number of deaths, myocardial infarctions, and strokes) in JUPITER
(Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin). We could thus here
propose polypill A, comprising an angiotensin-converting enzyme (ACE) inhibitor and a statin. Pill B, with two antihypertensives, a statin, and aspirin, could be proposed for those
with established hypertension as the newly-defined “primary
prevention.” Pill C would be for “secondary prevention” in
those diagnosed with coronary artery disease or equivalent,
and should also contain a 웁-blocker. Pill D could be used as
“tertiary prevention” after a stroke, myocardial infarction, or
revascularization, and might consist of two antiplatelets and
more potent antihypertensives, with indapamide. I believe this
is the right time for such a new classification of prevention
and polypills.3 There is also an emerging need for polypills in
heart failure (HF). New guidelines advocating at least four or
five drugs in patients with systolic HF with reduced ejection
fraction should speed up the commercialization of polypills
in this field. If a patient must take a diuretic, 웁-blocker, ACE inhibitor, eplerenone, and ivabradine, one may wonder what level of adherence is forecasted. The question is why we still do
not have: (i) a polypill with once-daily ACE inhibitor and eplerenone, the aldosterone antagonist of choice; and (ii) a polypill with ivabradine and a 웁-blocker. Although a combination of
two drugs affecting the renin-angiotensin system is not recommended in hypertension, use of such a combination in HF
is routine in patients with NYHA classes II-IV and an ejection
fraction of ⱕ35% without hypertension, hyperkalemia, or severe renal failure. A polypill with ivabradine and a 웁-blocker
should probably include carvedilol (given twice daily like ivabradine), which has been well evaluated in patients at all NYHA
stages. Vasodilatory third-generation 웁-blockers like carvedilol
reduce the heart rate in a self-restricting manner because of
a simultaneous decrease in peripheral resistance. Therefore,
additional rate reduction with ivabradine might be crucial.
In conclusion, many different MDCs will emerge in the coming
years, both in hypertension and cardiovascular prevention,
and in HF. We look forward to using them to improve patient
adherence in zero-order, primary, secondary, and tertiary prevention, as well as to reduce the number of pills taken in diseases like HF. ■
References
1. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165:1147-1152.
2. Smith R, MacCready T, Yusuf S. Combination therapy to prevent cardiovascular
disease. JAMA. 2013;309:1595-1596.
3. Siewaszewicz E, Filipiak KJ. Perspektywy pigułki typu polypill/polycap w chorobach serca i naczyń [in Polish]. Choroby Serca i Naczyń. 2010;7:131-140.
447
CONTROVERSIAL
QUESTION
7. R. O’Hanlon, Ireland
Rory O’HANLON, MD, MRCPI
St Vincent’s University Hospital Clinical
Director, Centre for Cardiovascular
Magnetic Resonance
Blackrock Clinic, Dublin
IRELAND
F
ixed-dose or flexible-dose combination antihypertensives have been studied in the medical literature for over
20 years, with publications dating back to 1990 demonstrating the beneficial effects of combining three antihypertensives in a single tablet.1 Indeed in 2003, the Joint National
Council–VII hypertension guidelines stated that fixed-dose
combination (FDC) therapies are more convenient as they simplify blood pressure (BP) treatment regimens, with more patients achieving target BP reduction with combination agents
than through uptitration of single agents to maximum doses.2
It is also widely recognized that the majority of hypertensive
patients require two or more different agents to achieve adequate BP control.3-5 This need for multiple agents to control
BP is reflected in the recent European guidelines published
in 2009.6 Initial treatment with combination antihypertensives
leads to a number of beneficial effects, and the majority of
studies demonstrate more effective BP control at introductory doses of combination agents. Furthermore, side effects
associated with higher doses of single agents are reduced
with combination therapies, which use smaller doses of the
individual agents. Compliance is also improved for a number
of reasons. Typically, there is less need for frequent physician
visits for drug uptitration; single-tablet regimens are always
more preferable to patients than multiple tablet regimens; and
as mentioned, the smaller doses of individual agents used in
combination pills are associated with fewer side effects. As
recently as 2003, Law et al demonstrated in a meta-analysis
of over 350 randomized controlled trials of antihypertensive
therapies that the side effects of all antihypertensive agents—
apart from renin-angiotensin-aldosterone system (RAAS) inhibitors—are dose-responsive. Furthermore, in certain situations, the effects of a second agent taken in combination
reduced the side effects of the first agent. The prime example
is ankle edema caused by calcium antagonists, an effect that
is reduced by combination of the calcium antagonist with a
RAAS inhibitor.
It is reassuring to note that combination agents incur significant cost savings to health economies. There are a number
of reasons for this, including improved patient compliance and
448
more appropriate BP reduction, leading to significant improvements in cardiovascular and stroke incidence and mortality.
Furthermore, combination agents are frequently less expensive to prescribe than the individual drug components. Bangalore et al published a nice paper in 2007 in which they
analyzed 68 studies investigating FDCs, identified through a
Medline search. This totaled just under 12 000 patients on
FDCs versus just under 8500 patients on free drug component regimens. While the study was not restricted to FDCs
for hypertension, the authors did demonstrate a reduction in
noncompliance of 24% to 26% with the use of an FDC versus
single medication regimens. The question of compliance was
also studied by Gupta et al, who published a meta-analysis in
2009 that included 15 studies, with just under 18 000 patients
included from trials reporting on drug compliance. The use of
FDCs (two antihypertensive agents in a single tablet) was associated with significantly better compliance than the corresponding free drug combinations, with beneficial improvements in BP and a reduction in adverse events.
This wealth of data in favor of FDCs should therefore encourage primary care physicians to use combination agents with
confidence and in the knowledge that, compared with single
drug regimens, adverse events are less common, costs are reduced, compliance is improved, and more patients will achieve
target BP reductions, thereby requiring fewer clinic visits. These
recommendations were incorporated into the updated British
Hypertension Society guidelines published in September 2012,
and have been endorsed by the National Institute for Health
and Clinical Excellence. These guidelines are also not secondary care–driven, but are instead primary care–focused. ■
References
1. Materson BJ, Cushman WC, Goldstein G, et al. Treatment of hypertension in
the elderly: I. Blood pressure and clinical changes. Results of a Department
of Veterans Affairs Cooperative Study. Hypertension. 1990;15:348-360.
2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National
Pressure. Hypertension. 2003;42:1206-1252.
3. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with
hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J
Kidney Dis. 2000;36:646-661.
4. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2
diabetes. N Engl J Med. 2001;345:851-860.
5. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4:393-404.
CONTROVERSIAL
QUESTION
8. E. J. Ramos, Philippines
Eugenio Jose F. RAMOS, MD,
FACP, FPCP, FPCC, MBA
Director, The Medical City Cardiovascular
Center, The Medical City
Ortigas Avenue, Pasig City, 1605
Metro-Manila, PHILIPPINES
A
ddressing the issue of hypertension is a challenge not
only because it is in many instances an asymptomatic
condition, but also because reaching and maintaining BP targets is not easy and eventually requires the use of
multiple drugs, with the need to take into account respective
efficacy profiles and adverse effects.1,2 The impact of antihypertensive drugs on clinical outcomes along the continuum of
cardiac and vascular diseases has been well documented,
with many landmark trials. All of these drugs reduce BP, but
do not all show positive effects on clinical outcomes. These
trials have provided us with sufficient documented evidence
to significantly influence medical decision-making, but this remains suboptimally utilized in clinical practice. The tendency
to extrapolate data and attribute positive outcomes to “class
effects” contributes to the wide gap between progress in our
knowledge of hypertension per se and the effectiveness of
antihypertensive treatment in primary and secondary prevention settings.
Uncontrolled hypertension eventually leads to end-organ damage, not only because of the adverse effects of increased pressure on the vasculature, but also because of the neurohormonal abnormalities that occur. It stands to reason, therefore,
that whatever it takes to control BP—by monotherapy at the
start, or by combination therapy eventually—must be started early and chosen well, not only on the basis of BP reduction efficacy, but also of the drugs’ impact on the metabolic
changes in hypertension, which—ironically—may be aggravated by some drugs themselves. Right from the start, therefore, drug choices must be based on what the evidence
demonstrates, particularly on whether or not the drugs actually improve clinical outcomes.
While a significant reduction in BP by any antihypertensive
may positively impact a clinical outcome—for example, reduce
the risk of stroke—the metabolic changes that some classes
of antihypertensives cause, such as the increased risk of diabetes posed by 웁-blockers or thiazide diuretics,3 should compel astute clinicians to nuance their choices and look beyond
simple BP reduction. This is particularly the case as even if
populations at risk start with monotherapy, effective BP control will eventually require the use of combination therapy involving two, three, or even four drugs. Moreover, there are significant differences among drugs belonging to the same class,
which should warn clinicians against assuming a “class effect” and extrapolating clinical benefits. For example, angiotensin-converting enzyme (ACE) inhibitors, which have been
shown to have positive outcomes in primary and secondary
prevention settings, cannot just be substituted with angiotensin receptor blockers, even if the latter also affect the reninangiotensin-aldosterone system. Then again, not all ACE inhibitors are the same. This is where the treatment challenge
is compounded, particularly when multiple drugs are used in
combination.
The landmark trials in hypertension are there to guide the clinician, yet the clinician’s choice of which multiple-drug combination to use can be flawed by erroneous or inconsistent
interpretation of data. One such landmark trial is the ASCOT
trial (Anglo-Scandinavian Cardiac Outcomes Trial),4 which has
provided the clinician with evidence that can be used to decide which drug combination works in preventing cardiovascular events, and which just lowers BP. In evidence-based
medicine, it behooves the clinician to choose drugs that: (i)
have synergistic or complementary benefits when used together, none of which should cause or aggravate the metabolic abnormalities in hypertension; (ii) have protective effects
on the endothelium and target organs affected by hypertension; (iii) can retard or reverse the structural changes brought
about by remodeling after organ injury; and (iv) most importantly, have documented evidence of a positive impact on clinical outcomes based on controlled randomized trials, when
taken singly or in combination, in both primary and secondary prevention settings. ■
References
1. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2002;20:1461-1464.
2. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and the European Society
of Cardiology. J Hypertens. 2007;25:1105-1187.
3. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs.
J Hypertens. 2006;24:3-10.
4. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with
an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicenter randomized controlled trial. Lancet. 2005;366:895-906.
449
CONTROVERSIAL
QUESTION
9. H. A. Remah Mohammed, Saudi Arabia
Hosam Ahmed REMAH MOHAMMED, MD
Cardiology Department
Al-Hammadi Hospital, P.O. Box 55004
Riyadh 11534
SAUDI ARABIA
E
vidence from the Blood Pressure–Lowering Treatment
Trialists Collaboration (BPLTTC) showed that the cardiovascular benefits associated with blood pressure (BP)
lowering are directly related to the degree of BP control, irrespective of the agents used. However, the question of whether
certain agents—alone or in combination—exert a benefit beyond BP reduction is the source of longstanding controversy. A meta-analysis of several major randomized clinical trials
suggested that the use of angiotensin-converting enzyme
(ACE) inhibitors in patients with coronary heart disease provides a benefit beyond BP lowering. Similarly, it has been suggested that calcium channel blockers (CCBs) and angiotensin
receptor blockers (ARBs) have beneficial effects for stroke prevention beyond their BP-lowering effects, suggesting differential effects on other determinants of cardiovascular outcomes
not related to BP. It is therefore not too difficult to believe that
for the same level of BP control, different agents may generate different effects in terms of primary and secondary cardiovascular protection.
The relative benefits of ACE inhibitors and ARBs have been
controversial. Meta-analyses have suggested that ACE inhibitors may be superior to ARBs in terms of preventing coronary heart disease events. On the other hand, other analyses
have suggested that ARBs have superior benefits for stroke
prevention that go beyond BP lowering. With great anticipation, the ONTARGET trial (ONgoing Telmisartan Alone and
in combination with Ramipril Global Endpoint Trial) studied
the effect of ACE inhibitors, ARBs, and their combination in a
large-scale trial of high-risk individuals. Overall, it was shown
that neither agent was superior to the other or to the combination. Moreover, in stark contrast to the expected results, the
combination induced a significant increase in hard renal end
points, although proteinuria was significantly improved. By
contrast, the HYVET trial (HYpertension in the Very Elderly Tri-
450
al) was stopped early due to the observation of large benefits for all cardiovascular events in the active intervention group
(ACE inhibitors and thiazide-like diuretics). The VALUE trial
(Valsartan Antihypertensive Long-term Use Evaluation) studied cardiac morbidity and mortality among hypertensive patients with high cardiovascular risk, and reported no differences
in the primary composite end point; however, myocardial infarction and stroke occurred less commonly in patients receiving CCBs than ARBs. The ASCOT trial (Anglo-Scandinavian
Cardiac Outcomes Trial) evaluated two combination antihypertensive regimens in patients with three or more common
cardiovascular risk factors but without established coronary
heart disease: a standard regimen (웁-blocker/thiazide) versus
a newer regimen (CCB/ACE inhibitor). The newer regimen was
clearly superior in terms of preventing cardiovascular events
overall, and significantly so for most of the primary, secondary, tertiary, and post hoc end points studied. CAFÉ (Conduit
Artery Function Evaluation) and other substudies of the BPlowering arm of ASCOT found that lower central BP and nocturnal systolic BP control—strong predictors of cardiovascular
outcomes—were in part responsible for the differential effects
on cardiovascular outcomes in favor of the new regimen.
Interestingly, a recent meta-analysis of clinical trials in hypertension looked at 20 randomized controlled morbidity-mortality trials with 158 998 patients using either ACE inhibitors or
ARBs in the active treatment arm.1 Only 3 out of 20 trials—
ASCOT, ADVANCE (Action in Diabetes and cardioVAscular
disease: Preterax and DiamicroN MR Controlled Evaluation),
and HYVET (34 242 patients)—demonstrated significant reductions in all-cause mortality (13% when pooled; 95% confidence interval, 0.81-0.93; P<0.0001). All three trials had
treatment strategies that included perindopril, while indapamide was used in two of the trials and amlodipine in one. Neither the level of patient risk nor the trial duration could explain
the results. This indicates that fixed-combination perindopril/
amlodipine may provide physicians with the opportunity to
replicate the cardiovascular risk reduction seen in ASCOT in
daily clinical practice. ■
Reference
1. van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme
inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998
patients. Eur Heart J. 2012;33:2088-2097.
CONTROVERSIAL
QUESTION
10. M. Rizzo, Italy
Manfredi RIZZO, MD, PhD
Biomedical Department of Internal
Medicine and Medical Specialties
University of Palermo
Via del Vespro, 141
90127, Palermo, ITALY
C
ombining multiple drugs in a single pill offers a convenience that can significantly improve poor adherence to therapy, as well as therapeutic inertia. Additional benefits of combining agents from different classes
include improved efficacy and safety and a reduction in cardiovascular events. In patients for whom dual therapy is inadequate, multiple-drug therapy in a single pill offers a simplified
and effective treatment strategy.1 The burden of hypertension
is increasing in Europe and North America, and it has been
estimated that hypertension affects about 80 million adults in
the USA; yet, although antihypertensive agents are able to
significantly improve blood pressure levels, only 50% of hypertensive patients achieve blood pressure control.1
In recent years, a large number of randomized clinical trials
and meta-analyses have demonstrated that blood pressure
reduction is the main determinant of primary and secondary
cardiovascular prevention.2 Indeed, the goal of antihypertensive therapy is to reduce the cardiovascular risk associated
with the elevation in blood pressure levels. Many patients require at least two antihypertensive agents, and current international guidelines emphasize the need for combination regimens for initial antihypertensive therapy.
Furthermore, for those patients requiring three drugs, it has
been shown that an effective approach is to use a combination of agents with complementary mechanisms of action,
such as a renin-angiotensin-aldosterone system blocker, a
calcium channel blocker, and a diuretic.1 Recently, it has been
suggested that novel approaches to multiple-drug combinations for cardiovascular prevention should be considered,
including tablets manufactured with the drugs placed at opposite ends with a drug-free layer placed between them, or
tablets divided into discrete, separate segments, which may
provide additional benefits for initial close titration and dosage
adjustments.2
Bangalore and Ley published a comprehensive review of all
the available clinical evidence and scientific guidelines proposing multiple-drug combinations in hypertension, including
combinations of an angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor plus a calcium channel
blocker or diuretic.3 Once-daily treatment with a single pill was
effective and well-tolerated, reducing the pill burden, simplifying the treatment regimens, and improving adherence to
therapy. These significant beneficial effects helped patients to
reach and maintain their blood pressure targets, and ultimately, to achieve their short-term and long-term treatment goals
for comprehensive cardiovascular risk reduction in both primary and secondary prevention.
It should also be highlighted that triple-combination regimens
resulted in a greater proportion of patients achieving control of
blood pressure compared with patients receiving dual-combination regimens, with significantly lower levels of blood
pressure reported after only 2 weeks at maximum doses.1 In
summary, multiple-drug combinations in hypertension and cardiovascular prevention offer a convenience that can address
the barriers to reaching therapeutic targets, both for primary
and secondary prevention. Physician acceptance of a singlepill combination of drugs for reducing cardiovascular risk is
moderate to high, at least when considering the clinical approach to its use.4 The perspectives of physicians may, however, evolve towards a still greater acceptance with more availability of such multiple-drug combinations for use in both
primary and secondary cardiovascular prevention. ■
References
1. Chrysant SG. Single-pill triple-combination therapy: an alternative to multipledrug treatment of hypertension. Postgrad Med. 2011;123:21-31.
2. Angeli F, Reboldi G, Mazzotta G, et al. Fixed-dose combination therapy in hypertension: cons. High Blood Press Cardiovasc Prev. 2012;19:51-54.
3. Bangalore S, Ley L. Improving treatment adherence to antihypertensive therapy:
the role of single-pill combinations. Expert Opin Pharmacother. 2012;13:345355.
4. Viera AJ. The polypill to prevent cardiovascular disease: physicians’ perspectives.
Curr Opin Cardiol. 2011;26:438-442.
451
CONTROVERSIAL
QUESTION
11. R. S. Tan, Singapore
Ru San TAN, MBBS, MRCP, FAMS
Senior Consultant & Director, Clinical Trials
National Heart Centre Singapore
17 Third Hospital Avenue, Mistri Wing
SINGAPORE 168752
C
ontemporary hypertension guidelines advocate targeted intensive pharmacological intervention in highrisk patients identified by global cardiovascular risk
quantitation. In uncomplicated mild hypertension, blood pressure lowering with drugs averts target organ damage, but in
randomized controlled trials, it does not appear to significantly influence hard cardiovascular outcomes.1 The latter is not
unexpected given the necessary short trial durations relative
to the time required to develop outcomes in this inherently
low-risk population. In high-risk patients, the presence of either clinical disease (diabetes or cardiovascular or renal disease) or subclinical target organ damage portends an adverse
prognosis. However, a critical review of prospective randomized controlled trials found scant evidence that more intensive
blood pressure lowering can improve cardiovascular outcomes in these high-risk patients or improve the risk level to
a low-risk category.2 Hence, the recommended thresholds
for initiation of drug therapy, as well as target blood pressure
goals, are similar for both high- and low-risk patients.2 This
begs the fundamental question of whether differentiation of
primary and secondary preventive approaches to hypertension management is practical or necessary, especially when
viewed against the larger management challenge of endemic suboptimal attainment of blood pressure goals that cuts
across all risk categories. As the majority of hypertensive patients will require two or more drugs for optimal blood pressure
control, a unified approach focused on maximizing individual
blood pressure goal attainment using initial combination therapy is both pragmatic and rational.
Combination therapy, even at low doses of component drugs,
acts synergistically on multiple pathways to lower blood pressure more efficaciously than sequential high-dose monotherapy.3 Not only are patients more likely to achieve blood pressure goals with combination therapy, the time to blood pressure
goal attainment is shortened considerably.4 The latter has an
452
important impact on the reduction of cardiovascular outcomes,
independent of drug treatment,5 which should garner support for the use of combination therapy in high-risk patients.
With combination therapy, adverse event rates are not additive; this is either because of fewer dose-dependent side effects or neutralization of adverse events by complementary
drug interactions.3 Even in mild hypertension, where attainment of blood pressure goals is deemed less urgent, a persuasive case should be made for initiating combination therapy
on the grounds of improved tolerability with no compromise
on efficacy.
Single-pill combinations, preferably comprising long-acting
drugs taken once daily, should be used where possible.2 In a
meta-analysis comparing two-drug single-pill combinations
with equivalent free doses of component drugs, treatment adherence was significantly enhanced by more than 20% with
single-pill combinations. Moreover, there were nonsignificant
trends toward lower adverse events (20% reduction), larger
absolute blood pressure reduction, and improved goal attainment (30% increase), the latter possibly driven by higher compliance.6 Currently, various two-drug and three-drug single-pill
combinations with various dose permutations are commercially available for hypertension treatment. By simplifying hypertension management, they improve treatment adherence
and persistence, as well as the success rate and speed of
blood pressure goal attainment. They constitute a feasible
and promising strategy for combating treatment barriers to
achieving and maintaining blood pressure goals in all risk categories of hypertensive patients. ■
References
1. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev. 2012;8:CD006742.
3. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ.
2003;326:1427-1431.
4. Weir M, Levy D, Crikelair N, Rocha R, Meng X, Glazer R. Time to achieve bloodpressure goal: influence of dose of valsartan monotherapy and valsartan and
hydrochlorothiazide combination therapy. Am J Hypertens. 2007;20:807-815.
5. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.
Lancet. 2004;363:2049-2051.
6. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive. Hypertension. 2010;55:399-407.
CONTROVERSIAL
QUESTION
12. S. L. Tokgozoglu, Turkey
S. Lale TOKGOZOGLU, MD, FESC, FACC
Professor of Cardiology
Hacettepe University Faculty of Medicine
Hacettepe, Ankara
TURKEY
T
he border between primary and secondary prevention
is not clearly defined in the continuum of cardiovascular disease. Since the introduction of methods to determine subclinical atherosclerosis, we see more and more
patients one would initially categorize as being candidates for
primary prevention, but who are found to have atherosclerotic vascular disease on imaging. A more clinically-relevant approach would be to categorize the patients according to their
risk level. As the risk increases, more aggressive therapies for
prevention and treatment should be used. There are several
risk prediction scores, and in Europe, the one that should be
used to determine the risk of an individual patient is the SCORE
system (Systematic COronary Risk Evaluation).1 Moreover, it
has been shown that adding markers of organ damage to the
SCORE risk estimation improves risk prediction in the hypertensive patient.2 According to the 2012 prevention guidelines
of the European Society of Cardiology, individuals having any
of the following are categorized as having very high risk: documented cardiovascular disease by invasive or noninvasive
testing; diabetes mellitus (type 1 or type 2) with one or more
cardiovascular risk factors and/or target organ damage; severe
chronic kidney disease and a calculated SCORE of ⱖ10%.3
High-risk individuals are defined as those having any of the
following: markedly elevated single risk factors, such as familial dyslipidemia and severe hypertension; diabetes mellitus
(type 1 or type 2) but without cardiovascular risk factors or
target organ damage; moderate chronic kidney disease or a
calculated SCORE of ⱖ5%, and 10% for 10-year risk of fatal
cardiovascular disease.
Our main aim in treating the hypertensive patient is to decrease cardiovascular mortality and morbidity and prevent
end organ damage. To achieve this aim, optimal control of
blood pressure and other risk factors is necessary. The relationship between blood pressure and cardiovascular risk is
strong and graded, and reaching target blood pressure is
important to achieve maximum benefit. Most hypertensive
patients will need at least two agents to reach the targets that
have been defined in the guidelines.4 Patients also need to be
compliant in order to maintain the target levels throughout their
lifetime. A meta-analysis of 42 studies showed that combining
two agents from any two classes of antihypertensive drugs increases the blood pressure reduction much more than doubling the dose of one agent.5 For a combination to be more
effective, synergistic combinations should be chosen. The
guideline-recommended initial preferred combinations are a
renin-angiotensin-aldosterone system antagonist with either
a calcium channel blocker or a diuretic, according to current
evidence. Large-scale trials such as ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) and ACCOMPLISH (Avoiding
Cardiovascular events in COMbination therapy in Patients LIving with Systolic Hypertension) have shown a decrease in cardiovascular events with the use of these combinations in highrisk patients.6
The 2007 European Society of Hypertension/European Society of Cardiology guidelines recommend that combination of
two drugs be considered as initial treatment whenever hypertensive patients have high initial blood pressure or are classified as being at high/very high cardiovascular risk because
of the presence of organ damage, diabetes, renal disease, or
a history of cardiovascular disease. This is both because of
higher effectiveness and lower discontinuation rates, both of
which are extremely important for high-risk patients or those
with high initial blood pressure.
In conclusion, we should start thinking about the risk of the
patient rather than whether he or she is a primary or secondary prevention case, and regardless of whether the patient has
known cardiovascular disease or not, high-risk hypertensive
patients should be considered for combination therapy. ■
References
1. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24:9871003.
2. Sehestedt T, Jeppesen T, Hansen TW, et al. Risk prediction is improved by adding
markers of subclinical organ damage to SCORE. Eur Heart J. 2010;31:883-891.
3. The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by
representatives of nine societies and by invited experts). European guidelines on
cardiovascular disease prevention in clinical practice. Eur Heart J. 2012;33:
1635-1701.
4. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European
Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
5. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus
monotherapy in reducing blood pressure: meta-analysis on 11,000 participants
from 42 trials. Am J Med. 2009;122:290-300.
6. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428.
453
CONTROVERSIAL
QUESTION
13. M. Vrablik, Czech Republic
Michal VRABLIK, MD
Centre for Preventive Cardiology
3rd Department of Internal Medicine
1st Medical Faculty
Charles University
Prague
CZECH REPUBLIC
T
here is overwhelming documentation from clinical trials and epidemiological studies providing evidence of
measures that improve outcomes in cardiovascular patients. Every year, we learn about novel effective therapies in
the cardiovascular field and gain new information on combinations of pharmacological therapies for use in specific patient groups. As cardiovascular disease has multiple origins,
the approach to its prevention and treatment must be multifaceted and rely on the use of combination therapy. The first
and essential component of successful cardioprotective combination therapy is, of course, a lifestyle change.1 However,
such an approach does not lead to satisfactory control of risk
factors in most patients. Thus, drug therapies represent a necessary adjunct in most clinical situations.
The decision to start a patient on medication is based on several factors, the most important of which is careful risk stratification. Assessment of a patient’s risk status determines their
treatment goals as well as the modes of achieving these goals.
Initiation of pharmacotherapy, and any further approach to
management of individual cardiovascular risk factors, depends
on the patient’s risk. As there is a very thin line between socalled primary and secondary prevention (usually a few seconds when atherothrombosis occludes an artery and myocardial infarction or ischemic stroke develop), it seems more
feasible to categorize patients according to their risk. Highrisk or very-high-risk patients deserve the same attention and
aggressive risk factor management regardless of whether they
have had a vascular event or not.2 There is ample evidence
supporting this approach as a number of clinical trials both in
primary and secondary prevention have yielded similar results, and preventing the first event seems to be even more
important than averting a recurrence.3
Having said this, we have almost answered our controversial
question and it does not seem to be controversial anymore.
Those with increased cardiovascular risk require intensive
management of their risk factors, and we must offer these
patients pharmacotherapy to bring them to guideline-recommended targets. Only well-proven medications should be used
454
to avoid unnecessary polypragmasia, and in most cases, risk
factor control requires use of drug combinations. Hypertension can be controlled with monotherapy in less than 20% of
patients.4 Increasingly stringent goals for low-density lipoprotein cholesterol levels can be achieved with statins, but in
some patients, statin-fibrate or statin-ezetimibe combinations
might be needed. All type 2 diabetics should be treated with
metformin, but this medication alone does not usually lead
to satisfactory control of hyperglycemia. Moreover, patients
with advanced atherosclerosis should receive antiplatelet
therapy. Therefore, a high-risk individual with diabetes may require at least five different medications. Nevertheless, every
now and then, voices calling for “a conservative approach”
avoiding the use of multiple medications can be heard.
However, there is no documentation supporting such an approach. Experience from clinical trials conducted over the last
decade, together with positive trends in cardiovascular morbidity and mortality in developed countries, provide a clear answer. There are combinations of drugs that have been proven
unambiguously to bring benefit to a variety of clinical situations. Just one example: the ASCOT trial (Anglo-Scandinavian
Cardiac Outcomes Trial). The combination of an angiotensinconverting enzyme inhibitor, calcium channel blocker, and
statin reduced the risk of myocardial infarction by more than
50% in a high-risk population with no history of atherothrombotic events, thus showing a synergistic effect among the
therapies used.5
In conclusion, the use of drug combinations in the treatment
and prevention of cardiovascular disease is not only recommended by current guidelines and evidenced by the results
of well-conducted clinical trials, but most importantly, it is justified by the decline in cardiovascular disease mortality that
has accompanied wider implementation of this approach to
all individuals at increased risk. ■
References
1. Perk J, Backer GD, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of
the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur J Prev Cardiol. 2012;19:585-667.
2. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias. Atherosclerosis. 2011;217:3-46.
3. Tonelli M, Lloyd A, Clement F, et al. Efficacy of statins in primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ. 2011;183:e1190-e1202.
4. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus
monotherapy in reducing blood pressure: meta-analysis on 11,000 participants
from 42 trials. Am J Med. 2009;122:290-300.
5. Sever P, Dahlof B, Poulter N, et al. Potential synergy between lipid-lowering and
blood-pressure lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur
Heart J. 2006;27:2982-2988.
‘‘
COVERAM
A recent meta-analysis of 42
studies has shown that in most
cases the blood pressure reduction obtained by combining two
agents from any two classes of antihypertensive drugs is five times
that obtained with doubling the
dose of one agent… Not only are
blood pressure reduction and cardiovascular protection enhanced,
but tolerance is also improved by
initially lowering the dose of each
component and offsetting their
potential side effects.”
Optimizing combination
therapy for cardiovascular
protection: evidence
from landmark trials
b y N . C l a v re u l , Fra n c e
A
Nicolas CLAVREUL, PhD
Servier International
Suresnes, FRANCE
dvances in the field of cardioprotection have established the value of
combination therapy for hypertensive patients. If lowering blood pressure remains the primary goal of antihypertensive treatment, decreasing cardiovascular morbidity and mortality has emerged as the true objective
of hypertension management. Combining drugs with complementary modes
of action in a single pill offers a real advantage in terms of efficacy and rapidity of action. Patient adherence and tolerance to treatment are also enhanced,
ultimately resulting in greater cardiovascular protection. Major landmark trials in hypertension such as ASCOT (Anglo-Scandinavian Cardiac Outcomes
Trial), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), or HYVET (HYpertension in the Very Elderly
Trial) have demonstrated the clear advantage of combining the leading drugs
in their respective class—the angiotensin-converting enzyme inhibitor perindopril, the thiazide-like diuretic indapamide, and the calcium channel blocker
amlodipine— in reducing mortality. Recent meta-analyses have confirmed not
only that treatment with perindopril-based combinations results in a 13% reduction in all-cause mortality and a 22% reduction in cardiovascular mortality in hypertensive patients, but also that these combinations are the cornerstone of cardiovascular prevention in high-risk patients and diabetic patients.
Additional therapeutic needs should be fulfilled in the near future, when new
fixed combinations of these three drugs become available.
urrent guidelines in hypertension support the view that, whatever the drug
used, monotherapy will only control the blood pressure in a limited number
of patients in the long term.1 Of course, treatment initiation with monotherapy with consecutive uptitration at full-dose remains the most widely applicable
strategy for hypertensive patients. However, a recent meta-analysis of 42 studies
has shown that in most cases, the blood pressure reduction obtained by combining two agents from any two classes of antihypertensive drugs is five times that obtained with doubling the dose of one agent.2 This observation is supported by the
obvious advantage of combining the complementary pharmacological mode of actions of two or more drug classes. Not only are blood pressure reduction and cardiovascular protection enhanced, but tolerance is also improved by initially lowering
the dose of each component and offsetting their potential side effects. In addition,
it is unlikely that patients would be willing to try all the various monotherapies at fulldose prior to upgrading to combination therapy, which would ultimately be counter-
C
Nicolas Clavreul, Servier International,
50, rue Carnot, 92284 Suresnes
Cedex, France (e-mail:
[email protected])
Optimizing combination therapy for CV protection: evidence from landmark trials – Clavreul
455
COVERAM
productive when trying to reach the target objective of treating
hypertension: to lower cardiovascular morbidity and increase
life expectancy. Indeed, patients tend to be less reluctant to
follow their treatment when they reach blood pressure targets with their initial treatment as opposed to having to go
through multiple switches from one monotherapy to another.
Several recent studies have demonstrated the need to achieve
rapid blood pressure control in order to obtain better outcomes. It was already apparent in a post-hoc analysis of the
VALUE study (Valsartan Antihypertensive Long-term Use
Evaluation) that, independently of the treatment, the rate of
cardiovascular events was lower during the whole study for
patients who initially reached blood pressure control within
SELECTED
ABBREVIATIONS
ambulatory blood pressure monitoring
coronary artery disease
diastolic blood pressure
renin-angiotensin-aldosterone system
systolic blood pressure
ABPM
ACE
ARB
CAD
CCB
DBP
MI
RAAS
SBP
SELECTED
TRIAL ACRONYMS
ADVANCE
ASCOT
ASCOT-ABP
CAFE
EUROPA
HYVET
PICXEL
PREMIER
PROGRESS
QUIET
ROADMAP
STRATHE
UKPDS
VALUE
456
Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled
Evaluation
Ambulatory Blood Pressure
Conduit Artery Function Evaluation
EUropean trial on Reduction Of cardiac events
disease
Perindopril/Indapamide in a double-blind
Controlled study versus Enalapril in Left
ventricular hypertrophy
PREterax in albuMInuria rEgRession
Perindopril pROtection aGainst REcurrent
Stroke Study
QUinapril Ischemic Event Trial
Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention Study
STRAtegies of Treatment in Hypertension:
Evaluation
United Kingdom Prospective Diabetes Study
Valsartan Antihypertensive Long-term Use
Evaluation
the first month.3 This observation was reinforced further in a recent Italian cohort study in more than 200 000 patients who
were newly treated with antihypertensive drugs. Initiation with
a combination treatment resulted in a significantly better protection over the 6 years of follow-up, with a lower rate of coronary and cerebrovascular events.4 It seems reasonable to suggest that the more rapid and sustained reduction in blood
pressure afforded by combination treatment accounts for
these results. Newer single-pill formulations for combination
therapy also contribute greatly to helping patients attain controlled blood pressure by improving compliance. A 1-year
study in more than 100 000 patients showed that patients
whose antihypertensive treatment was initiated with a singlepill combination reached blood pressure targets more rapidly
than their counterparts who were treated with either monotherapy or free combinations.5 Single-pill combinations are,
therefore, expected to improve not only the rapidity of blood
pressure control, but also the survival rate.
How combining perindopril and indapamide
in a single pill contributed to better hypertension
management
Investigations aiming to demonstrate the potential benefit of
combination therapy in cardiovascular protection began early
on. Based on the assumption that combining a long-acting
angiotensin-converting enzyme (ACE) inhibitor, perindopril,
with a metabolically neutral diuretic, indapamide, as first-line
treatment would be more effective than a classic monotherapy strategy, the STRATHE trial (STRAtegies of Treatment in
Hypertension: Evaluation) compared treatment initiation with
Preterax (perindopril/indapamide) with a sequential strategy
(starting with a b-blocker and then adding an angiotensin receptor blocker [ARB] and a calcium channel blocker [CCB]),
or a step-by-step strategy (uptitration of an ARB and addition
of a thiazide diuretic) in grade 2 hypertensives.6 Preterax was
shown to rapidly control a greater number of patients than the
other strategies, paving the way for the first recognition of combination therapy as an option for treatment initiation in patients
with marked hypertension or at high cardiovascular risk.1 Preterax was also shown to be superior to enalapril or atenolol
in reducing blood pressure in hypertensive patients with left
ventricular dysfunction or diabetes.7-9 Preterax’s ability to preserve and regenerate the microcirculation to improve targetorgan function was observed in the PICXEL study (Perindopril/Indapamide in a double-blind Controlled study versus
Enalapril in Left ventricular hypertrophy),8 in which it achieved
a greater reduction in left ventricular hypertrophy than enalapril.
In the PREMIER study (PREterax in albuMInuria rEgRession),9
there was also a significantly greater reduction in albumin secretion with Preterax than with enalapril, which led to fewer
major cardiovascular outcomes.
Although blood pressure was recognized as an important
determinant of the risk of initial stroke in both normotensive
and hypertensive patients, and a linear correlation between
COVERAM
blood pressure levels and occurrence of ischemic stroke and The positive impact of perindopril/indapamide on the microcerebral hemorrhage was established,10 clinical uncertainty circulation was illustrated by a 21% reduction in the relative
risk of renal events, which was driven by a marked reduction
remained about the efficacy and safety of routine administrain microalbuminuria. A subsequent subanalysis of renal events
tion of a blood-pressure-lowering regimen in this population.
in ADVANCE revealed a consistent beneficial effect on kidney
In the PROGRESS study (Perindopril pROtection aGainst REfunction, independently of the blood pressure level achieved,
current Stroke Study), 6105 patients with a history of stroke or
with no threshold effect.14 Similarly, analysis of the 10 640 patransient ischemic attack, half of them hypertensive, were randomized to placebo or perindopril with addition of indapamide, tients with chronic kidney disease revealed a consistent benas required, on top of their current standard treatment.11 In efit in terms of renal and cardiovascular outcomes across all
stages of chronic kidney disease.15
patients assigned to the active treatment, blood pressure was
lowered by an average of 9 mm Hg for systolic
blood pressure (SBP) and 4 mm Hg for diastolic
PROGRESS
ADVANCE
HYVET
blood pressure (DBP). In patients who had reEnd
point
Hazard
ratio
(95%)
ceived the combination of perindopril and indapamide since randomization, the reduction in
All-cause mortality
NA
0.86 (0.75-0.98)
0.79 (0.65-0.95)
SBP/DBP was even greater (–12.3/–5 mm Hg).
–14%
–21%
This was associated with a 43% relative reducCV mortality
0.72 (0.55-0.95)
0.82 (0.68-0.98)
0.77 (0.60-1.01)
tion in the risk of stroke and a 42% reduction in
–28%
–18%
all major vascular events (Table I). Interestingly,
the protection afforded by combination theraFatal and/or
0.58 (0.38-0.89)
0.86 (0.76-0.98)
0.72 (0.30-1.70)
nonfatal MI
– 42%
–14%
py was similar whether patients were hypertensive or not.
Fatal and/or
nonfatal stroke
0.57 (0.46-0.70)
– 43%
0.94 (0.80-1.10)
0.61 (0.38-0.99)
–39%
Later on, these encouraging effects of Preterax
on microvascular and macrovascular events Table I. Landmark trials with perindopril/indapamide: main results.
spurred the launch of the ADVANCE trial (Ac- Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
tion in Diabetes and Vascular disease: Preter- Controlled Evaluation; CI, confidence interval; HYVET, HYpertension in the Very Elderly Trial. MI,
myocardial infarction; NA, not applicable; PROGRESS, Perindopril pROtection aGainst REcurrent
Ax and DiamicroN MR Controlled Evaluation), Stroke Study.
which evaluated the benefit of tight blood pres- Based on data from reference 11: PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041;
12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840; and reference 20:
sure control with Preterax in patients with dia- reference
Beckett NS et al. N Engl J Med. 2008;358:1887-1898.
betes, irrespective of whether they were hypertensive or not.12 The primary hypothesis was that a further In addition to increased survival with perindopril/indapamide
reduction in SBP below the 145 mm Hg achieved in the hyper- in diabetic patients, ADVANCE was the first and only trial to
tensive diabetic patients of UKPDS (United Kingdom Prospec- provide evidence of parallel reductions in microalbuminuria
tive Diabetes Study) would provide even greater protection and cardiovascular and all-cause mortality. In contrast, in the
in this high-risk population.13 A total of 11 140 patients in 20 recent ROADMAP trial (Randomized Olmesartan And Diabetes
MicroAlbuminuria Prevention Study), the 20% reduction in
countries were enrolled in ADVANCE. To be eligible, patients
microalbuminuria obtained with olmesartan treatment was not
had to have been diagnosed with type 2 diabetes at the age
associated with a reduction in cardiovascular outcome.16 A
of 30 years old or older, be 55 years old or older at study entry, and show evidence of elevated cardiovascular risk. Pa- recent meta-analysis in diabetic patients confirmed that only
tients were randomized to perindopril/indapamide or matchACE inhibitors, and not ARBs as a class, were associated with
ing placebo, on top of their previous standard therapy, with a significant improvement in renal protection, with a 29% reprogressive uptitration. Baseline blood pressure was 145/81
duction in micro/macroalbuminuria that was mostly driven by
mm Hg on average, and active treatment led to a further 5.6/ the results of ADVANCE.17 This effect resulted in a 16% reduc2.2-mm Hg decrease in blood pressure. In these conditions,
tion in all-cause mortality in the trials including ACE inhibitors,
perindopril/indapamide treatment was associated with a sigwhile there was no effect with ARBs. For all these reasons, the
nificant improvement in cardiovascular morbidity and mor- SBP target for diabetics was based on the results of ADVANCE
tality compared with standard therapy alone. As well as a and set at 135 mm Hg. This threshold has not been modified
significant 9% (P=0.04) reduction in the primary end point, since then, not even following more recent trials.18
a composite of major macrovascular events (cardiovascular
death, nonfatal stroke, and nonfatal MI) and microvascular The most recent demonstration of the cardiovascular protecevents (new or worsening renal or diabetic eye disease), there
tive effect of Preterax has come from an as-yet poorly docwere also significant reductions in cardiovascular death and umented fringe of the hypertensive population: very elderly
all-cause death, of 18% (P=0.04) and 14% (P=0.04), respec- hypertensive patients. The pilot study for HYVET (HYpertentively (Table I).12
sion in the Very Elderly Trial) in 2003 did not do much to clar-
457
COVERAM
The recently published ambulatory blood pressure monitoring (ABPM) data of the HYVET study
confirmed that blood pressure reduction with
the perindopril/indapamide combination, which
averaged 8/5 mm Hg over 24 hours, was the
main explanation for the difference in outcome.22
Interestingly, this substudy revealed that, on account of their 24h-blood pressure, half of the
HYVET population could be considered to have
“white-coat hypertension” and that, therefore,
treatment with perindopril/indapamide would
have been beneficial for them as well. In the absence of clear recommendations for these patients in the guidelines, this study could help to
improve prevention in this group of patients.
Patients dying from CV disease (%)
ify the situation, with the observation that an antihypertensive
strategy based on lisinopril and hydrochlorothiazide was associated with an increase in all-cause mortality, despite a significant reduction in stroke.19 In the main HYVET trial, which
included hypertensive patients aged 80 years or older, the
combination of perindopril and indapamide was clearly shown
to have effective blood pressure–lowering benefits in the
very elderly.20 The study results showed a 39% reduction in fatal stroke (P=0.046), a 21% reduction in all-cause mortality
(P=0.02), a 23% reduction in cardiovascular mortality (P=0.06),
and a 64% reduction in the incidence of fatal or nonfatal heart
failure (P=0.001) (Table I). The one-year extension of the trial also confirmed the need for early treatment initiation in this population.21
RRR
All-cause mortality
0.89 (0.81-0.99)
–11%
CV mortality
0.76 (0.65-0.90)
–24%
0.87 (0.79-0.96)
–13%
0.77 (0.66-0.89)
–23%
Table II. Treatment effects of amlodipine/perindopril in ASCOT.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; RRR, relative risk reduction.
Based on data from reference 24: Dalhöf et al. Lancet. 2005;366:895-906.
Atenolol + thiazide
HR=0.76
RRR=24%
P=0.001
3.0
2.5
2.0
1.5
Amlodipine +perindopril
1.0
0.5
0
0
1
2
3
4
5
6
Time (years)
Figure 1. ASCOT: Reduction in cardiovascular mortality in patients treated with
amlodipine/perindopril versus atenolol/thiazide diuretic .
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; CV, cardiovascular; HR, hazard
ratio; RRR, relative risk reduction.
After reference 27: Meurin. Am J Cardiovasc Drugs. 2006;6:327-334. © 2006, Adis Data Information BV.
Why a fixed-drug combination of perindopril
and amlodipine made sense
Coveram was launched as a fixed-combination of amlodipine and perindopril after the publication of the results of the
ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial),
which was considered to be a breakthrough in the management of hypertension.24 Indeed, in order to reach the newly
recommended blood pressure levels of 140/90 mm Hg set
by both the American and British guidelines,25,26 the need for
combination therapy had become more acute. However, there
was limited comparative data on treatment strategies. The investigators of ASCOT therefore decided to address the question of whether a strategy based on combining newer drugs
(amlodipine and perindopril) might provide additional benefits over the popular drugs used at the time (atenolol and a
thiazide diuretic). A total of 19 257 hypertensive patients (baseline blood pressure, 164/95 mm Hg) with at least three risk
Unadjusted HR (95% CI)
3.5
HYVET and ADVANCE also both provided evidence of the
antihypertensive efficacy and metabolic neutrality of therapeutic strategies including indapamide. The 2011 British guidelines for hypertension management now recommend using
thiazide-like diuretics such as indapamide rather than conventional thiazide-type diuretics such as hydrochlorothiazide.23
458
End point
factors, but who were free of coronary artery disease (CAD)
were enrolled in ASCOT. Despite there being only a small difference in brachial blood pressure reduction, the reduction in
all-cause mortality was significantly greater in the perindopril/
amlodipine arm (relative risk reduction, 11%; P=0.0247), and
this motivated the decision to stop the trial early, after 5.5 years.
In addition, cardiovascular mortality was reduced by 24%
(P=0.001), coronary events by 13% (P=0.007), and strokes by
23% (P=0.0003), all in favor of the perindopril/amlodipine
combination (Table II and Figure 1). In particular, the rates of
cardiovascular death in the two treatment arms diverged at
the very point where the majority of patients (78%) were treated with perindopril in addition to amlodipine rather than by
amlodipine alone (indicated by a red arrow on Figure 1).27
Substudies of ASCOT have provided clinical proof that reduction in brachial blood pressure alone cannot predict prognostic benefits. Indeed, since then, the importance of key
blood pressure parameters such as blood pressure variability, 24-hour blood pressure control, and central blood pressure has emerged following the demonstration that the 2.7
mm Hg difference in SBP reduction in favor of the amlodipine/perindopril group could only account for half of the differences in coronary and stroke events.28
COVERAM
Variability in SBP in patients with arterial hypertension has
been shown to be a powerful predictor of stroke and coronary
events, independent of mean SBP.29 In ASCOT, perindopril/
amlodipine was more effective in controlling intra-visit blood
pressure variability (variability between repeated measures in
a single medical visit) and between-visit blood pressure variability, a parameter considered to be a predictive indicator of
long-term prognosis in guidelines. Statistical adjustment confirmed that this reduction in blood pressure variability contributed to the better cardioprotection afforded by perindopril/amlodipine, a combination that the UK’s National Institute
for Health and Clinical Excellence (NICE) declared to be “the
best available evidence-based treatment option to suppress
blood pressure variability.”23
In the ASCOT-ABP substudy (Anglo-Scandinavian Cardiac
Outcomes Trial–Ambulatory Blood Pressure), ABPM demonstrated an early and effective reduction in nocturnal blood
pressure, which was observed during the entire follow-up,
with a mean difference of 2.2 mm Hg in nighttime SBP in favor of the perindopril/amlodipine regimen.30 In addition, the
CAFÉ study (Conduit Artery Function Evaluation), which was
initiated one year after randomization—when all treatments
were already uptitrated in order to reach the blood pressure
targets—evaluated central aortic pressures and hemodynamic indexes in a subset of patients.31 Despite a minimal and nonsignificant difference in brachial blood pressure between the
two arms (∆BP, 0.7 mm Hg; P=0.2), the difference in central
blood pressure was largely in favor of the perindopril/amlodipine group (∆ central aortic SBP, 4.3 mm Hg; ∆ central aortic
pulse pressure, 3 mm Hg; P<0.0001 for both). This discovery offered a potential additional explanation to the better outcome observed with this combination.
The clinical complementarity and synergy of perindopril and
amlodipine used in combination was further demonstrated
in a recent subanalysis of the EUROPA trial (EUropean trial on
Reduction Of cardiac events with Perindopril in stable coronary Artery disease).32 The purpose of this substudy was to
determine the effect on cardiac outcomes of adding perindopril to long-term treatment with a CCB in the CAD patients of
EUROPA. This substudy, therefore, focused on patients who
received a CCB for the whole duration of the trial, including
those who were randomized to the perindopril group or the
placebo group. The two populations had exactly the same
baseline characteristics and the addition of perindopril to a
CCB was shown to result in a 46% reduction (P<0.01) in allcause mortality and in a 35% reduction (P<0.05) in the primary
end point, a composite of cardiovascular mortality, nonfatal
myocardial infarction (MI), and resuscitated cardiac arrest. Interestingly, when compared with the population who received
placebo without a CCB, the benefit provided by the perindopril/CCB combination reached a 69% reduction in all-cause
mortality and a 71% reduction in cardiovascular death!
Thus, Coveram, which is indicated in both hypertension and
CAD, stands out among the currently available combinations
of renin-angiotensin-aldosterone system (RAAS) inhibitors and
CCBs in having proven efficacy in decreasing the risk of death
and cardiovascular events.
PERINDOPRIL-BASED COMBINATIONS
n
HR (95% CI)
(random effects model)
P value
0.818
42 373
1.02 (0.92 to 1.11)
0.747
0.87 (0.81 to 0.93)
<0.001
34 242
0.78 (0.70 to 0.87)
<0.001
0.90 (0.84 to 0.97)
0.004
76 615
0.88 (0.77 to 1.00)
0.051
n
HR (95% CI)
(random effects model)
P value
ALLHAT (lisinopril)
ANBP-2 (enalapril)
Pilot HYVET
(lisinopril, enalapril)
JMIC-B (lisinopril,
enalapril, imidapril)
42 373
0.99 (0.89 to 1.10)
ASCOT* (perindopril)
ADVANCE* (perindopril)
HYVET* (perindopril)
34 242
All ACE inhibitor trials
76 615
ACE inhibitor
trial (ACE inhibitor)
0.6
0.8
1.0
1.2
Favors
Favors
ACE inhibitor control
–13% all-cause mortality
0.6
0.8
1.0
1.2
Favors
Favors
ACE inhibitor control
– 22% CV mortality
Figure 2. Perindopril-based combinations and mortality reduction in hypertension trials.
Abbreviations: ACE, angiotensin-converting enzyme; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation;
ALLHAT, Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; ANBP-2, Second Australian National Blood Pressure (study); ASCOT, AngloScandinavian Cardiac Outcomes Trial; CV, cardiovascular; HR, hazard ratio; HYVET, HYpertension in the Very Elderly Trial; JMIC-B, Japan Multicenter Investigation
for Cardiovascular diseases B.
After reference 35: Ferrari and Boersma. Expert Rev Cardiovasc Ther. 2013;11:705-717. © 2013, Expert Reviews Ltd.
459
COVERAM
A recent meta-analysis by van Vark et al, which considered
20 trials evaluating RAAS inhibitors in hypertension and included 158 998 patients, reported that only in three trials was
the active treatment significantly better at reducing mortality
than the comparator: ASCOT, ADVANCE, and HYVET.33 These
three trials all had perindopril as part of their active treatment,
combined with amlodipine in ASCOT, and with indapamide for
ADVANCE and HYVET. Treatment with perindopril-based combinations resulted in a 13% reduction in all-cause mortality and
a 22% reduction in cardiovascular mortality (Figure 2, page
459).34,35 In contrast, none of the ARB trials showed any further
decrease in mortality. The results of this study were echoed
in a very recent new meta-analysis including 108 212 high-risk
patients without heart failure where ACE inhibitors and ARBs
were compared with placebo, and ACE inhibitors were shown
to reduce all-cause death by 8.3% while ARBs had not such
effect.36 In PROGRESS and EUROPA, perindopril-based regimens were once again the only ones to reduce both the primary outcome (cardiovascular death, MI, and stroke) and MI
(Figure 3).
The consistent evidence showing the ability of ACE inhibitors
to further reduce morbidity and mortality in hypertensive and
high-risk patients is now acknowledged not only in the literature, but also in guidelines,37 and even by some health authorities,38 who recommend ACE inhibitors for first-line use and reserve ARBs for patients who are intolerant to ACE inhibitors.
New combinations… for unsatisfied medical needs
New complementary combinations aiming to fulfill the needs
of all patients are on the horizon: Natrixam, the first and only
Perindopril/amlodipine
Perindopril/indapamide
combination of amlodipine and indapamide, which specifically addresses the issue of uncontrolled systolic hypertension,
and Triplixam, the triple combination of perindopril, amlodipine, and indapamide.
The 2009 reappraisal of the European guidelines on Hypertension Management acknowledged the protection afforded
by CCB/diuretic single-pill combinations against stroke and
cardiac outcomes, and gave this combination preferred status based on promising results from randomized controlled
trials, including VALUE.39 Indeed, in this high-risk population,
the amlodipine/diuretic combination protected patients against
MI (–19%) significantly better than the valsartan/diuretic strategy and showed a positive trend on stroke as well.
Diuretic/CCB combinations have also been shown to successfully reduce outcomes in patients with hypertension in
other trials.40,41 In van Vark’s recent meta-analysis of mortality
in hypertension trials, amlodipine and indapamide were also
found to be among the only three antihypertensive drugs to
significantly reduce mortality.33
Indapamide SR directly lowers peripheral resistance and has
a direct vasorelaxant effect on blood vessels which complements the vasodilation produced by amlodipine and enhances
the overall blood pressure reduction (Figure 4). Both drugs
control blood pressure over 24 hours, have been shown to reduce SBP variability,42 and share the common advantage of
being the most effective in lowering central blood pressure.43
In particular, a meta-analysis has shown that indapamide is
more effective than hydrochlorothiazide in reducing blood
pressure.44 Moreover, its neutral metabolic profile
has led NICE to recommend that, when a diuretic
is needed, a thiazide-like diuretic such as indapamide be preferred to hydrochlorothiazide.23
Hypertensive patients
ACE inhibitors: –10%
ARB: NS
At-risk patients
ACE inhibitors: – 8%
ARB: NS
Diabetic patients
ACE inhibitors: –16%
ARB: NS
Perindopril
Perindopril/indapamide
Perindopril/amlodipine
All-cause mortality
Figure 3. Mortality reduction in major meta-analyses including perindoprilbased combinations.
All-cause mortality reduction with ACE inhibitors and ARBs in different types of population:
at-risk patients, hypertensive patients, and diabetic patients.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker;
NS, not significant.
Based on data from reference 17: Lv et al. Cochrane Database of Syst Rev. 2012;12:CD004136.
doi:10.1002/14651858.CD004136.pub3; reference 33: van Vark et al. Eur Heart J. 2012;33,
2088-2097; and reference 36: Savarese et al. J Am Coll Cardiol. 2013;61:131-142.
460
The complementary action of these two strongly
active drugs appears to be particularly effective in
lowering SBP, a parameter for which there remains
a critical clinical need. A recent publication confirmed that, while DBP is frequently controlled in clinical practice, SBP is rarely, if ever, controlled.45 In addition, a low active RAAS is found in approximately
25% to 30% of hypertensive patients; as a result,
a combination of RAAS blockers will not be of much
benefit in these patients. The new amlodipine/indapamide combination will, therefore, be a welcome
addition to the range of therapeutic strategies available to physicians.
Indeed, there is still a great need for better blood
pressure control. Despite improvements in the treatment of hypertension, blood pressure remains uncontrolled in 60% of patients treated with a twodrug therapy,46 as demonstrated in a large pool of
COVERAM
Perindopril
Indapamide
Amlodipine
ACE
ANG II
BK
Antioxidant
NO
Ca2+
ANTIVASOCONSTRICTION
Renal sodium
excretion
PGI2
PGE2
VASODILATATION/VASORELAXATION
VOLUME DEPLETION
DECREASED BLOOD PRESSURE – CARDIOVASCULAR PROTECTION
patients (11 182 patients), whatever their sex or the initial twodrug therapy used. Triple therapy is more effective than twodrug therapy and monotherapy in reducing both SBP and
DBP. This superiority in blood pressure lowering ultimately results in organ protection, with a superior reduction in stroke
and ischemic heart disease.47 This was shown in a subanalysis of ADVANCE focusing on the patients who received a
CCB at baseline and all through the trial.48 There was a significant 28% reduction in total mortality and an almost significant 24% reduction in cardiovascular mortality in the patients
who received the perindopril/indapamide/CCB triple combination compared with the patients who received placebo in
addition to CCB. In addition, a prospective, multicenter, observational study in 12 064 patients with stage 1 or stage 2 primary hypertension reported a further reduction of 30 mm Hg
in SBP with perindopril/amlodipine/indapamide combination
after 4 months of treatment.49 This efficacy was maintained
over 24 hours, as demonstrated in an ABPM subanalysis, and
was clinically significant on account of the fact that 70% of
patients with uncontrolled hypertension at inclusion were already receiving treatment with ACE inhibitors/ ARBs ± hydrochlorothiazide.
Figure 4.
Complementary
modes of action
of perindopril,
amlodipine, and
indapamide as
a basis to fixeddose combination.
Abbreviations:
ACE, angiotensinconverting enzyme;
ANG II, angiotensin
II; BK, bradykinin,
NO, nitric oxide;
PGE2 , prostaglandin E2 ; PGI2 ,
prostacyclin
(prostaglandin I2 ).
Conclusion
Over the years, therapeutic advances in the management of
hypertension have emerged as a result of landmark trials which
have contributed to the recognition by all guidelines that the
purpose of treating hypertension is, above all, to reduce cardiovascular morbidity and mortality. Modern trials with combination therapy were true breakthroughs and have erected
evidence-based medicine as the gold standard.
Indeed, not only have they demonstrated the lifesaving benefits of perindopril-based combinations such as Coveram or
Preterax in a wide range of populations, from hypertensive patients to CAD or diabetic patients, but they have also provided the first clinical demonstrations that a reduction in all key
blood pressure parameters (brachial blood pressure, 24-hour
blood pressure, central blood pressure, and blood pressure
variability), as well as microcirculatory disorders and targetorgan damage, can contribute to a greater reduction in cardiovascular complications. This successful combination of some
of the most active drugs will be expanded by the arrival of
new fixed-dose combinations, for the benefit of both doctors
and patients. ■
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BMJ. 1998;317:703-713.
14. De galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces
renal events in type 2 diabetes. J Am Soc Neprol. 2009;20:883-892.
15. Lambers Heerspink HJ, Ninomiya T, Perkovic V, et al. Effects of a fixed combination of perindopril and indapamide in patients with type 2 diabetes and
chronic kidney disease. Eur Heart J. 2010;31:2888-2896.
16. Haller H, Sadayoshi I, Izzo JL, et al. Olmesartan for the delay or prevention of
microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364:907-917.
17. Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF. Antihypertensive
agents for preventing diabetic kidney disease. Cochrane Database of Syst Rev.
2012;12:CD004136. doi:10.1002/14651858.CD004136.pub3.
18. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects
of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med.
2010;362:1575-1585.
19. Bulpitt CJ, Beckett NS, Cooke J, et al; Hypertension in the Very Elderly Trial
Working Group. Results of the pilot study for the HYpertension in the Very Elderly Trial. J Hypertens. 2003;1:2409-2417.
20. Beckett NS, Peters R, Fletcher AE, et al; HYVET study group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:18871898.
21. Beckett N, Peters R, Tuomilehto, et al. Immediate and late benefits of treating
very elderly people with hypertension: results from active treatment extension to
hypertension in the very elderly randomized controlled trial. BMJ. 2012;344:
d7541.
22. Bulpitt CJ, Beckett N, Peters R, et al. Does white coat hypertension require
treatment over age 80?: results of the HYpertension in the Very Elderly Trial ambulatory blood pressure side project. Hypertension. 2013;61:89-94.
24. Dalhöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with
an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian
Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet. 2005;366:895-906.
25. Fagan TC. Evolution of the Joint National Committee Reports, 1988-1997 JNC.
Arch Intern Med. 1997;157:2401-2402.
26. Ramsay LE, Williams B, Johnston D, et al. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ. 1999;319:630-635.
27. Meurin P. The ASCOT trial: clarifying the role of ACE inhibition in the reduction
of cardiovascular events in patients with hypertension. Am J Cardiovasc Drugs.
2006;6:327-334.
28. Poulter NR, Wedel H, Dahlöf B, et al. Role of blood pressure and other variables
in the differential cardiovascular event rates noted in the Anglo-Scandinavian
Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet.
2005;366:907-913.
variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895-905.
30. Dolan E, Stanton AV, Thom S. Ambulatory blood pressure monitoring predicts
cardiovascular events in treated hypertensive patients—an Anglo-Scandinavian
cardiac outcomes trial substudy. J Hypertens. 2009;27:876-885.
31. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressurelowering drugs on central aortic pressure and clinical outcomes. Circulation.
2006;113:1213-1225.
32. Bertrand ME, Ferrari R, Remme WJ, et al. Clinical synergy of perindopril and
calcium-channel blocker in the prevention of cardiac events and mortality in
patients with coronary artery disease. Post hoc analysis of the EUROPA study.
Am Heart J. 2010;159:795-802.
inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998
patients. Eur Heart J. 2012;33:2088-2097.
34. Ferrari R, Fox K, Bertrand M, et al. Effect of angiotensin-converting enzyme
(ACE) inhibitors and angiotensin II receptor blockers (ARBs) on cardiovascular
mortality in hypertension: a meta-analysis of randomized controlled trials. Eur
Heart J. 2012;32(abstract suppl):951.
35. Ferrari R, Boersma E. The impact of ACE inhibition on all-cause and cardiovascular mortality in contemporary hypertension trials. Expert Rev Cardiovasc Ther.
2013;11:705-717.
36. Savarese G, Constanzo P, Cleland JGF, et al. A meta-analysis reporting effects
of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
in patients without heart failure. J Am Coll Cardiol. 2013;61:131-142.
37. National Heart Foundation of Australia and the Cardiac Society of Australia and
New Zealand. Reducing risk in heart disease: an expert guide to clinical practice for secondary prevention of coronary heart disease. Melbourne, Australia:
National Heart Foundation of Australia; 2012.
38. Agence Nationale de Sécurité du Médicament. Médicaments antihypertenseurs
agissant sur le système rénine-angiotensine: rappels des précautions d’emploi
et des règles de bon usage. Point d’information. March 13, 2013. Available at
http://ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Medicaments-antihypertenseurs-agissant-sur-le-systeme-renine-angiotensinerappels-des-precautions-d-emploi-et-des-regles-de-bon-usage-Point-d-information.
39. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high
cardiovascular risk treated with regimens based on valsartan or amlodipine:
the VALUE randomised trial. Lancet. 2004.363:2022-2031.
40. Zanchetti A, Gene Bond M, Hennig M, et al. Calcium antagonist lacidipine
slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation. 2002;106:2422-2427.
41. Matsuzaki M, Ogihara T, Umemoto S, et al. Prevention or cardiovascular events
with calcium channel blocker-based combination therapies in patients with
hypertension: a randomized controlled trial. J Hypertens. 2011;20:1649-1659.
42. Zhang Y, Agnoletti D, Safar ME, Blacher J. Effect of antihypertensive agents on
blood pressure variability: the NatriliX SR versus candesartan and amlodipine in
the reduction of systolic blood pressure in hypertensive patients (X-CELLENT)
study. Hypertension. 2011;58:155-160.
43. Morgan T, Lauri J, Bertram D, Anderson A. Effect of different antihypertensive
44. Baguet JP, Legallicier B, Auquier P, Robitail S. Updated meta-analytical approach to efficacy of antihypertensive drugs in reducing blood pressure. Clinical Drug Invest. 2007;27:735-753.
45. Tocci G, Rosei EA, Ambrosioni E, Borghi C, et al. Blood pressure control in
Italy: analysis of clinical data from 2005-2011 surveys on hypertension. J Hypertens. 2012;30:1065-1074.
46. Thoenes M, Neuberger HR, Volpe M, Khan BV, Kirch W, Böhm M. Antihypertensive drug therapy and blood pressure control in men and women: an international perspective. J Hum Hypertens. 2010;24:336-344.
47. Kjeldsen SE, Messerli FH, Chiang CE, Meredith PA, Liu L. Are fixed-dose combination antihypertensives suitable as first-line therapy? Curr Med Res Opin.
2012;28:1685-1697.
48. Chalmers J, Arima H, Woodward M, Poulter NR, Mancia G. Effects of combination of perindopril, indapamide and calcium channel blockers on death and
cardiovascular outcomes in patients with type 2 diabetes in the ADVANCE trial.
J Hypertens. 2013;31(e-suppl A):e111.
49. Pall D. The antihypertensive efficacy of the perindopril-amlodipine-indapamide
combination. J Hypertens. 2012;30(e-suppl A):e503.
Keywords: blood pressure; cardiovascular protection; combination therapy; hypertension management
462
COVERAM
OPTIMISATION DES ASSOCIATIONS MÉDICAMENTEUSES ET
PROTECTION CARDIOVASCULAIRE : CONCLUSIONS DES GRANDS ESSAIS CLINIQUES
Les récentes avancées dans le domaine de la protection cardiovasculaire ont mis en évidence l’intérêt d’utiliser des
associations médicamenteuses dans l’hypertension. Si la réduction de la pression artérielle demeure la finalité première d’un traitement antihypertenseur, la prévention de la morbidité et de la mortalité cardiovasculaire représente
désormais l’objectif à atteindre lors de la prise en charge du patient hypertendu. Associer des médicaments ayant des
modes d’action complémentaires dans un seul comprimé offre un réel avantage en termes d’efficacité et de rapidité
d’action. En outre, la meilleure adhérence des patients à leur traitement ainsi que l’amélioration du profil de tolérance
se traduisent aussi par un plus haut niveau de protection. Les grands essais cliniques que représentent ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) et HYVET (HYpertension in the Very Elderly Trial) ont d’ailleurs clairement démontré
l’avantage d’associer les médicaments antihypertenseurs leaders dans leur classe : l’inhibiteur de l’enzyme de conversion perindopril, le diurétique thiazidique indapamide ainsi que le bloqueur des canaux calciques amlodipine. De récentes méta-analyses ont en effet confirmé, d’une part, que les traitements en association basés sur le perindopril
permettent une réduction de 13% de la mortalité toutes causes ainsi qu’une réduction de 22% de la mortalité cardiovasculaire, et d’autre part, que ces traitements sont désormais reconnus comme le fondement de la prévention cardiovasculaire du patient à haut risque et du patient diabétique. Avec les nouvelles associations fixes combinant ces
mêmes molécules à venir, ce sont bientôt de nouveaux besoins thérapeutiques qui trouveront une réponse adaptée.
463
‘‘
INTERVIEW
Combination therapy should
be the first option for effective hypertension management. This therapeutic strategy can lead to a more
rapid reduction, and possibly normalization, of blood pressure values and to a consequent decrease
in cardiovascular risk. In addition,
available scientific evidence clearly indicates that combining ACE
inhibitors and calcium antagonists
can specifically provide adjunctive
protection from clinical events.”
Combinations in hypertension
and cardiovascular prevention:
are they additive or synergistic?
I n t e r v i e w w i t h S . Tad d e i , I t a l y
T
Stefano TADDEI, MD
Professor of Internal Medicine
Department of Clinical and
Experimental Medicine
University of Pisa
Pisa, ITALY
he correct use of combination therapy is crucial both to improve blood
pressure control and to reduce cardiovascular events. Antihypertensive
drugs can be effectively combined if they have different and complementary mechanisms of action. Thus, a typical combination contains drugs
blocking (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker) and stimulating (calcium antagonist or diuretic) the renin angiotensin system. An effective combination therapy is a combination with additive
or synergistic effects. The effect of a combination is additive when the blood
pressure reduction it induces is the sum of the single effects of each of its components, while it is synergistic when its clinical efficacy is greater than the sum
of the effects of the single components. A synergistic effect is clearly demonstrated when, despite similar blood pressure control, one drug combination
leads to a better outcome than another drug combination. This was the case
in ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure
Lowering Arm) and ACCOMPLISH (Avoiding Cardiovascular Events through
Combination Therapy in Patients Living with Systolic Hypertension), two trials
that demonstrated that ACE inhibitor/calcium antagonist combination results
in significant better protection than 웁-blocker/diuretic or ACE inhibitor/diuretic combination, respectively. It is worth noting that there is currently no evidence showing that angiotensin receptor blocker/calcium antagonist combination is as effective as ACE inhibitor/calcium antagonist combination. In
conclusion, in hypertensive patients, optimal treatment should be based on
combination therapy, and the combination of an ACE inhibitor with a calcium
antagonist should be the first choice. This strategy should lead to improved
blood pressure control and better protection from cardiovascular events.
What are the advantages of combining multiple-action drugs from
the pharmacological and clinical perspectives?
Prof Stefano Taddei, Department of
Clinical and Experimental Medicine,
University of Pisa, Via Roma 67,
56126 Pisa, Italy
464
sually, in the treatment of essential hypertension, a great emphasis is placed
on choosing the right drug for treatment initiation, despite the demonstration
that monotherapy can normalize blood pressure values in no more than 30%
to 40% of patients with grade 1 and 2 hypertension, and that it is absolutely not
effective in patients with grade 3 hypertension. Thus, for the majority of patients,
combination therapy should not be an option, but the cornerstone of antihypertensive treatment.
U
Combinations in hypertension and CV prevention: additive or synergistic? – Taddei
INTERVIEW
However, merely combining antihypertensive drugs together is not enough to obtain an effective combination treatment,
and expert selection of specific compounds with definite characteristics leading to a positive interaction is required. This is
a crucial issue since the combination of antihypertensive drugs
can lead to different results. In terms of blood pressure reduction, combining antihypertensive drugs can theoretically produce the following effects. (i) A combination that is not rational may have negative effects, which means that it produces
the same (or lower!) blood pressure reduction as each of its
single components. Combinations with a positive interaction
can either have (ii) additive or (iii) synergistic effects. The effect of a combination is additive when its blood pressure–
lowering effect is the sum of the effects of each single component. In contrast, a combination has a synergistic effect when
it produces an effect that is greater than the sum of the effects of its single components. However, while negative or
additive effects are defined according to the extent of blood
pressure reduction, synergistic effects are related to blood
pressure–independent cardiovascular protection.
Basically, when used rationally, combination therapy should
overcome the several limitations of antihypertensive drugs
used as monotherapy. The mechanisms determining the superiority of combination therapy over single-drug administration involve the pharmacological and clinical characteristics
of drug classes. Concerning antihypertensive efficacy, one major problem of monotherapy is the activation of reflex mechanisms that counterbalance, and therefore limit, the degree of
blood pressure reduction. For example, diuretics and calcium
antagonists may cause reflex activation of the renin angiotensin
system (RAS), while angiotensin receptor blockers (ARBs) increase plasma concentrations of angiotensin II (whose beneficial effect on AT2 receptors has never been demonstrated
in clinical conditions), and reductions in angiotensin II and aldosterone plasma concentrations with ACE inhibitors can be
counterbalanced by angiotensin escape. This explains why
the antihypertensive potency of drugs used as monotherapy
is relatively modest: a single drug can easily lower blood pressure values, but only in rare cases will it be able to normalize
this clinical parameter.
In contrast, combination therapy can overcome these limitations, but only if the drugs to be combined are selected on
account of their different and complementary mechanisms
of action. Thus, it is wise to combine a drug blocking the RAS
(ACE inhibitors, ARBs, b-blockers) with drugs that stimulate
this system (calcium antagonists, diuretics, vasodilators). In
the same way, drugs activating the sympathetic nervous
system should be combined with drugs blocking sympathetic activity. This is a fundamental aspect, which should be
considered when choosing combinations of antihypertensive
drugs. Unfortunately, this is not always the case in clinical practice. A typical example is the combination of an ACE inhibitor
with a b-blocker. This combination is used in the treatment of
hypertensive patients because of its effective cardiovascular
protection in specific clinical conditions such as post–myocardial infarction or heart failure. However, it has no additive
effect on blood pressure reduction since both drugs block
the RAS, as clearly demonstrated in the ALLHAT study (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial),1 where the blood pressure reduction obtained
with the combination of lisinopril and atenolol was significantly inferior to that obtained with the combination of chlorthalidone or amlodipine with atenolol.
Other limitations of monotherapy are related to adverse metabolic effects or the incidence of side effects. It is well established that diuretics can significantly alter carbohydrate and
lipid profiles, and that patients very often have to stop treatment with calcium antagonists, despite effective blood pressure reduction, because of ankle edema. Most of these limitations can be significantly reduced by combination therapy
and it has been demonstrated that RAS blockers can limit
both metabolic alterations induced by diuretics and ankle edema caused by calcium antagonists.
Finally, combination therapy can also offer adjunctive advantages from a clinical point of view. Rapid normalization of blood
pressure is an important target of antihypertensive treatment,
especially in patients at high or very high risk. In line with this
recommendation, recent evidence, although obtained by retrospective analysis, indicates that antihypertensive treatment
initiated with combination therapy can induce a more rapid
blood pressure reduction and/or normalization than monotherapy, and that this more rapid blood pressure control is
associated with a better outcome.2 In addition, combination
therapy results in a significantly greater reduction in global
cardiovascular, coronary, and cerebrovascular events than
monotherapy, independent of drug classes or blood pressure control.3
SELECTED
ACCOMPLISH Avoiding Cardiovascular Events through
Combination Therapy in Patients Living with
Systolic Hypertension
ACE
ADVANCE
Action in Diabetes and Vascular Disease
ALLHAT
Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial
ARB
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm
EUROPA
EURopean trial On reduction of cardiac events
disease
HYVET
Hypertension in the Very Elderly Trial
RAS
renin angiotensin system
465
INTERVIEW
Thus, there is solid evidence that combination therapy offers great advantages over monotherapy, not only in terms of
blood pressure reduction, but also because it provides specific cardiovascular protection. However, there are differences
in efficacy among the different possible combinations of antihypertensive drugs, and, therefore, it is crucial to choose certain combinations over others.
Which properties/effects of combination therapy
are considered to be additive?
s previously mentioned, the effects of combination
therapy that are considered to be additive are related to blood pressure reduction. Usually, the combination of drugs with complementary mechanisms of action
makes it possible to obtain a reduction in blood pressure that
is the sum of the effects of its single components. Thus, from
a clinical point of view, it is important to avoid those combinations that do not produce an additive effect or those that
have been clearly demonstrated to be inferior to other options.
In addition to the already mentioned ACE inhibitor (or ARB)/
b-blocker combination, other drug classes that should never
be combined are ACE inhibitors and ARBs, since both block
the RAS. Finally, another combination that should be absolutely avoided because of its negative effect is that of doxazosin—
an a1-blocker—with clonidine—an a2-agonist. In this case,
considering that the specificity for a receptor subtype is always relative, especially in clinical conditions, one drug reduces the blood pressure–lowering effect of the other, and
the outcome is, therefore, negative.
A
Apart from these specific examples, all other combinations of
antihypertensive drugs have additive effects and are, therefore, useful to obtain better blood pressure control. This is
highlighted by the availability of fixed combinations that increase the compliance of hypertensive patients considerably.
In addition to classical fixed combinations of RAS blockers
or b-blockers with diuretics, new fixed combinations of RAS
blockers with calcium antagonists are now available and increase the chance of choosing the best therapeutic strategy for hypertensive patients.
Is there any clinical difference between the use of a RAS blocker/diuretic combination and a RAS blocker/calcium antagonist combination? Concerning blood pressure lowering, both
regimens seem to be similarly effective. Their tolerability is also
similar, especially considering that RAS blockers reduce the
metabolic alterations induced by diuretics and ankle edema
induced by calcium antagonists.
However, blood pressure reduction is not the only mechanism
for cardiovascular protection and since scientific evidence
clearly indicates that some drug classes are better than others, as a consequence, some drug combinations are also better than others.
466
What does pharmacological and/or clinical synergy
mean?
combination has a clearly demonstrated synergistic
effect when, despite similar blood pressure control, it
leads to a better outcome than another drug combination. This kind of evidence indicates that the beneficial
effect of treatment is determined by specific mechanisms that
amplify the outcome related to blood pressure reduction.
A
In line with this are the results of ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering
Arm)4 and ACCOMPLISH (Avoiding Cardiovascular Events
through Combination Therapy in Patients Living with Systolic
Hypertension),5 which demonstrated that the combination of
an ACE inhibitor with a calcium antagonist results in significantly greater cardiovascular protection than b-blocker/diuretic or ACE inhibitor/diuretic combinations, respectively.
It is clear from this line of evidence that (i) different combinations of antihypertensive drugs, while producing a similar blood
pressure reduction, have a different impact on clinical outcomes, and that (ii) the combination of an ACE inhibitor with a
calcium antagonist offers the best cardiovascular protection in
hypertensive patients. In addition to the previously mentioned
ASCOT and ACCOMPLISH trials, an interesting analysis of
the results of EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease)
demonstrated a significant synergy between perindopril and
calcium antagonists, with a significant supplementary impact
on cardiac outcomes and mortality.6
Whether the beneficial effect of ACE inhibitor/calcium antagonist combination might be extrapolated to ARB/calcium antagonist combination is an interesting question. It should be
stated that it is scientifically incorrect to credit ARBs with the
same efficacy as ACE inhibitors. A meta-analysis evaluating
studies performed in hypertensive patients has demonstrated that ACE inhibitors, but not ARBs, can significantly reduce
total mortality further than comparators, the most important
clinical end point.7 It is worth noting that this beneficial effect
was essentially driven by the results of ASCOT, ADVANCE (Action in Diabetes and Vascular Disease),8 and HYVET (Hypertension in the Very Elderly Trial),9 which are all perindoprilbased clinical trials. This evidence was further reinforced by
another meta-analysis comparing the effect of ACE inhibitors
or ARBs versus placebo in high-risk patients.10 The results of
this study confirmed that ACE inhibitors significantly reduce
several hard end points such as myocardial infarction, heart
failure, and total mortality, but that ARBs, as a class, do not.
Another fundamental argument against the equivalence of
ARB/calcium antagonist combination and ACE inhibitor/calcium antagonist combination is the lack of specific trials, such
as ASCOT-BPLA or ACCOMPLISH, evaluating the effective-
INTERVIEW
ness of ARB/calcium antagonist combination versus any other combination of antihypertensive drugs, a lack of evidence
which was clearly highlighted in the European Hypertension
Guidelines.
In conclusion, combination therapy should be the first option for effective hypertension management. This therapeutic strategy can lead to a more rapid reduction, and possibly
normalization, of blood pressure values and to a consequent
decrease in cardiovascular risk. In addition, available scien-
tific evidence clearly indicates that combining ACE inhibitors
and calcium antagonists can specifically provide adjunctive
protection from clinical events.
Although ACE inhibitors are considered to be first-choice
drugs, especially on the basis of the results of recent metaanalyses,7,10 maybe it is time for us to change our attitude in
clinical practice and start considering ACE inhibitor/calcium
antagonist combination as the first-choice treatment for the
best protection from cardiovascular events. ■
References
1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial. Major outcomes in high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT). JAMA. 2002;288:2981-2997.
2. Gradman AH, Parisé H, Lefebvre P, et al. Initial combination therapy reduces the
risk of cardiovascular events in hypertensive patients: a matched cohort study.
Hypertension. 2013;61:309-318.
3. Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. Hypertension. 2011;58:566-572.
4. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906.
5. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk pa-
tients. N Engl J Med. 2008;359:2417-2428.
6. Bertrand ME, Ferrari R, Remme WJ, Simoons ML, Deckers JW, Fox KM; EUROPA Investigators. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study. Am Heart J. 2010;159:
795-802.
inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998
patients. Eur Heart J. 2012;33:2088-2097
8. Patel A; ADVANCE Collaborative Group, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the
ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
9. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-1898.
10. Savarese G, Costanzo P, Cleland JG, et al. A meta-analysis reporting effects
of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J Am Coll Cardiol. 2013;61:131-142.
Keywords: ACE inhibitors; angiotensin receptor blockers; calcium antagonists; essential hypertension; cardiovascular risk;
perindopril
LES
ASSOCIATIONS DANS L’ HYPERTENSION ET LA PRÉVENTION CARDIOVASCULAIRE
SONT- ELLES SYNERGIQUES OU ADDITIVES ?
Bien utiliser les associations médicamenteuses est essentiel afin d’améliorer le contrôle de la pression artérielle et de
diminuer le nombre d’événements cardiovasculaires. Des antihypertenseurs aux mécanismes d’action différents et
complémentaires peuvent être associés efficacement. Une association classique contiendra donc des médicaments
bloquant le système rénine angiotensine (inhibiteur de l’enzyme de conversion [IEC] ou antagoniste du récepteur de
l’angiotensine [ARA]) et d’autres le stimulant (antagoniste calcique [AC] ou diurétique). Un traitement d’association
efficace combine des effets additifs ou synergiques. L’effet est additif lorsque la diminution de pression artérielle induite représente la somme de chacun des effets de chaque composant. L’effet est synergique lorsque l’efficacité clinique est supérieure à la somme des effets des composants pris isolément. L’action synergique est évidente lorsque
les résultats d’une association médicamenteuse sont meilleurs que ceux d’une autre, et ce, malgré un contrôle identique de la pression artérielle. C’était le cas des études ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm) et ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in
Patients Living with Systolic Hypertension) dans lesquelles, respectivement, la protection obtenue par l’association
IEC/AC s’est montrée significativement meilleure que celle des associations bêtabloquants/diurétiques ou IEC/diurétiques. Remarquons qu’il n’existe actuellement pas de preuves d’une équivalence d’efficacité entre l’association
ARA/AC et l’association IEC/AC. Pour conclure, un traitement antihypertenseur optimal est une association qui comporte en première intention un IEC et un AC, ce qui devrait offrir un meilleur contrôle de la pression artérielle et une
meilleure protection contre les événements cardiovasculaires.
467
‘‘
U P DAT E
In diseases such as hypertension, it is evident that a better
understanding of the mechanisms
of the interactions between genetics and a variety of environmental factors is of the utmost importance. These include interactions
between stress, sodium intake/
other nutritional factors, physical
activity, or antihypertensive medications, and specific genetic polymorphisms, copy number variants,
and other genetic variants.”
Can genetics influence the
choice of antihypertensive
combination therapy?
b y P. H a m e t a n d J . Tre m b l a y, C a n a d a
I
Pavel HAMET, OQ, MD, PhD,
FRCP, FRSM, FAHA, FCAHS
n this early postgenomic era, the field of pharmacogenomics is now progressively entering a phase of clinical utility evaluation. In terms of therapeutics, many genomic markers have been identified that have an impact on drug metabolism, transport, and targets. Companion diagnostics is a
rapidly evolving field that exists in parallel to the development of drugs, and
will have future applications for personalized health care. When an opposite
effect is observed with two different combinations of antihypertensive drugs
in a clinical trial, differences can be expected at the level of genomic polymorphisms or transcriptional effects between subsets of study participants. With
the increasing availability of effective fixed-dose combinations of antihypertensive drugs, the development of companion diagnostics may offer rational
guidance for selection of the most appropriate combinations for long-term use
in individuals.
Genetic influence on key blood pressure parameters
ardiovascular death remains the number one cause of mortality and number
one health burden in Canada and throughout the world, with hypertension
the leading risk factor.1-3 It is thus relevant that hypertension remains one of
the most difficult complex diseases to resolve at the causal genetically-driven level,
with many other pathological conditions in recent years having had fundamental
aspects of their genetics revealed through the use of novel global genomic technologies. The complexity of hypertension is reflected in the fact that only about 30% to
40% of blood pressure variability is genetically determined, with environment playing a major causal role and interactions between genetic and environmental factors
also being of great importance. The past debate on the relative importance of nature
versus nurture in shaping human development is nowadays understood in terms of
gene-environment interactions. Although still not fully accepted, it is now evident
that a more relevant question is not which of the two is the most important, but
rather how these two determinants of life can—and do—interact. In diseases such
as hypertension, it is evident that a better understanding of the mechanisms of the
interactions between genetics and a variety of environmental factors is of the utmost importance. These include interactions between stress, sodium intake/other
nutritional factors, physical activity, or antihypertensive medications, and specific genetic polymorphisms, copy number variants, and other genetic variants.4 There are
several examples in the literature of the impact of a single allelic variant with a pleiotropic effect not restricted to a specific phenotype. One example is the fat mass and
C
Johanne TREMBLAY, PhD,
FCAHS, FAHA
Centre de Recherche du
Centre Hospitalier de
l’Université de Montréal
Quebec, CANADA
Prof Pavel Hamet or Prof Johanne
Tremblay, Centre de Recherche,
CHUM Technopôle Angus,
2901 rue Rachel Est, Bureau 401F,
Montréal, Quebec H1W 4A4, Canada
(e-mail: [email protected]
or [email protected])
468
Can genetics influence the choice of antihypertensive combination therapy? – Hamet and Tremblay
U P DAT E
obesity–associated gene, FTO. A single nucleotide polymorphism (SNP) in this gene (rs9939609) has been widely described as being associated with obesity and other components of the metabolic syndrome, but recent evidence also
points to a specific impact of the environment in the form of
high levels of dietary saturated fat, which accentuates the
risk of obesity in carriers of a specific allele of this particular
SNP.5 In our studies of obesity and hypertension, we have observed that FTO is particularly susceptible to environmental
modulation.6 We showed that the association of the FTO gene
with blood pressure is only apparent after withdrawal of antihypertensive medication, as the latter overshadows the relationship of the gene with blood pressure without affecting
its relationship with obesity.7 It has also been demonstrated
that the genetic risk for hypertension, as defined by an aggregate of most of the known risk alleles for obesity discovered
in recent genome-wide association studies (GWAS), may be
attenuated by as much as 40% by physical exercise.8 Most of
the phenotypes associated with cardiometabolic regulation—
including hypertension and its cardiovascular outcomes—are
polygenic in nature. This has best been demonstrated by a
multistage GWAS performed in nearly 200 000 individuals of
European descent, which identified 29 previously-known or
new SNP variants that influence blood pressure through pathways leading to the development of hypertension and its outcomes, including stroke and coronary heart disease.9 We have
shown a similar polygenic contribution in the French-Canadian
founder population, which points to synaptic plasticity pathways as forming a crossroads between hypertension, habitual substance use, obesity, and mental and physical stress10
in a paradigm of gene-environment interactions.
We strongly believe that the ingredients required for resolution of the pathophysiology of hypertension include much
more detailed phenotyping, lifelong observation of pathogenetic evolution, reduction of disease heterogeneity, and
integration of environmental data using ecogenomic11 and
epigenomic tools (www.epigenome.org).
Genetic influence on pharmacodynamic and
pharmacokinetic properties of hypertension
In humans, genetic variation is recognized as being an important determinant of drug response variability. Between 20%
and 95% of individual variability is genetically based, a result
of sequence variations in drug target proteins, drug-metabolizing enzymes, or drug transporters, which can alter drug
efficacy, drug side effects, or both. Genetic polymorphisms
of proteins involved in drug targeting (ie, pharmacodynamics) and drug metabolism and transport (ie, pharmacokinetics) are the most important causes of individual variability in
drug safety and efficacy. Some genetic variations can affect
these factors by changing the biological context or environmental sensitivity of the drug response. Examples of genetic
polymorphisms of antihypertensive drug targets are the wellknown insertion/deletion (I/D) variants located in intron 16 of
the angiotensin-converting enzyme (ACE) gene. McNamara
et al demonstrated that the ACE D allele was associated with
significantly poorer survival in patients with heart failure and
systolic dysfunction.12 The finding of increased left ventricular dimensions in patients with the DD genotype was in accordance with previous reports, and could be explained by
presumably greater concentrations of circulating and tissue
angiotensin II associated with the DD genotype. In addition,
high doses of ACE inhibitors and b-blockers had the greatest impact in patients with the DD variant (P=0.001) and the
least impact in those with I/D and II genotypes (P=0.38). The
ACE I/D genotype was also associated with the occurrence
of cough, a common side effect of ACE inhibitors. In a recent
meta-analysis of 11 trials that included 906 cases of ACE inhibitor–related cough and 1175 controls, Li et al confirmed a
significant association between the ACE I/D polymorphism
and ACE inhibitor–related cough in those studies that involved
participants with a mean age of >60 years,13 but not in studies in which the mean age of participants was ⱕ60 years. This
supports the notion that the ACE I/D polymorphism is an agedependent predictor of risk for ACE inhibitor–related cough.
The genetics of drug-metabolizing enzymes (pharmacokinetics) also plays a critical role in interindividual differences in antihypertensive drug response and adverse drug reactions. The
most important class of drug interactions involves the cytochrome P450 microsomal enzyme system.14 The ability to metabolize a drug along a specific pathway of the cytochrome
P450 enzyme system can be modulated by genetic polymorphisms. With CYP450 polymorphisms, individuals may process
the medication too rapidly (ultrarapid metabolizers) rendering
it ineffective, or too slowly (poor metabolizers) causing drug
concentrations to build up in the blood, potentially causing
adverse reactions, or in the case of prodrugs, ineffective activation. The CYP2C9, CYP2C19, and CYP2D6 enzymes are
highly polymorphic and together account for about 40% of
hepatic human phase I metabolism. The polymorphisms of
CYP1A2, CYP2A6, CYP2B6, and CYP2C8 also contribute to
interindividual differences in drug metabolism. CYP2D6 is probSELECTED
ACE
ADVANCE
Action in Diabetes and VAscular disease:
Preterax and DiamicroN MR Controlled
Evaluation
ASCOT
GWAS
genome-wide association study
HCTZ
hydrochlorothiazide
I/D
insertion/deletion (genotype variant)
SNP
single nucleotide polymorphism
469
U P DAT E
ably the most extensively studied drug-metabolizing enzyme
in humans; its polymorphism has high clinical importance and
was the first among the polymorphic CYP450s to be characterized at the molecular level. Today, more than 48 different
drug substrates have been identified for this enzyme, and
CYP2D6 is responsible for about 25% of the metabolism of
known drugs. About 10% of the general population has a slowacting form of this enzyme, and 7% have a super-fast-acting
form. In total, 35% are carriers of an abnormally functioning
CYP2D6 allele. The pharmacokinetics of b-adrenergic blocking agents such as propranolol are strongly affected by inducers and inhibitors of CYP2D6. Calcium channel blockers are
substrates for, and inhibitors of, CYP3A4. Most ACE inhibitors (eg, enalapril, fosinopril, perindopril, quinapril, ramipril,
and trandolapril) are prodrugs metabolized in the liver, although captopril and lisinopril are not. Some animal studies
indicate that prodrugs may undergo CYP3A4-dependent biotransformation. However, ACE inhibitors are not involved in
significant cytochrome P450–mediated interactions with other drugs. The angiotensin receptor blockers losartan and irbesartan seem to be primarily metabolized by CYP2C9, but hydrochlorothiazide (HCTZ) and chemically-related diuretics are
not metabolized by CYP450s, but rather are eliminated by the
kidney.15
A growing number of drugs have companion diagnostics, and
more than a dozen marketed medications propose or recommend genetic testing for optimal treatment. These examples
of the successful use of pharmacogenetic testing, unraveling
the basis for certain individual drug responses caused by single-gene polymorphisms, can guide future pharmacogenomics
research and its application. Realistically, pharmacogenomics
will require complex polygenic and gene-environment considerations in order to prove its clinical utility.
The final response to a drug is determined not only by the
aforementioned polymorphisms in genes involved in its metabolism, transport, and target, but also importantly in its gene
function, ie, transcriptomic consequences. These, in turn, are
the final reflection of complex regulation at the gene expression level, which is subject to intergenic DNA sequence influences, such as those of noncoding RNA. Research into gene
pathways and networks, the integration of genetics and genomics, proteomics, metabolomics and epigenetics, noncoding RNA derived from hypothesis-free investigation through
GWAS, and prospective clinical trials evaluating the utility and
cost-effectiveness of genetic testing in drug therapy are a few
examples of areas of exploration that must continue.
Pharmacological target polymorphisms that can
modify treatment efficacy
Drug/test combinations (Rx-Dx) using companion diagnostics
have the potential to provide many clinical benefits to patients,
including identification of potential responders to a specific
drug, identification of individuals at risk of adverse events, or
470
use as an adjunct tool for monitoring responses to drugs. A
new drug and its companion diagnostics should be developed in parallel, with a cross-reference in the labeling information of both products. The US Food and Drug Administration
has recently decided to accelerate the approval of drugs accompanied by companion diagnostics.16 In cancer treatment,
it is now possible to prioritize small therapeutic molecules by
integrating various omics databases.17
Rationalized drug selection is progressing in such difficult areas as hepatocellular carcinoma, where combination of wholetumor genomic and transcriptomic data with epigenomic
analysis is leading to improved tumor classification and drug
selection.18 Similarly, in renal cell carcinoma, assessment of
resistance to sorafenib is based not only on genomic polymorphisms, but also its reversibility as detected in studies of
tumor transcriptome.19
In the field of hypertension, as mentioned, an international consortium of blood pressure GWAS identified 29 SNPs associated with hypertension, which also predicted heart failure,
stroke, and ischemic heart disease.9 Marques et al published
a meta-analysis of 74 available microarray experiments integrating genome-transcriptome approaches to identifying
genes exhibiting altered expression in the kidney, adrenal
gland, heart, and artery of spontaneously hypertensive rats
and Lyon hypertensive rats compared with normotensive controls.20 When possible, they separately analyzed the results
obtained in young animals (less than 6 weeks of age) from
the results obtained in adult rats to differentiate between the
onset and maintenance phases of hypertension. While both
phases may share common pathophysiological mechanisms,
they suggested that different gene sets are responsible for the
development and maintenance of hypertension. In another
study, transcriptional analysis was performed in spontaneously hypertensive rats with left ventricular hypertrophy treated
with different classes of antihypertensive agents, which confirmed the importance of cell growth/proliferation, signal transduction, development, and muscle contraction/cytoskeleton
functional groups.21 Although similar genes were affected by
the use of different antihypertensives during the course of reduction of left ventricular hypertrophy, therapy with: (i) quinapril;
(ii) doxazosin and quinapril combination; and (iii) losartan
showed distinct patterns of gene expression. We can expect
that when biological differences are noted between two drugs,
their functional impact at the gene level will also be different.
Thus, for instance, the effects of HCTZ on blood pressure and
metabolism are different from those of indapamide. We found
that when indapamide or HCTZ were given to patients for a
period of 6 months, different proliferative activities were seen
in platelet extracts from these patients, depending on which
drug they had been given. Indapamide treatment resulted in
much lower proliferative activity, despite HCTZ causing a more
pronounced blood pressure reduction, actually similar to that
U P DAT E
of an ACE inhibitor.22 As HCTZ is the most frequently-used
antihypertensive drug in combination therapy, but combination therapy with indapamide has been shown to be effective
in lowering total mortality, we recently compared the transcriptomic profile of kidneys from spontaneously hypertensive rats
treated with indapamide or HCTZ. Our preliminary results
showed that while the expression of 218 genes was modulated in the same direction by both drugs,23 645 and 593 genes
were differentially expressed with use of HCTZ and indapamide, respectively. Our data indicate that the differences observed between the two drugs could reside in their differential capacity to induce hypotensive and proliferative genes.
It is important to underline here that this type of study is feasible in humans: genomic DNA (for SNPs, copy number variations, epigenetics) is readily obtained from circulating nuclear
cells from whole blood or from lymphocytes. Moreover, mRNA
and DNA can now be obtained from the same sample of
blood using RNAase inhibitors and specialized tubes for relatively easy separation of DNA and RNA. Importantly, RNA
extracted from blood has proven useful in the study of the
expression of many genes, including those of drug metabolizing enzymes.24
The therapeutic orientation in hypertension is rapidly changing from single drug therapy to fixed-drug combinations, even
as initial therapy, as combinations are more effective in reaching therapeutic targets and are sometimes subject to fewer
side effects through combination of complementary pathways.
Since “hard” clinical outcome studies are currently a prerequisite for uptake of a drug by physicians, the decline observed
in total mortality with use of the combination of amlodipine
and perindopril versus atenolol and HCTZ in the ASCOT trial
(Anglo-Scandinavian Cardiac Outcomes Trial) was seminal in
supporting the amlodipine–perindopril combination; ADVANCE
(Action in Diabetes and VAscular disease: Preterax and DiamicroN MR Controlled Evaluation) was similarly seminal for
support of the combination of perindopril with indapamide
versus “usual therapy.” ACCOMPLISH (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with
Systolic Hypertension) compared the combinations of amlodipine and benazepril with amlodipine and HCTZ. The calcium channel blocker and ACE inhibitor combination demonstrated a significant superiority on the composite outcome of
death and cardiovascular events (primary end point),25 and
renal events, as revealed by estimated glomerular filtration rate
(eGFR) levels.26 However, the biological difference between
these two combinations was revealed through a subanalysis
of diabetic individuals in ACCOMPLISH.27 While the ACE inhibitor–calcium channel blocker combination was superior to
the ACE inhibitor–HCTZ combination in lowering eGFR levels
(–2.2% versus -9.9%), it actually led to an increase in microalbuminuria of 92.2 mg/g. By contrast, the ACE inhibitor–
HCTZ combination produced a decrease of 20.1 mg/g in
microalbuminuria levels at the end of the study. Our interpretation of these results is that a subset of diabetic individuals
Network-based
target identification
Unmet needs
identification
Validation and
optimization
Comparative network analysis of
RESPONDERS vs. NONRESPONDERS
(outcome-dependent)
Markers (hubs) in
ACE inhibitor/diuretic responders
Markers (hubs) in
ACE inhibitor/CCB responders
Validation and optimization
(eg, deep sequencing)
Figure. Proposed framework for the future development of personalized medicine
Abbreviations: ACE, angiotensin-converting enzyme; CCB, calcium channel
blocker.
may exist in whom the combination of an ACE inhibitor with
a calcium channel blocker is beneficial for many outcomes,
while in another subset of diabetic indviduals, this combination can clearly be detrimental to renal function, as reflected
by the increase in micoalbuminuria levels. This is particularly
relevant, as microalbuminuria is a predictor of outcomes in the
general population and in both type 1 and type 2 diabetics.28-30
We therefore propose the joint use of biomarkers and genetic markers that have demonstrated predictive power for cardiovascular outcomes31 in the identification of individuals who
will better respond to specific drug combinations. This should
be carried out within the framework for the future development of personalized medicine outlined in the scheme illustrated in the Figure. ■
References
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2. Joffres MR, Hamet P, MacLean DR, L'Italien GJ, Fodor G. Distribution of blood
pressure and hypertension in Canada and the United States. Am J Hypertens.
2001;14:1099-1105.
3. Mathers CD, Loncar D. Projections of global mortality and burden of disease
from 2002 to 2030. PLoS Med. 2006;3:e442.
4. Pausova Z, Tremblay J, Hamet P. Gene-environment interactions in hyperten-
sion. Curr Hypertens Rep. 1999;1:42-50.
5. Phillips CM, Kesse-Guyot E, McManus R, et al. High dietary saturated fat intake
accentuates obesity risk associated with the fat mass and obesity-associated
gene in adults. J Nutr. 2012;142:824-831.
6. Pausova Z, Syme C, Abrahamowicz M, et al. A common variant of the FTO gene
is associated with not only increased adiposity but also elevated blood pressure in French Canadians. Circ Cardiovasc Genet. 2009;2:260-269.
7. Noël A, Seda O, Tremblay J, et al. The impact of pharmacological environment
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on capacity to identify the genetic components of hypertension. Presented at:
23rd International Society of Hypertension Congress; 26-30 September, 2010;
Vancouver, Canada.
8. Li S, Zhao JH, Luan J, et al. Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective
population study. PLoS Med. 2010;7:e1000332.
9. Ehret GB, Munroe PB, Rice KM, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103109.
10. Nikpay M, Seda O, Tremblay J, et al. Genetic mapping of habitual substance
use, obesity-related traits, responses to mental and physical stress, and heart
rate and blood pressure measurements reveals shared genes that are overrepresented in the neural synapse. Hypertens Res. 2012;35:585-591.
11. Dumas P, Kren V, Krenova D, Pravenec M, Hamet P, Tremblay J. Identification
and chromosomal localization of ecogenetic components of electrolyte excretion. J Hypertens. 2002;20:209-217.
12. McNamara DM, Holubkov R, Postava L, et al. Pharmacogenetic interactions
between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol. 2004;44:2019-2026.
13. Li YF, Zhu XM, Liu F, et al. Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: a meta-analysis.
PLoS One. 2012;7:e37396.
14. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5:6-13.
15. Flockhart DA, Tanus-Santos JE. Implications of cytochrome P450 interactions
when prescribing medication for hypertension. Arch Intern Med. 2002;162:405412.
16. Schmidt C. Challenges ahead for companion diagnostics. J Natl Cancer Inst.
2012;104:14-15.
17. Knox C, Law V, Jewison T, et al. DrugBank 3.0: a comprehensive resource for
‘omics’ research on drugs. Nucleic Acids Res. 2011;39:D1035-D1041.
18. Marquardt JU, Galle PR, Teufel A. Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies. J Hepatol. 2012;56:267-275.
19. Zhang L, Bhasin M, Schor-Bardach R, et al. Resistance of renal cell carcinoma
to sorafenib is mediated by potentially reversible gene expression. PLoS One.
2011;6:e19144.
20. Marques FZ, Campain AE, Yang YH, Morris BJ. Meta-analysis of genome-wide
gene expression differences in onset and maintenance phases of genetic hypertension. Hypertension. 2010;56:319-324.
21. Gallego-Delgado J, Connolly SB, Lázaro A, et al. Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies. Hypertens Res. 2009;32:347-357.
22. Hadrava V, Kruppa U, Russo RC, Lacourciere Y, Tremblay J, Hamet P. Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. Am Heart J. 1991;122:1198-1203.
23. Dumas P, Corbeil G, Godefroid G, Tremblay J, Hamet P. Differential transcriptomics of indapamide and hydrochlorothiazide in SHR kidney. Poster presented at: 24th Meeting of the International Society of Hypertension; September
30-October 4, 2012; Sydney, Australia.
24. Siest G, Jeannesson E, Marteau JB, et al. Transcription factor and drug-metabolizing enzyme gene expression in lymphocytes from healthy human subjects.
Drug Metab Dispos. 2008;36:182-189.
25. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:
2417-2428.
26. Bakris GL, Sarafidis PA, Weir MR, et al. Renal outcomes with different fixeddose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet. 2010;375:1173-1181.
27. Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. 2010;
56:77-85.
28. de Boer IH, Sun W, Cleary PA, et al. Intensive diabetes therapy and glomerular
filtration rate in type 1 diabetes. N Engl J Med. 2011;365:2366-2376.
29. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc
Nephrol. 2009;20:1813-1821.
30. Smink PA, Lambers Heerspink HJ, Gansevoort RT, et al. Albuminuria, estimated GFR, traditional risk factors, and incident cardiovascular disease: the
PREVEND (Prevention of Renal and Vascular Endstage Disease) study. Am J
Kidney Dis. 2012;60:804-811.
31. Wong MG, Perkovic V, Woodward M, et al. Circulating bone morphogenetic
protein-7 and transforming growth factor-beta 1 are better predictors of renal end points in patients with type 2 diabetes mellitus. Kidney Int. 2013;83:
278-284.
Keywords: companion diagnostics; gene-environment interaction; genetic polymorphism; hypertension; pharmacogenomics
LA
GÉNÉTIQUE PEUT- ELLE INFLUER SUR LE CHOIX DES ASSOCIATIONS ANTIHYPERTENSIVES
?
A l’aube de cette ère post-génomique, le domaine de la pharmacogénomique entre maintenant progressivement
dans une phase d’évaluation de son utilité clinique. En termes de traitement, de nombreux marqueurs génomiques
ayant un impact sur le métabolisme, le transport et les cibles médicamenteuses ont été identifiés. Le domaine des
tests diagnostiques dits « compagnons » évolue rapidement, en parallèle au développement des médicaments, et
aura à l’avenir des applications en matière de médecine personnalisée. Lorsque dans une étude clinique on observe
des effets opposés avec deux associations différentes d’antihypertenseurs, on peut s’attendre à ce qu’il y ait des différences au niveau des polymorphismes génomiques ou des effets transcriptionnels entre des sous-groupes de participants. Étant donné le nombre croissant d’associations à doses fixes d’antihypertenseurs efficaces disponibles,
le développement de tests diagnostiques compagnons pourrait permettre de choisir de façon rationnelle les associations les plus appropriées pour une utilisation à long terme.
472
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OF FRANCE
tep back in time to celebrate
the centenary of one of the
most beautiful perfoming
venues in Paris, the Théâtre des
Champs-Elysées, which held the
premiere of The Rite of Spring 100
years ago, and the bicentenary of
the birth of French physiologist
and philosopher Claude Bernard,
who introduced the experimental
method in medicine. Taking nothing for granted, Bernard was convinced that knowledge progressed
constantly and evolved over time.
Read on to find out more…
S
Claude Bernard (1813-1878)
and experimental medicine
C . R é g n i e r, Fra n c e
La leçon de Claude
Bernard by Léon
Lhermitte shows
Bernard with his pupils
in his Collège de France
laboratory.
© Wellcome Library, London.
The Théâtre des
Champs-Elysées: the venue
that launched a masterpiece
D . M a r s h , Fra n c e
Every year some
300 000 people come
to the Théâtre des
Champs-Élysées in
Paris for concerts and
recitals in the main
auditorium, plays at
the Comédie, and exhibitions in the Studio.
© Bertrand Rindoff
Petroff/Getty Images.
473
A TOUCH
espite his preference for
literature, Claude Bernard
was urged to take up the
study of medicine. He became an
“intern” at the Hôtel-Dieu de Paris
where he met the great physiologist François Magendie whom
he succeeded at the Collège de
France. For Bernard, scientific truth
had to be objective and demonstrable: “Theories are only hypotheses, verified by more or less numerous facts. Those verified by the
most facts are the best but even
then they are never final, never to
be absolutely believed.”
OF
FRANCE
D
Claude Bernard (1813-1878)
and experimental medicine
b y C . R é g n i e r, Fra n c e
© All rights reserved
A
Christian RÉGNIER, MD
Pierre and Marie Curie University
(UPMC – Paris 6)
International Society for the
History of Medicine (ISHM)
9 rue Bachaumont
75002 Paris
(e-mail:
[email protected])
s a pioneer of modern physiology, then as a philosopher who laid the
foundations of the experimental method in medicine, Claude Bernard
(1813-1878) is an emblematic figure in French science of the mid-19th
century. His method, discoveries, and vocabulary left a lasting mark on medicine. He worked on a range of topics in parallel between 1844 and 1865: hepatic glycogenesis, nutrition and pancreatic secretion, the effects of curare, gas
exchange in red blood cells, and sensory and motor innervation. This colossal
undertaking had but a single aim: to define the concept of the milieu intérieur
(‘environment within’) that subtends all animal or plant life. Pasteur, who concentrated on much more practical research topics, was his ardent supporter.
In 1865, he was one of the few scientists to offer an enthusiastic welcome to
the publication of Claude Bernard’s Introduction to the study of experimental
medicine, a philosophical manifesto on medical research and the conditions
subtending life. Yet the two scientists fell out around 1877 over conflicting interpretations of anaerobic alcoholic fermentation. Claude Bernard was the first
French scientist to receive a State funeral. On February 16, 1878, after the service in the church of Saint-Séverin, 4000 mourners followed the cortege to Père
Lachaise cemetery. Republicans lost no time in claiming this agnostic Second
Empire senator as their own, thus marking the entry of modern science into
the political arena: politicians transposed to the social sciences the experimental method that Claude Bernard had applied to medicine.
o use a word which he himself introduced into the vocabulary of French
science, nothing “determined” Claude Bernard to become a doctor, an experimenter of genius, a pioneer of modern physiology, and a man of whom
a former student, the physiologist and politician Paul Bert (1833-1886), recalled:
“He made discoveries the way that others breathe. With grace and good faith. It
was his cardinal quality. In everything he did he showed the same deep sincerity
of the scientist in search of the truth for its own sake and for the sake of the truths
that follow.”1
T
474
Born on July 12, 1813 into a family of winemakers in Saint Julien en Beaujolais, near
Villefranche sur Saône (department of the Rhône), Claude Bernard learned Latin,
Greek, geometry, and arithmetic from the fathers in the diocesan school, but did not
sit the baccalaureate. He was imbued with Cartesian philosophy and the Romantic
movement.
Claude Bernard and experimental medicine – Régnier
A TOUCH
OF
FRANCE
Claude Bernard acted on this advice without further ado.
After passing an Arts baccalaureate, he enrolled in the Paris
Faculty of Medicine in November 1834, qualifying as a junior
resident five years later, although only 26th out of 29. On December 7, 1843, he defended his doctoral thesis Gastric juice
and its role in nutrition, only to fail the university lecturer examination, the agrégation, the following year. He made friends
during his student years with the future psychiatrist ErnestCharles Lasègue (1816-1883), and the pioneering bacteriologist and microbiologist Casimir Davaine (1812-1882).3,5
In the footsteps of the master, François Magendie
Claude Bernard spent most of his residency at the since demolished La Charité hospital in Paris under Alfred Velpeau
(1795-1867) in surgery and Pierre Rayer (1793-1867) in medicine. Rayer took him under his wing, introducing him to the
positivist Émile Littré. Future physician to Napoleon III (18081873), Rayer’s interests were in kidney disease, diabetes, and
dermatology; he was impressed by the young doctor’s powers of deduction. Claude Bernard also did residencies at the
Hôtel-Dieu under the surgeon Jacques Gilles Maisonneuve
(1809-1897) and at the Salpêtrière under the psychiatrist
Pierre Falret (1794-1870).3,5
Photographic portrait of Claude Bernard (1813-1878) by
Guillemet. Musée Claude Bernard. © Coll. BIU Santé (Paris).
At 19, he was taken on as an assistant by a pharmacist in
nearby Vaise, and began delivering some of his preparations
to the School of Veterinary Medicine in Lyon. This introduced
him to their laboratories, operating rooms, and animal houses. He stayed with the pharmacist for 19 months, at which
point his apprenticeship was abruptly terminated after he
made a mistake in one of his concoctions.2,3 After tasting fleeting success with several performances of
his vaudeville La rose du Rhône in a Lyon
theater, he came to Paris in November 1834
to deliver a newly-completed historical romance, Arthur de Bretagne, to Saint-Marc
Girardin (1801-1873), a member of Parliament, professor of literature at the Sorbonne,
and theater critic. Legend has it that this illustrious figure advised him: “You have a
background in pharmacy, young man. Why
not study medicine? You could do better
writing scientific articles. Keep literature for
relaxation.”2-4
By pure chance, in 1841 at the Hôtel-Dieu, he came under
François Magendie (1783-1855), for whom the chair in experimental medicine had been established at the Collège de
France ten years previously. A former surgeon, Magendie had
published multiple papers on experimental physiology between 1809 and 1816, including the celebrated Elementary
compendium of physiology, which for long had been a standard work in the field. As a member of the Academy of Sciences since 1821, he had founded the first French physiology
journal, the Journal de physiologie expérimentale et pathologique (which folded in 1831). Magendie described the mo-
The house in which Claude Bernard was born,
in Saint Julien en Beaujolais (department of the
Rhône, France). Photo taken in 1931. Born into a
family of winemakers, Bernard learned Latin,
Greek, geometry, and arithmetic at the local
diocesan school.
© Coll. Académie Nationale de Médecine.
475
A TOUCH
OF
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tor function of the ventral spinal nerve roots and provided a
partial explanation of the sensorimotor reflex. He also studied the mechanism of action of strychnine using methods that
heralded modern pharmacology.
Having noted Claude Bernard’s skill with the scalpel (so the
legend goes), Magendie appointed him as his assistant from
1841 to December 1844; he taught him the discipline required
to conduct experiments using live animals, introduced him
to vivisection, and trained him in the critical appraisal of scientific dogmas and systems. Master and pupil worked together on neurophysiology, cerebrospinal fluid, thermoregulation, and pharmacology.3,5,6
Françoise Martin, the financially well-endowed daughter of
a Paris physician, putting money troubles behind him. After
patching up the relationship with Magendie (thanks to peacemaking by Rayer), he stood in for him at the Collège de France
in 1847, teaching the winter semester. Magendie then transferred his laboratory and chair to him from 1852; Claude Bernard became his official successor on Magendie’s death in
1855.3,5,6
In his inaugural lecture on February 29, 1856, Claude Bernard
paid tribute to his departed mentor: “Mr Magendie felt a truly
extraordinary repulsion towards thinking in systems […] His
predominant idea was to fix the experimental method in medicine and physiology once and for all […] When people said to
him: ‘According to such and such a law, things should happen in such and such a way’ or ‘Analogy shows that events will
follow such and such a course’, he’d reply: ‘I have no idea;
conduct an experiment and tell me what you find.’ ‘Conduct
an experiment’ was his stock answer for forty years to all questions of this kind. […] He only said what his eyes had seen,
and he would wait for other experiments and experiences
to supply new items of evidence that might solve the problem […] So finally, gentlemen, you can see that although science has had the misfortune to lose Mr Magendie, he remains
with us in spirit and the method we received from him is what
continues to guide us today.”7
Claude Bernard was always attached to the style of teaching
dispensed at the Collège de France, describing it as being directed at science in the making rather than at science made:
“It must always reflect the state of the art in medical science,”
in contrast to the teaching dispensed in the faculties which
he characterized as based on the acquisitions of the past.
19th century French School painting of François Magendie.
Oil on canvas. Magendie is considered as a pioneer of modern experimental physiology. © Bibliothèque de l’Académie Nationale de Médecine.
In 1844, after failing the agrégation, Claude Bernard experienced a period of doubt compounded by disagreement with
his mentor, who shut him out of the laboratory. Magendie accused him of privileging theory at the expense of practice.
Claude Bernard was also having financial problems conducting his own research in his laboratory in the Cour Saint André
des Arts. Rayer found him some additional income preparing dissections for the lithographer Jacob who was illustrating
Bourgery’s celebrated Anatomical Atlas.
In 1845, with his friend Lasègue, he opened a laboratory and
private physiology school which closed fairly quickly due to a
lack of students. In May of the same year, he married Marie
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Claude Bernard was an indifferent public speaker but he interspersed his lectures with impromptu experiments, attracting a large audience from around the world, some of whom
became his disciples: Arsène d’Arsonval, Paul Bert, Albert
Dastre, Louis Gréhant, Willy Kühne, Élie de Cyon, Louis Ranvier, Ivan Setchenov, Angelo Mosso, Edmé Vulpian, Louis
Charles Malassez, Peter Ludwig, Benjamin Ball, Austin Flint,
and William Horner.3,5,6
Skills and methods
Claude Bernard conducted his experiments in the modest
laboratory of the Collège de France (known as “the cellar”),
at the Sorbonne, in the National Museum of Natural History,
at the School of Veterinary Medicine in Maisons-Alfort, and in
slaughterhouses. His friend Ernest Renan (1823-1892), who
held the Hebrew chair at the Collège de France, recalled: “It
was a striking spectacle to see him in his laboratory, thoughtful, sad, absorbed, totally focused, and unsmiling. He felt he
was doing sacred work, celebrating a kind of sacrifice. His long
fingers delved into the wounds like those of an augur in Antiquity, chasing mysterious secrets within the entrails of victims.”
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Collège de France
(Paris). Claude
Bernard attended
François Magendie’s
courses here and
himself became a
professor at the
Collège de France
in 1853. Photomechanical reproduction.
Maison parisienne
Berthaud frères.
© Coll. BIU Santé (Paris).
La leçon de Claude Bernard by Léon Lhermitte shows Bernard with his pupils in his Collège de France laboratory. © Wellcome Library, London.
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Renan took over Claude Bernard’s chair at the French Academy. The practice of vivisection earned the physiologist the
profound disapproval of many detractors, in particular his own
wife and two daughters who joined anti-vivisectionist leagues
such as the Animal Protection Society (registered as being of
public utility in 1866).8
Bernard had a solid grounding in anatomy, “a simpler science than physiology, and one which thus should be subordinate to it, rather than dominate it. Any explanation of the
phenomena of life based exclusively on anatomical considerations is necessarily incomplete.” He had no time for “vitalism”, a theory still in vogue at the start of the 19th century
which held that the phenomena of life were subject not to the
laws of physics and chemistry but to a “vital force” emanating
from living tissues. Yet he admired the work of Xavier Bichat
(1771-1802), “the greatest anatomist of the modern era,” without sharing the vitalist theories contained in his Treatise on
membranes (on tissue anatomy) published in 1800.7,9
Bernard was an excellent chemist. He admired the discoveries made by Antoine Laurent de Lavoisier (1743-1794) and
Pierre de Laplace (1749-1827). He worked with the chemist
Charles Barreswill (1817-1870) in the laboratory of ThéophileJules Pelouze (1807-1867) in rue Dauphine. He also studied the biochemistry of fats with his chemist friend Marcellin
Berthelot (1827-1907). In his doctoral thesis (1843) on the
role of gastric juice in digestion, he used his chemistry training
to measure fasting and postprandial gastric acidity.5,10
Unlike the German physiologists, he made little use of measuring instruments to quantify the phenomena of life; he even
criticized German physiology for too often being reducible
to a series of physicochemical reactions. The Germans reciprocated by considering Claude Bernard an impulsive and
romantic experimentalist overinclined to generalization. He
also made little use of the microscope, on the grounds that it
“narrowed the mind.” In the Red notebook where he entered
his more private thoughts, he wrote: “An excess of microscopy
does a disservice to physiology. It ends up making everything the same, leaving us with effects without causes.” This
accounts for his reservations over the cell pathology research
by Rudolf Virchow (1821-1902) that failed to take cell chemistry reactions into account.1,5,10
While acknowledging the contribution of mathematics and statistics in establishing quantitative demonstrations, Bernard
issued this warning to fellow experimentalists: “It is not that
I wish to outlaw the application of mathematics to biological
phenomena, since this ultimately is where the future of the science lies; but my conviction is simply that a general equation
is impossible for the moment: the qualitative study of phenomena must necessarily precede their quantitative study.”4,8,9,11
Claude Bernard made daily jottings of his observations,
thoughts, and comments, together with lecture and reading
notes, on the most varied of materials, mostly backs of envelopes, loose sheets of paper, and little notebooks. Archived
in the Collège de France, Academy of Sciences, Academy of
Medicine and the Claude Bernard Museum in Saint Julien en
Beaujolais, this scattered material was assembled and classified in the late ’60s by Mirko D. Grmek, who tracked and
unraveled the innermost thoughts and intellectual trajectory—marked by failure, frustration, and success—of a man in
search of truth.
Illustrated Anatomical Atlas. By Jean-Marc Bourgery and Claude
Bernard, and the anatomist and artist Nicolas-Henri Jacob.
Anterior view of the superficial muscles of the trunk.
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Determined to pursue his research in the absence of any preconceived ideas and to keep his mind entirely free, Claude
Bernard worked on several fronts simultaneously. Comparing and contrasting his experiences and experiments, he was
always reworking his notes and observations in the conviction that knowledge constantly progressed and evolved over
time. The thread running through all his experiments and discoveries was his drive to understand the milieu intérieur, or
environment within.10,12
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Color lithograph of the pancreas by Borromée and Lackerbauer from Claude Bernard’s 1859 paper on the pancreas and
the role of pancreatic juice in digestion.
Marcellin Berthelot in his laboratory. Wood engraving by Guth
and Florian. Claude Bernard’s notes on alcoholic fermentation
were published five months after his death by Berthelot.
Main research interests:5,10,11,13
◆ Glycogenesis (1843-1857). His research on “animal glycogenesis” began with the famous “liver wash-out” experiment
(1855). Later, with Charles Barreswill, he chemically identified
glycogen as the precursor of glucose. His doctor of science
thesis on hepatic glycogenesis (1853) paved the way for enzymology.
◆ Nutrition (1843-1860). The publication in 1859 of his Report
on the pancreas and the role of pancreatic juice in digestion
marked the first stage of his studies in nutrition. He discovered the function of bile in protein digestion and in 1860 published his Lectures and physiological experiments on nutrition.
◆ Mechanism of action of curare and strychnine (1843-1853).
“Curare simply interrupts something motor that creates an
electrical connection between muscle and nerve through movement.” Claude Bernard predicted the existence and role of
the motor plate but could not prove it experimentally. However, he was wrong about the site of action of curare, locating
it at the distal extremity of the motor nerve.
◆ Carbon monoxide poisoning and the mechanisms of oxygen-carbon dioxide exchange (1846-1856). He explained the
role of red blood cells in respiration, showing that oxygen
bound to hemoglobin: “These respiratory elements circulate
with the blood and alternately absorb oxygen on contact with
air, at the lung surface, then transport it into the depths of the
milieu intérieur, in contact with the fixed histological elements
of living tissues.”
◆ Nervous system (1844-1858). In addition to his unfinished
studies on the anatomy and physiology of the chorda tympani, he described in particular the role of vagal inhibition of
the heart, and the vasoconstrictor and vasodilator nerves of
the sympathetic system. In 1858, he published his Lectures
on the physiology and pathology of the nervous system.
The milieu intérieur concept was his major work. He built it
brick by brick between 1851 and 1878. He expounded the
concept in December 1857: “Physiologic phenomena in higher organisms take place in organic and highly perfected milieux intérieurs possessing balanced physicochemical properties.” The milieu intérieur regulates blood acidity and body
temperature, adjusting them to changes external to the body.
“The milieu intérieur has to be liquid because water is essen-
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tial for chemical reactions and for displaying the properties
of living matter.” In studying the vectors of cell interaction
(although without developing the concept of remote-acting
hormones), he expounded the concept of “internal secretion,” namely an organ’s ability to secrete a substance and
release it directly into the bloodstream. The French philosopher Georges Canguilhem (1904-1995) pronounced the milieu intérieur concept as having constituted a sort of “Copernican revolution.” 5,10,11,14
1865: The experimentalist mutates into
a philosopher
On December 30, 1913 at the Collège de France on the centenary of Claude Bernard’s birth, the philosopher Henri Bergson (1859-1941) declared: “The Introduction to the study of
experimental medicine is for us a little like what the Discours
de la méthode was for both the 17th and 18th centuries. In
each case we find ourselves in the presence of a genius who
began by making great discoveries and then wondered how
one had to proceed in order to have done so: although paradoxical in appearance, this is the only natural order of events,
since the reverse order has been attempted much more often and has never succeeded.”15
The issue of philosophy in medico-scientific experimentation
was far from an academic abstraction for Claude Bernard:
it was the direct result of the questions and doubts that assailed him on achieving experimental results that overthrew
conventional scientific thinking. “There comes a time in one’s
scientific career when it is good to collect one’s thoughts, take
stock and ask where one has arrived and where one is heading,” he wrote in his Principles of experimental medicine. “I believe this to be particularly useful when studying a science as
complex, obscure, and poorly defined as medicine.”
Physiology in the hands of Claude Bernard was not just a
branch of anatomy, physics, or chemistry; it involved the development of multiple temporary hypotheses that were reworked in the light of experimentation and the responses of
the live animal. Claude Bernard also set physiology apart from
the empiricism of medicine by endowing it with its own concepts developed through specific methods of investigation.10,11
The principles of Bernard’s philosophy can be found in notes,
lectures, and several of his publications throughout his life,
the best known being the Introduction to the study of experimental medicine published in 1865, written when resting and
Paul Bert by Mascre-Souville. Oil on canvas, 58x48 cm.
A brilliant student of Claude Bernard, physiologist, and politician,
Paul Bert was elected to the Académie des Sciences in 1882.
© RMN-Grand Palais/Droits réservés.
Jacques Arsène d’Arsonval, member of the Institut de France in
his biological physics laboratory at the École des Hautes Études.
Maison parisienne Neurdein. © Coll. BIU Santé (Paris).
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convalescing at his house in Saint Julien en Beaujolais, bought
in 1861. One year previously, he had experienced the first
symptoms of colitis, together with migraine and joint pain,
diagnosed by Rayer and Davaine as a “a chronic form of
cholera.” It was during one of these stays that he read, criticized and was inspired by the work of Auguste Comte (17981857), the founder of positivism. “Comte’s idea of considering
positivist philosophy in terms of scientific generalities is wrong.
It is absolutely essential to get down to the details.”
The Introduction was the first chapter in Claude Bernard’s major contribution to philosophy (it remains part of the philosophy baccalaureate curriculum). As well as in the notes contained in the Red notebook and Principles of experimental
medicine (collated and published in 1947 by Léon Delhoume),
he developed his philosophical ides in his Lectures on the
phenomena of life common to animals and plants, published
posthumously in 1878-1879, in which he insisted on the fundamental unity between the two worlds.
As for his 1867 Report on the progress and practice of general physiology in France, this was more political, in that it was
commissioned by Victor Duruy (1811-1894), minister of public education, in preparation for the Third Universal Exhibition
to be held in Paris the same year. It was Napoleon III’s intention to use the Exhibition to showcase French science, in direct competition with science in German-speaking countries
where heavy investment and decentralized organization had
produced remarkably effective results.
Already esteemed by the Emperor and his wife—in 1864 they
had invited him to spend a week at the Château de Compiègne—Claude Bernard wrote in the report that “general
physiology” should be established as a science in its own
right and receive the same level of State funding as that earmarked for “the long-established sciences securely positioned
within the social fabric.”2,4,10,11,13,16
The Introduction to the study of experimental medicine received a lukewarm welcome from physicians both in France
and abroad; physiology journals ignored it on the grounds
that its subject matter fell outside their scientific purview. Yet
the book was a more than positive report on over 20 years of
successful research rewarded by its author’s appointment to
the Faculty of Sciences and Collège de France. The book was
not translated into English until 1927, into Spanish in 1936,
and into German in 1961.
Claude Bernard invented “determinism,” a word that he introduced into French. “The primordial principle in the basic
sciences is determinism. [...] All vital phenomena, whatever
they may be, are subject to strict determinism, and this determinism cannot possibly be anything other than physicochemical determinism. [...] Determinism is everything. It is inescapable. [...] We must take it as an experimental axiom that
Introduction to the Study of Experimental Medicine
by Claude Bernard, published by Baillière, Paris 1865.
© Wellcome Images.
in living beings as much as in inanimate matter, absolute determinism governs the conditions under which every phenomenon exists. This means, in other words, that once the condition for a phenomenon is known and met, the phenomenon
should always recur necessarily, at the experimenter’s command. To deny this would amount to nothing less than denying science itself.” This principle influenced future generations of scientists: an experiment must be reproducible in
order to be validated.4,5,8,9,11
Maintaining that scientific truth is objective and demonstrable,
not revealed or imposed, and that phenomena must always
be approached with the question “how” rather than “why,”
Claude Bernard based his “method” on three cardinal principles: observation, experimentation, and deductive reasoning.
Because Nature only allows a limited number of facts to be
observed, these need to be prolonged or evoked by experiment. By combining with chemistry, physics, and all the exact
sciences, physiology becomes able to be explain all living phenomena, whether normal or pathological.4,5,8
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CLAUDE BERNARD (1827-1878) – THE
ROUTE TO GLORY
1839 - Junior resident to Magendie at the Hôtel-Dieu in
Paris.
1855 - Election to Magendie’s Chair of Experimental Medicine at the Collège de France.
1843 - Doctor of medicine thesis on gastric juice.
1561 - Member of the Academy of Medicine.
1844 - Failure at the agrégation examination required for
university lecturers.
1864 - Napoleon III receives Claude Bernard and Louis Pasteur in Compiègne.
1845 - Experimental physiology prize from the Academy
of Sciences for his studies on spinal nerve function.
1865 - Publication of the Introduction to the study of experimental medicine.
1847 - Substitute for Magendie at the Collège de France.
1867 - Report on the progress and practice of general
physiology in France (for the Universal Exhibition). Commander, Legion of Honor. Chairman, Society of Biology.
1848 - Chairman, Society of Biology. Experimental physiology prize for research on pancreatic function.
1849 - Knight, Legion of Honor.
1868 - Membership of the French Academy. Transfer of
Sorbonne chair to the National Museum of Natural History.
1851 - Further experimental physiology prize for discovering a new function of the liver in man and animals.
1869 - Chairman, Academy of Sciences. Senator, Second
Empire.
1853 - Fourth physiology prize from the Academy of Sciences for experimental research into the cervical sympathetic chain. Doctorate of Sciences.
1872 - Chairman, French Association for the Advancement
of Science.
1854 - Election to the Membership of the Academy of
Sciences. Professorship of General Physiology at the Sorbonne (personal chair).
In wanting hospitals to be equipped with integrated laboratories so that physicians could relate their clinical knowledge
to physiologic experimentation, Claude Bernard looked forward to proclaiming the imminent demise of empirical medicine. However, he came up against the hostility of the Academy of Medicine, for whom the primacy of the anatomo-clinical
method—another great pride of 19th century French medicine—was sacrosanct.
Claude Bernard versus Louis Pasteur: the issue
of modern biology
Already crowned in glory for his at once “patriotic” and practical approach to medicine, Louis Pasteur (1822-1895) was
immediately alert to the importance of the Introduction in
guiding medical research methodology. An already recognized scientist, Pasteur had attended Claude Bernard’s lectures at the Faculty of Sciences in 1860 and those on “experimental medicine” given in the winter of 1862-1863 at the
Collège de France. On November 7, 1806 he published an
article in Le Moniteur Universel: “Nothing as clear, complete,
and profound has been written on the actual principles behind the supremely difficult art of experimentation. This book
is barely known because written at a level that few these days
can reach. […] Claude Bernard’s arguments have the same
clarity and robustness as the sciences of physics and chemistry.” The day after the article appeared, Claude Bernard re-
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1876 - Commissaire, Paris Universal Exhibition. Copley
Medal, Royal Society, London.
1878 - State funeral.
plied: “Your work has caused your name to be writ large and
it has placed you in the forefront of contemporary experimentalists; I have no better way of saying that the admiration you
profess for me is entirely reciprocal. We must have been born
to get along together as we are both driven by the same passion and same feelings for true science.”
In 1859, Claude Bernard had written a favorable report to
the Academy of Sciences supporting the award of the Montyon prize in experimental physiology to Pasteur for his work
on alcoholic fermentation and the isomers of tartaric acid;
he had drawn attention to the “physiological bent to his research” and the “experimental skills of this distinguished scientist.” The two leading lights in French 19th century medical
research appeared to be working in perfect harmony.4,5,8,17
However, they were to fall out around 1877 when in his Principles of experimental medicine Claude Bernard deplored
the fact that “Pasteur follows his ideas and wants to bend
the facts accordingly, whereas I follow the facts and aim to
coax out the ideas more or less by themselves. Pasteur wants
to direct Nature, whereas I let Nature direct me: I follow Nature […] I am Nature’s secretary. Pasteur and the a priorists
are out to dictate Nature’s responses to suit their own ideas.”
Bernard was skilled at exploiting serendipity starting from hypotheses that were not always correct; Pasteur performed
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QUOTATIONS
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CLAUDE BERNARD
“When we encounter a fact that contradicts a prevailing theory, we must accept the fact and abandon the
theory, even if the theory is backed by great names and
generally accepted.”9
“The fixity of the internal world is the precondition for
free and independent life.”4
“It is what we think we already know that prevents us
from learning.”9
“If we really wanted to recognize services rendered to
science, the frog would have pride of place.”9
“A fact is nothing in itself, its only value lies in the idea attached to it or by the evidence it provides.”9
“Observation is the investigation of a naturally-occurring
phenomenon, and experiment the investigation of a
phenomenon modified by the investigator.”1
“Science proceeds by revolution and not by pure and
simple addition. This is because of theories that are always consecutive.”1
“The experimenter forces Nature to reveal her secrets
by attacking and questioning her from every direction;
but he must never respond on her behalf or pay lip service to her responses, by recognizing only those results
that favor or confirm his hypothesis.”9
“The only certainty is inside us. We are conscious of a
fact, it is what is true. We are not absolutely conscious
of a theory; it is always provisional.”1
“It is not enough to say: I made a mistake; one must say
how the mistake was made.”9
experiments to confirm his intuitions. Pasteur immediately
threw back at Claude Bernard the accusation that he was
using a system-based approach.
In reality the two men disagreed on the factors and conditions
for alcoholic fermentation. Having devoted many years of his
life to this question (one of national interest), Pasteur attributed the transformation of sugar into alcohol under anaerobic conditions to the presence of microorganisms. Claude
Bernard believed that this chemical transformation depended on soluble “culture agents” (ferments), and not exclusively on living cells, but was unable to demonstrate this experimentally and published nothing on the question in his lifetime.
His notes on alcoholic fermentation were published in July
1878 by the chemist Marcellin Berthelot, five months after
his death; they aroused the wrath of Pasteur.
Monument to Claude Bernard in the main square of Saint-Julien
en Beaujolais (department of the Rhône).
© Coll. Académie Nationale de Médecine.
The “culture agent” turned out to be an enzyme, zymase, isolated in 1897 by the German scientist Eduard Büchner (18601917). “Pasteur fully acknowledged what discouraged Claude
Bernard, who proved the victim of his definitions, beholden
despite himself to Lavoisian biochemistry (oxygen as the condition of life) […] It was his respect for Lavoisian dogma that
made him unable to accept certain data in physiology […]
That is why he preferred to define alcoholization as simple molecular degradation,” wrote the philosopher-physician François Dagognet.5,8,11,17,18
This dispute between the two giants of French science raised
the whole question of modern biology. For Claude Bernard,
a functioning live organism was an organism that destroyed
itself by itself little by little via physicochemical phenomena
tending towards death. Pasteur was something of a “vitalist”
and thought along different lines, focusing on the external insults that threatened the fine balance of living organisms. As
a prisoner of his “determinism” and hence of his “ideas”, Claude
Bernard became unable to grasp the full implications of cell
pathology and germ theory. The heated debate between the
two giants of French science paved the way to modern scientific medicine, with Claude Bernard considering disease as
a process disruptive of the milieu intérieur while Pasteur viewed
it as an external interference independent of any determination.17,19 ■
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References
1. Bernard C. Cahier de notes 1850-1860 [Notebooks 1850-1860]. Paris, France:
Gallimard; 1965.
2. Marduel MA. Claude Bernard – Un physiologiste natif du Beaujolais, sa vie,
son œuvre [Claude Bernard – A Beaujolais physiologist’s life and work]. Paris,
France: Société des Gens de Lettres; 2006.
3. Debray-Ritzen P. Claude Bernard ou un nouvel état de l’humaine raison [Claude
Bernard or a new state of human reason]. Paris, France: Albin Michel; 1992.
4. Lévy I. Un disciple d’Esculape, Claude Bernard, face à Thalie [A disciple of Asclepius, Claude Bernard, meets Thalia]. Rev Prat. 1996;46(7):795-798.
5. Grmek MD. Le legs de Claude Bernard [The legacy of Claude Bernard]. Paris,
France: Fayard; 1997.
6. Holmes FL. Physiology and experimental medicine. In: Grmek MD, Fantini B,
eds. Shugaar A, translator. Medical thought from Antiquity to the Middle Ages.
Cambridge, MA: Harvard University Press; 2002.
7. Bernard C, Magendie F. Leçon d’ouverture du cours de médecine du Collège de
France, 29 février 1856 [Inaugural lecture in medicine at the Collège de France,
29 February, 1856]. Paris, France: J.B. Baillière; 1856.
8. Grmek MD. Raisonnement expérimental et recherches toxicologiques chez
Claude Bernard [Claude Bernard’s experimental reasoning and toxicological
research]. Geneva, Switzerland: Droz; 1973.
9. Bernard C. An introduction to the study of experimental medicine. Henderson LJ, ed. Greene HC, translator. London, UK: Macmillan & Co Ltd; 1927.
Reprinted: New York, NY: Dover Publications Inc; 1957.
10. Prochiantz A. Claude Bernard, la révolution physiologique [Claude Bernard: revolution in physiology]. Paris, France: Presses Universitaires de France; 1990.
11. Bernard C. Principes de médecine expérimentale [Principles of experimental
medicine], Paris, France: Presses Universitaires de France; 1947.
12. Michel J, ed. La nécessité de Claude Bernard [The necessity of Claude Bernard]. Paris, France: Méridiens Klincksieck; 1991. Republished: Paris, France:
L’Harmattan; 2002.
13. Bernard C. Notes pour le rapport sur les progrès de la physiologie [Notes for
the report on the progress of physiology]. Paris, France: Collège de France;
1979.
14. Canguilhem G. The normal and the pathological. Fawcett CR, Cohen RS, translators. New York, NY: Zone Books; 1991.
15. Bergson H. La philosophie de Claude Bernard [The philosophy of Claude Bernard]. Paris, France: Presses Universitaires de France; 2012.
16. Bernard C. Lectures on the phenomena of life common to animals and plants.
Hoff HE, Guillemin R, Guillemin L, translators. Springfield, IL: Thomas; 1974.
17. Michel J. Le différend Pasteur/Bernard: un débat de clôture pour la biologie du
XIXème siècle? [The Pasteur/Bernard dispute: a closing debate on 19th century biology?]. In: Donzelli M, ed. La biologia: parametro epistemologico del XIX
secolo. Naples, Italy: Liguori Editore; 2003.
18. Dagognet F. Méthodes et doctrines dans l’œuvre de Pasteur. [Methods and
doctrines in the work of Pasteur]. Paris, France: Presses Universitaires de France;
1967.
19. Sinding C. Le clinicien et le chercheur: des grandes maladies de carence à
la médecine moléculaire [Clinician and research scientist: from the great deficiency diseases to molecular medicine]. Paris, France: Presses Universitaires
de France; 1991.
CLAUDE BERNARD (1813-1878) ET LA MÉDECINE EXPÉRIMENTALE
« PHYSIOLOGIE, PHYSIOLOGIE , C’EST EN MOI… »
Pionnier de la physiologie moderne puis philosophe ayant jeté les bases de la méthode expérimentale en médecine,
Claude Bernard (1813-1878) est une figure emblématique de la science française de la seconde moitié du XIX e siècle.
Sa méthode, ses découvertes, son langage marquèrent durablement la médecine. Ses travaux furent variés et menés
simultanément entre 1844 et 1865 : la fonction glycogénique du foie, la nutrition et la sécrétion pancréatique, la curarisation, les échanges gazeux érythrocytaires, les nerfs sensitifs et moteurs. Cette œuvre colossale tendait vers un
but unique : définir la notion de “milieu intérieur”, à l’origine de toute vie animale ou végétale. Pasteur qui aborda des
thèmes de recherche beaucoup plus pratiques fut un fervent partisan de Claude Bernard. En 1865, il fut l’un des rares
scientifiques à le soutenir lors de la parution de l’Introduction à la médecine expérimentale, manifeste philosophique
sur la recherche médicale et les conditions de la vie. Les deux savants se brouillèrent vers 1877 pour une divergence
d’interprétation sur la fermentation alcoolique anaérobie… Claude Bernard, fut le premier scientifique auquel la République accorda des funérailles nationales. Le 16 février 1878, après la cérémonie religieuse en l’église Saint Séverin,
4000 personnes suivirent le cortège jusqu’au cimetière du Père Lachaise. Agnostique, sénateur d’Empire, Claude
Bernard fut très vite récupéré par les républicains, ce qui marqua l’entrée de la science moderne en politique ; sa
méthode expérimentale appliquée à la médecine fut transposée par les hommes politiques aux sciences sociales.
484
A TOUCH
echnology espoused art at
the 1913 Paris opening of
the Théâtre des ChampsElysées on the Avenue Montaigne
(twinned since 1967 with Madison
Avenue in New York City). Built in
just two years in reinforced concrete elevated to the nobility of the
building materials of antiquity by
architect Auguste Perret, the theater continues to play host to the
greatest performers of the world
of classical music.
OF
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T
The Théâtre des
Champs-Elysées: the venue
that launched a masterpiece
b y D . M a r s h , Fra n c e
D
avid Marsh, BSc and PhD in Biophysics (King’s College London), worked as a research scientist at Brandeis University in the United States (protein biochemistry), at
the Mongolian State University in Ulan Bator (biophysics), and at the École Normale
Supérieure in Paris (neurobiology). Author of fifty scientific and cultural articles, he now works
as a medical editor and translator (French and Spanish to English) and writer at Servier International. One of his passions includes classical music, and he has been an avid concert-goer
for over thirty years.
David MARSH, BSc PhD
Servier International
DTC Medical Publications Division
50 rue Carnot
92284 Suresnes Cedex
FRANCE
T
he wealthy and fashionable set took umbrage that May evening in Paris.
Catcalls and whistles filled the theater, derisive laughter, cries of “Ta
gueule!” (“Shut your trap!”). A frightful ruckus. The Countess de Pourtalès,
the doyenne of Parisian society, flourished her fan and shouted: “This is the
first time in sixty years that anybody has dared make fun of me!” The pandemonium drowned out the music. Backstage, perched atop a chair, the ballet-master shouted instructions unheard by the dancers. The composer fled
the auditorium and watched from the wings. “I have never again been that
angry.” Thus was Igor Stravinsky’s ballet The Rite of Spring launched upon
an unsuspecting world one hundred years ago, at the newly opened Théâtre
des Champs-Élysées, the brainchild of Gabriel Astruc, journalist, theater manager, and impresario. His ‘new temple of art’ nigh on bankrupted Astruc, but
years later he wrote: “I do not regret my folly, for from my ruin sprang The Rite
of Spring.”
abriel Astruc flicked open the lid of his pocket watch. Just twenty-four hours
till the fulfillment of the dream that had occupied his thoughts night and day
for the past seven years: the opening of the—of his—Théâtre des ChampsÉlysées. An achievement worthy of this, his fiftieth year. As he turned into the Avenue
Montaigne, the leaden sky over Paris was clearing and the rain fell lighter. The theater’s frontage gleamed in the gaslit street, its rectilinear design broken only by a
white marble bas-relief of ‘Apollo and the Muses,’ hinting at music and dance within.
G
Standing there that late March evening in 1913, thinking through the last details of
the grand opening the next day, little could Gabriel Astruc have guessed that a riotous assembly in his theater would soon change the world of classical music forever. And write his ‘new temple of art’ into the pages of history.
The Théâtre des Champs Elysées: the venue that launched a masterpiece – Marsh
485
A TOUCH
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Clio, the Muse of History, has looked kindly upon the Théâtre
des Champs-Élysées. And upon its creator, Gabriel Astruc.
Our story begins in the early years of the 20th century. Director of a Parisian music society, journalist and playwright, impresario, Astruc found Paris wanting. Where was its Royal Opera
House (London, 1858), its Festspielhaus (Bayreuth, 1876), its
Prinzregententheater (Munich, 1901)? Of the French capital’s
43 theaters, only the Opera, the Théâtre du Châtelet, La Gaîté,
and, at a pinch, the Opéra-Comique, were equipped for fullscale concerts or operatic productions. And they were hidebound, saw modernity as a threat, and shunned innovation.
Astruc vowed to build a theater forward-looking in its architecture and bold in its choice of music.
Things began well. In 1906, Paris City Hall promised Astruc
a site on the Champs-Élysées (whence the theater’s name),
where once an old circus had stood, and the architectural
studies began. But three years later, the plans now well advanced, City Hall reneged on its promise following an anti-Semitic campaign (Astruc was Jewish) orchestrated by Charles
Maurras, the principal ideologist of Action Française, an extreme right-wing political movement.
Gabriel Astruc
(1864-1938).
Between 1905
and 1912,
Gabriel Astruc
brought to
Paris many
leading figures
of classical
music, including
Nellie Melba,
Enrico Caruso,
Richard Strauss,
the Ballets
Russes, and
Arturo Toscanini,
before founding
the Théâtre
des ChampsÉlysées.
© Studio Lipnitzki/
Roger-Viollet.
Every year some 300 000 people come to the Théâtre des Champs-Élysées in Paris for concerts and recitals in the main auditorium,
plays at the Comédie, and exhibitions in the Studio. © Bertrand Rindoff Petroff/Getty Images.
486
A TOUCH
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FRANCE
The Théâtre des Champs-Élysées in Paris was Gabriel Astruc’s
“new temple of art.” © Roland Schlager/APA/Corbis.
Art nouveau wrought iron volutes adorn the red-carpeted stairs
of the Théâtre des Champs-Élysées. All rights reserved.
A new conception of the performing arts
ture. Their backing was rewarded by privileges such as personal admission to the theater and its stage, and a box for
dress rehearsals. Shareholders were no longer bystanders, but
took part in the life of the theater and its creative process. Set
apart from other music venues, the theater on Avenue Montaigne embodied a new conception of the performing arts: the
quest for entertainment had yielded to the wish to appreciate
singular and original works. Revelers looking for an evening’s
amusement gave way to men and women seeking a deeper
more lasting experience. The very design—perfect visibility from
every seat, comfort, feeling of well-being—showed that the
theater was no longer a place of fleeting impressions, of transience, but rather one of contemplation, where audiences were
encouraged to linger, to reflect, to seek inspiration.
City Hall’s shameful back down was perhaps a blessing in
disguise, for it triggered the ‘shift westwards’ of the capital’s
cultural center of gravity, for which Astruc claimed kudos. A
plot of land was found on the Avenue Montaigne (named for
Michel de Montaigne, the 16th century essayist). Formerly
called ‘Widows’ Alley,’ until the mid-19th century this street
conjured images of horse-drawn carriages bearing the bereaved, forbidden by society to appear in public during mourning. Thereafter it transmuted into an avenue lit by streetlamps,
an atmosphere suggestive of a nightlife lived openly and not
in the shadows.
To drum up investment for his theater project, Astruc appointed Gabriel Thomas to oversee a limited liability company.
Thomas, a former stock marketer, discerning art lover, auditor and later CEO of the Musée Grévin (waxwork museum)
in Paris, raised 3 500 000 francs, equivalent today to about
11.5 million euros (15 million US dollars). Among the investors
were the Rothschild banking family, Sir Ernest Cassel (British
merchant banker), and John Pierpoint Morgan (American financier), who brought gravitas and financial clout to the ven-
The first season
The Théâtre des Champs-Élysées opened its doors on 31
March 1913 for the ‘first inaugural gala’ and the first of six performances of Hector Berlioz’s opera Benvenuto Cellini, based
on the life of the eponymous Florentine polymath of the High
Renaissance. It had premiered at the Opéra de Paris in 1838,
with just four performances, but had not been heard since.
487
A TOUCH
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Astruc had been at pains to revive this vocally demanding
work deemed unplayable by some musicians and unloved by
the public. Writing years later, a tad immodest but rightly so,
Astruc described his delight at the response of the critics
who “praised to the skies the daring manager who had rehabilitated the memory of Berlioz.”
Maestro Inghelbrecht opened the concert with Chabrier’s
Ode à la musique followed by Lalo’s Scherzo symphonique,
before handing the baton to Saint-Saëns who conducted his
symphonic poem Phaéton. Fauré directed his La Naissance
de Vénus for soloists, choir, and orchestra, d’Indy and Dukas
conducted their music, Debussy led the orchestra in a performance of Prélude à l’après-midi d’un faune, and SaintSaëns then returned to the stage to close the concert with
excerpts from his cantata La Lyre et la harpe.
The 1913 season continued with a series of concerts of Beethoven’s nine symphonies conducted by Felix Weingartner
and the premiere of Fauré’s opera Pénélope on 10 May. And
then, on Thursday 29 May, came the much-awaited premiere
of Igor Stravinsky’s new ballet.
The Rite of Spring
As musical expectancy rose, so did the mercury. The temperature soared to 30°C, a record for the month of May in Paris,
which stands to this day. A fine test indeed of the audience’s
cool and of the theater’s newfangled system of ventilation. The
latter passed muster, but the former was lost as harsh rhythms
and dissonant sounds from Pagan Russia filled the hall and
foot-stomping dancers trampled on two centuries of ballet
tradition.
Not everyone was caught unawares. The critic of L'Écho de
Paris had foreseen as much when he attended the final rehearsals, fearing that the public would react badly if they felt
they were being mocked. Some clearly did. The smart set
were there to pay homage to orchestral and balletic convention, not to be scandalized, to have people cocking a snook,
to be a laughingstock. They wasted no time in making their
feelings known. The conductor that evening, Pierre Monteux,
recalled that “Everything available was tossed in our direction.”
The ‘Bohemians,’ on the other hand, the writer and filmmaker Jean Cocteau asserted, were there to hail the avant-garde,
“to acclaim, right or wrong, anything that is new, because of
their hatred of the boxes” (ie, the smart set).
Costume design by Leon Bakst (1866-1924) for The Young
Girl (danced by Tamara Karsavina) in Igor Stravinsky’s 1910 ballet
The Firebird, choreography by Michel Fokine. © Getty Images.
Astruc again showed his devotion to his country’s music a few
days later. “Mr G. Astruc was anxious,” reported the newspaper Le Figaro, “that this concert should include only masterpieces of French music. Emmanuel Chabrier, Edouard Lalo,
Camille Saint-Saëns, Gabriel Fauré, Vincent d’Indy, Claude Debussy, Paul Dukas, such were the names on the program. […]
Each of these masters was represented by one of his most
significant works. […] But to its symbolic and, if you will, commemorative value, the concert at the Théâtre des ChampsÉlysées added a rare attraction, since each composer conducted his own work. And the departed were given voice by
the experienced and talented Mr Inghelbrecht, who no longer
has anything to prove.”
488
In this centennial year of both the Théâtre des Champs-Élysées and The Rite of Spring, it is hard to credit the uproar
sparked by a work which has become a staple of the repertoires of all the leading orchestras and which the American
composer and conductor Leonard Bernstein called “the most
important piece of music of the 20th century.”
Astruc’s first season was a triumph; it was also his last. Financially overextended, he was ejected from the theater and the
sets and costumes were impounded. For the following stopgap season Covent Garden and the Boston Opera Company
presented operas, and then the theater fell silent at the outbreak of the Great War. Theater life resumed in 1919 with a
short season presented by Anna Pavlova's ballet company,
followed later by innovative performances and premieres,
A TOUCH
like the Swedish Ballets’ production of
Francis Picabia's ‘instantaneist’
ballet Relâche, with “two acts
and one cinematographic
intermission, and the tail
of Francis Picabia’s dog,”
and music by Erik Satie.
Astruc meanwhile took
his business nous
and organizational
skills to radio and advertising, worked as
a theater manager
for Philippe de Rothschild, and helped
Marcel Proust proofread the first edition
of Du Côté de chez
Swann (Swann’s Way), a
favor that Proust returned
by offering Astruc advice
when he was writing his memoir, Le Pavillon des fantômes.
Modern times
The Théâtre des Champs-Élysées was the first
modern building in France to be listed as a historic monument, in 1957. Later, threatened by real estate plans, it was
bought by the Deposits and Consignments Fund, a governmental institution, which renovated the theater in the 1980s
and agreed to the construction of a rooftop panoramic restau-
OF
FRANCE
One-tenth scale model (2.4 x 0.5 m)
by Maurice Denis of the dome of the
Théâtre des Champs-Élysées.
© RMN-Grand Palais (musée d’Orsay)/
Gérard Blot/ADAGP.
rant. Structurally, the
theater could bear no
additional weight, so
the restaurant—Maison Blanche—was
suspended above it,
like a bridge.
Although it alters the
building’s three-dimensional space, the
restaurant is invisible
from the Avenue Montaigne and is more part of
the roofscape of Paris than
of the street-level architecture.
The theater continues to stage operas,
symphonic and chamber concerts, recitals,
dance, and pop events, and is home to the Orchestre National de France and the Orchestre Lamoureux.
The Orchestre Philharmonique de Radio France and the
Ensemble Orchestral de Paris play here often, and guest orchestras come from Vienna, Munich, London, Amsterdam,
Saint Petersburg, New York, and beyond.
•••
Detail from the frescoes by Maurice Denis which encircle the base of the dome of the Théâtre des Champs-Élysées. © All rights reserved.
489
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THE BALLETS RUSSES
By the early 1900s, the 200-year-old art of ballet had seen
better days. Lackluster productions, second-rate music,
feeling trumped by technique (albeit in decline for decades).
Then came Sergei Pavlovich Diaghilev and his Ballets
Russes.
nals variously as the “most important moment in the history of twentieth-century music” and ‘a near-riot,’ throughout which, Stravinsky later wrote, Monteux continued conducting, “apparently impervious and as nerveless as a
crocodile.”
Yet it might never have happened. Had it not been for the
conservatism of the art world in turn-of-the-century Russia, an exasperated Diaghilev may not have tried his luck
in Paris, where art lovers flocked to see his ‘Exhibition of
Russian Art.’ The following years he offered the Parisians
music and opera by Russian composers, and in 1909 presented a “Russian Season” devoted entirely to dance. Thus
were born the Ballets Russes.
The dancers and choreographers: 19th century male
dancers cut a sorry figure—neglected by choreographers,
ignored by ballet audiences, playing second fiddle to ballerinas. The Ballets Russes changed all this by raising technical standards and introducing some of the most gifted
danseurs in the history of ballet—Michel Fokine, Serge Lifar,
Léonide Massine, George Balanchine, and Vaslav Nijinsky—who partnered luminaries like Anna Pavlova, Tamara
Karsavina, Mathilde Kschessinska, Ida Rubinstein, and Bronislava Nijinska.
The early seasons of ballets to music by Borodin, Chopin,
Arensky, Ravel, and Debussy, and above all Stravinsky
(The Firebird and Petrushka), were a critical and popular
success. To bring the Ballets Russes to his newly opened
Théâtre des Champs-Elysées for the 1913 season, concert
promoter Gabriel Astruc paid Diaghilev 25 000 francs for
each performance (equivalent today to about 82 000 euros
or 107 000 US dollars). On the program was Stravinsky’s
new ballet, The Rite of Spring.
The conductor Pierre Monteux later admitted that on hearing Stravinsky play a piano version of The Rite of Spring his
“one desire was to flee that room and find a quiet corner
in which to rest [his] aching head.” Diaghilev, persuasive
as always, won him over: “This is a masterpiece, Monteux,
which will completely revolutionize music and make you famous, because you are going to conduct it.” The premiere
at the Théâtre des Champs-Elysées has entered the an-
Some also left their mark on the history of ballet as choreographers. Nijinsky worked for Diaghilev on Debussy’s
L'Après-midi d'un faune and Jeux, and most famously on
The Rite of Spring. Nijinsky’s younger sister, Bronislava
Nijinska, also choreographed productions, including Stravinsky’s Les Noces and Milhaud’s Le Train Bleu. Other
dancer-choreographers included Léonide Massine, who
replaced Nijinsky both as ballet-master and Diaghilev’s
lover, and George Balanchine.
The designers and costumiers: Alexandre Benois, who
had collaborated with Diaghilev from their student days in
Saint Petersburg, contributed stage sets and costume designs to early productions by the Ballets Russes, notably
Petrushka. Léon Bakst worked on The Firebird, L’Aprèsmidi d’un faune, and Daphnis et Chloé. And Nicholas Roe-
Igor Stravinsky
with Vaslav
Nijinsky in
costume as
Petrushka,
ca. 1911.
© Bettmann/
CORBIS.
Members
of the Ballets
Russes in
the 1913 Paris
production of
The Rite of
Spring. Private
Collection.
© Roger-Viollet
Paris.
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A TOUCH
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For the 1920
choreographic
adaptation of
Igor Stravinsky’s
symphonic poem
The Song of the
Nightingale, Henri
Matisse (seated)
designed the
sets and Leonid
Massine created
the choreography.
© Lebrecht Music &
Arts/Corbis.
Portrait by Leon
Bakst (18661924) of Sergei
Pavlovich
Diaghilev with
his Nurse, 1906.
(oil on canvas).
State Russian
Museum, St. Petersburg, Russia.
© AKG-images.
rich, the Russian polymath, created a daring aesthetic that
played no small part in the sensation that accompanied
the premiere of The Rite of Spring.
Pablo Picasso worked on three Diaghilev ballets, including
Pulcinella by Stravinsky, who was excited by the idea of
working with the Spanish master. Diaghilev was less than
enthused after seeing Picasso’s first offering. His vision was
of an abstract version of commedia dell’arte, yet here was
Picasso aping something out of a frothy operetta. Diaghilev
threw Picasso’s drawings on the floor, stamped on them,
and angrily demanded that he start anew, before walking
out and slamming the door behind him.
Henri Matisse, initially reluctant to become involved with the
Ballets Russes, was in the end won over by Diaghilev’s
legendary charm, deployed on one occasion at an unannounced visit to Matisse’s home outside Paris, accompanied by Stravinsky, who played through some of his music for Le Chant du Rossignol on the artist’s grand piano.
When despite himself Matisse voiced a few ideas for the
scenery, Diaghilev clinched it by flattery: “There’s your décor all settled. It’s absolutely essential you do it, there’s no
one but you who could.”
The impresario: Self-proclaimed ‘man of contradictions,’
protean, a hard taskmaster, charismatic, a manipulator of
the press, dictatorial, an eye for talent, superstitious, a man
whose religion was art. Sergei Pavlovich Diaghilev was born
in 1872 into a wealthy family with a town house in Perm
(Russia) and a country estate. He studied piano and singing
and learned to move with ease among the landed gentry
and upper classes. When his father bankrupted the family vodka business, Sergei enrolled at the Faculty of Law in
Saint Petersburg, where he took lessons in painting and
studied music with a view to becoming a composer, until
Rimsky-Korsakov told him he lacked talent.
The Ballets Russes never had a permanent home. Nor did
Diaghilev. With a manservant for company he lived out of
two suitcases in expensive hotels, on credit, lurching from
one financial crisis to another, and from the arms of one of
his principal male dancers to the next. When he died penniless, in Venice in 1929, the French fashion designer Coco
Chanel, who had worked with him on Le Train Bleu, paid for
his funeral and burial on the cemetery island of San Michele.
The legacy: In debt, hounded by creditors, the Ballets
Russes disbanded after Diaghilev’s death. Yet their legacy
lives on. Serge Lifar restored the reputation of the Paris
Opera Ballet, where he was ballet master for a quarter of a
century. George Balanchine co-founded in 1948 the New
York City Ballet and remained its ballet master for more than
35 years. And Tamara Karsavina was a founder member
of the Royal Academy of Dance and helped set up The
Royal Ballet, founded by Ninette de Valois, who said that
everything she knew about running a ballet company she
had learned from Diaghilev.
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THE
NOBILITY OF REINFORCED CONCRETE
"In a few months the most elegant neighborhood in Paris
will have a new palace: the Théâtre des Champs-Élysées
will open its doors to the public… on the Avenue Montaigne… in the quarter of Paris that has become the veritable center of the capital." Thus did the Ballets Russes
herald the new venue for their 1913 season.
Gabriel Astruc, its creator, saw the Théâtre des ChampsÉlysées as a rival to state venues that offered the same musical fare to one and all. Resolutely modern in programming
and architecture alike, Astruc’s theater allied French taste,
English comfort, and German technology.
The theater’s unity of design, from façade to innards, betrays no trace of the ups and downs attendant upon its conception, which evolved over the years through the work of
four architects. Aided by Roger Bouvard, Henri Fivaz drew
up the initial plans for a site on the Champs-Élysées, but
resigned when they were rejected. Shortly afterwards the
Paris Town Hall backtracked on its offer of the ChampsÉlysées site and a plot was found nearby on the Avenue
Montaigne. Walled on three sides by existing buildings, the
new site imposed jigsaw-like constraints, but with this limitation came an economic advantage, since the theater
would have not four façades, but one.
Bouvard devised new plans with the Avenue Montaigne site
in mind. Hired as a consultant, Henry Van de Velde made
changes to Bouvard’s designs, with a view to investing the
theater with a more contemporary feel. The idea was to
use reinforced concrete, for
stylistic reasons, of course, but
also because of the clayey
subsoil and the fact that the
River Seine was hard by. With
this in mind Van de Velde
sought help from the building contractors Auguste and
Gustave Perret, who were
keen advocates of reinforced
concrete. Their role was to
erect the theater using the
plans worked on by Bouvard and Van de Velde, but the
Perrets ended up having a major say in the design. And
ever since their name has been indissolubly linked with
the architectural planning and construction of the Théâtre
des Champs-Élysées.
The artists who worked on the theater—Maurice Denis (frescoes), Henri Lebasque and Édouard Vuillard (paintings),
Jacqueline Marval (foyer), Ker Xavier Roussel (stage curtain), René Lalique (glass lamps), Antoine Bourdelle (sculptures)—made no concessions to the outmoded orthodoxy
of the traditionalists. Much to the delight of the avant-gardists. Yet the theater gave a nod to tradition with its symmetrical frontage, marble facings within and without, its cornices and sculpted metopes.
Audience comfort was sacrosanct: deep seats with two
armrests, a novel heating and ventilation system, elevators
and shallow steps between the three floors, a lounge area,
a bar. The same norms of convenience, practicality, and elegance were applied to administrative offices, to rehearsal rooms, and to dressing rooms—baths with hot and cold
water, sewage disposal toilets, amenities often lacking in
the performers’ everyday lives.
Safety, too, was paramount. Time had done little to dim
memories of the 1887 inferno at the Opéra-Comique in
which 84 people perished. The theater’s design facilitated
access by firefighters and the fire risk was lowered by the
use of reinforced concrete,
fireproof materials, and electricity instead of gas. One century on, the 300 000 concertgoers and thousands of
performers who come to the
Théâtre des Champs-Élysées each year would doubtless agree with Auguste Perret that “Architecture seizes
space, circumscribes, encloses, bounds it. A labor of
the mind, it has the privilege
of creating magical places.”
Dance, a stone bas-relief
(1909) by Antoine Bourdelle
(1861-1929), from the
frontage of the Théâtre des
Champs-Élysées.
© The Bridgeman Art Library.
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•••
From the outset Gabriel Astruc and his architects
conceived of a single complex with three theaters:
the main auditorium for concerts, ballet, and opera,
with 1920 seats in a space that could in fact accommodate 3000, to heighten comfort, and two
smaller theaters, the Comédie (1200 seats) for drama and the Studio (800) for exhibitions.
The roll-call over the years of playwrights and performers at the Comédie includes Paul Claudel,
singer and actress Mistinguett, once the highestpaid female entertainer in the world, Jean Cocteau
and Darius Milhaud, George Bernard Shaw (Arms
and the Man), Louis Jouvet, and Jean Giraudoux
(three plays premiered). More recently, Yasmina
Reza’s play Art premiered here, winning two Molière
awards.
Centenary season
Set design by Nicolas Roerich (1874-1947) for Alexander Borodin’s opera
Prince Igor, 1909. © The Bridgeman Art Library.
In the Spring of 2013, the Théâtre des Champs-Élysées celebrated its centenary by reliving some of the great events that
marked its first one hundred years, notably a performance of
The Rite of Spring with Vaslav Nijinsky’s original choreography,
reconstructed by the music historians Millicent Hodson and
Kenneth Archer. The centenary season also included concert
versions of the operas Benvenuto Cellini by Berlioz and Pénélope by Fauré, and a homage to another major event in the
theater’s history—the first Paris appearance in October 1925
of Josephine Baker, the American ‘Queen of the Wild Dance,’
in La Revue Nègre, with a jazz band from New York. The watchword of the Théâtre des Champs-Élysées over the last hundred years has been continuity. A spectator from the 1920s
or the 1950s would not feel out of place if he were to return
to a concert this very evening. Continuity, plus diversity and
modernity. Three heartfelt principles of the man who one
hundred years ago on a rainswept night stood on the Avenue Montaigne before his dream made real, the Théâtre des
Champs-Élysées. The man whose single-mindedness and
acumen made everything possible. Gabriel Astruc. ■
Further reading
– Abram J. La magie du béton armé. In: Auguste et Gustave Perret. Le Théâtre
des Champs-Élysées. 2nd ed. Paris, France: Jean-Michel Place éditions; 2004:
8-42.
– Astruc G. Le Pavillon des fantômes. Paris, France: Grasset; 1929.
– Benjamin G. How Stravinsky’s Rite of Spring has shaped 100 years of music.
The Guardian. Wednesday 29 May 2013. http://www.guardian.co.uk/music/2013/
may/29/stravinsky-rite-of-spring
– Brockway W, Weinstock H. Men of Music. New York, USA: Simon and Schuster;
1966.
CENTENAIRE
DU THÉÂTRE DES
– Huesca R. Le théâtre des Champs-Élysées à l'heure des ballets russes. Vingtième Siècle. Revue d'histoire. 1999;63:3-15. http://www.persee.fr/web/revues/
home/prescript/article/xxs_0294-1759_1999_num_63_1_3850
– Monteux, DG. It’s All in the Music: The Life and Work of Pierre Monteux. New York,
USA: Farrar, Straus and Giroux; 1965.
– Schonberg HC. The Lives of the Great Composers. 3rd ed. New York, USA: WW
Norton & Company; 1997.
– Théâtre des Champs-Elysées. Saison 2012-2013. Centenaire du Théâtre des
Champs-Élysées.
CHAMPS -ÉLYSÉES
À
PARIS
Le milieu parisien chic et fortuné prend la mouche ce soir de mai. Sifflets et hurlements remplissent le théâtre, rires
moqueurs et « Ta gueule » fusent ! Un grabuge épouvantable. La comtesse de Pourtalès, doyenne de la société parisienne, brandit son éventail et crie : « C’est la première fois en 60 ans qu’on ose se moquer de moi ! ». Le tohubohu étouffe la musique. Derrière la scène, perché sur une chaise, le maître de ballet hurle des instructions inaudibles par les danseurs. Le compositeur s’enfuit de la salle et regarde depuis les coulisses. « Je n’ai jamais été aussi
furieux que ce jour-là ». C’est ainsi que le ballet d’Igor Stravinsky, le Sacre du printemps, s’ouvre il y a un siècle sur
un monde qui ne se doute pas de ce qui l’attend, au tout nouveau théâtre des Champs-Élysées, fruit des travaux de
Gabriel Astruc, journaliste, directeur de théâtre et impresario. Son « nouveau temple de l’art » a failli ruiner Astruc, mais
quelques années plus tard il écrit : « Je ne regrette pas ma folie, puisque de ma ruine sortit le Sacre du printemps ».
493
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