Isolated systolIc hypertensIon 3 : 2 Raminder Singh,

Isolated systolic hypertension
3:2
Raminder Singh, Mumbai
Until the 1980’s the diastolic blood pressure (DBP) was assumed to be the most relevant hemodynamic
parameter for prognosis of hypertensive patients. Elevated systolic pressure was considered as an
inevitable consequence of aging and many physicians were reluctant to pay credence to the need
for therapy of elevated systolic blood pressure. There was a radical change in thinking based on
epidemiological studies and reports by insurance companies which led to recognition of elevated
systolic blood pressure (SBP). The term isolated systolic hypertension (ISH) has been introduced
particularly in elderly subjects, since SBP is known to rise with advancing age; where as diastolic
blood pressure (DBP) usually levels off and tends to decrease in elderly.1 According to the National
Health and Nutrition Examination Survey (NHANES) III, ISH is the most prevalent type of untreated
hypertension over 60 years of age. ISH represents a substantial health care problem as the target BP
is very difficult to attain by drug therapy.
According to JNC-VI and WHO/ISH guidelines, ISH is now defined as BP >140/<90 mmHg, this
criteria is more stringent than older definition of ISH >160/<90.2
Etiology of ISH
Apart from ISH seen with advancing age, ISH can also be seen in young patients 3 (obese, smokers, low
education and socioeconomic status), hyperthyroidism, hyperaldosteronism, renal insufficiency and
failure, renal artery stenosis, drug induced (NSAIDS, COX-2 inhibitors, corticosteroids, cyclosporine),
herbal remedies, excess alcohol use, obstructive sleep apnoea, anaemia, beriberi, Paget’s disease and
cancer (due to release of humoral pressor substances or hypercalcemia).
Pathophysiology of ISH
ISH largely reflects progressive structural and functional deterioration of arterial wall involving
endothelial dysfunction, atherosclerosis, aortic stiffness and increased wall stress and pulse pressure.
According to the hypothesis, atherosclerosis, triggered by vascular endothelial damage and mechanical
strain from each stroke volume, plays a central pathophysiological role. Atherosclerosis progressively
leads to the replacement of elastin by collagen and other structural proteins and the build of calcium
in the arterial wall, and this in turn leads to hypertrophy and fibrosis of arterial smooth muscle. All
these factors lead to increased vascular stiffness which results in reduction in arterial compliance and
decreased of ‘Windkessel function’ of large arteries.
Renin angiotensin system plays an important role in pathogenesis of arterial stiffness by decreasing
elastin content and increasing collagen of arterial wall. Proliferating small muscle cells in the arterial
wall results in increased thickness, stiffening, and partial loss of contractility. 4
Classification of ISH
ISH is classified as shown in Table 1.
Symptoms and Signs
In most elderly, ISH is asymptomatic. Epistaxis may be a presenting feature. Cardiac dysfunction
is indicated by symptoms of coronary artery disease, heart failure, arrhythmias. Stroke, intermittent
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and death (J–curve phenomenon).7 Several intervention
studies in ISH have demonstrated beneficial effects of
treatment of ISH.
Table 1 : Classification of ISH
Category
Blood Pressure (mmHg)
Diastolic
Systolic
Optimal
<120
And
<80
Benefits of treatment of ISH
Normal
<130
And
< 85
130-139
Or
80-89
Several interventional trials such as STOP-1, STOP-2 and
MRC Elderly have clearly demonstrated that treatment of
hypertension in elderly is beneficial and protective against
stroke8 and coronary artery disease. In most of these trials,
no clear distinction was made between ISH and ordinary
hypertension. However a major percentage of elderly
hypertensives recruited for such studies showed hemodynamic
characteristics of ISH. A few clinical trials have enrolled
patients with well defined ISH.
High-normal
ISH
Stage 1
140-159
And
<90
Stage 2
160-179
And
<90
Stage 3
≥180
And
<90
claudication due to peripheral arterial disease, aortic aneurysm,
aortic dissection, features of hypertensive retinopathy, renal
insufficiency or failure may be present. Severe hypertension
or an abrupt rise of BP may cause headache, blurred vision
or dizziness.
Evaluation of ISH
An initial evaluation of ISH should include assessment
for other cardiovascular risk factors, end organ damage,
identifiable secondary causes of hypertension and potentially
contributing lifestyle factors (diet, exercise, alcohol, smoking,
body weight, drugs).
Physical examination should include assessment of peripheral
pulses, optic fundi, thyroid, heart, lungs, kidney and
neurological system. Abdominal and carotid bruit should be
carefully looked.
Interventions Trials concerning ISH
Systolic Hypertension in the Elderly (SHEP)9
Elderly patients with defined ISH were treated with low dose
chlorthalidone (with the option to add atenolol or reserpine),
in comparison with placebo. Active treatment brought about
the following significant beneficial changes / reductions:
•
non- fatal stroke – 37%
•
nonfatal MI – 33%
•
left ventricular failure – 54%
There were obvious trends (although not significant) towards
decrease in
Ambulatory BP Monitoring (ABPM) is of value in elderly
patients to confirm the diagnosis of hypertension if clinic BP
is more than 140/90 mm Hg (White coat effect), to identify
non dippers and to assess response to drugs.
•
TIAs (-25%)
•
Total mortality (-13%)
•
Cardiovascular mortality (-20%)
Home BP measurement (HBPM) can be suitable alternative
to monitor the response to treatment. The devices are easily
available and user friendly.
•
Cerebrovascular mortality (-29%)
•
Coronary mortality (-15%)
Investigations for end organ damage should include hematocrit,
urine analysis for proteinuria, BUN, serum creatinine, uric
acid, electrolytes (sodium, potassium, calcium), blood
glucose, lipid profile, thyroid function test, ECG, X-ray
chest. Echocardiography, carotid doppler, renal doppler, CT
abdomen/ chest, USG abdomen and polysomnography (in
obese subjects) may also be required.
ISH as a risk factor
In addition, this study has confirmed and emphasised the
beneficial effects and safety of low dose diuretics in elderly
hypertensives.
Systolic Hypertension in Europe (SYST-EUR)10 Trial
In large number of ISH patients active treatment with the
calcium antagonist nitrendipine (with optional add on enalapril
and /or hydrochlorothiazide) was compared with placebo, in
a double blind randomized design.
The Framingham study5 and The Multiple Risk Factor
Intervention Trial6 (MRFIT) showed that SBP levels are
stronger predictors of cerebrovascular and cardiovascular
events than diastolic BP (DBP).
A significant reduction (by 42%) in the incidence of stroke
and vascular dementia (by -50%) by nitrendipine treatment
was found.
It should be realized that a too low DBP is also dangerous in
those with coronary artery disease. DBP below 60 mm Hg may
be associated with an increased risk of myocardial infarction
The design of this trial, performed with Chinese ISH patients,
was very similar to that of the SYST-EUR study. In the Chinese
Systolic Hypertension in China (SYST-China)11 Trial
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Isolated Systolic Hypertension
patients active treatment with nitrendipine significantly
reduced the following endpoint phenomenon:
•
total stroke – 38%
•
stroke mortality -58%
•
all cause mortality -39%
•
cardiovascular mortality -39%
•
fatal and non-fatal cerebrovascular events -37%
1.Life style changes:
The lifestyle changes recommended for patients with
isolated systolic hypertension are the same as those for
patients with other forms of hypertension.
a. Weight reduction: Decrease in body weight decreases the incidence of hypertension and the viceversa is also true, reduction in 1.0kg body weight
decreases blood pressure by 1.6/1.3 mmHg. It
improves insulin sensitivity, sleep apnoea and the
sensitivity to sodium decreases. It is advisable to
maintain ideal body weight (BMI 18.5 – 24.9 kg/
m2).
b. Dietary sodium restriction: Moderate degrees of sodium restriction to 2.4 gm/day results in SBP reduction by 2 - 8 mm Hg. Indian patients with ISH are
more responsive to sodium restriction, because of
their lower renin responsiveness. In Indians there
is hidden salt in many food items and common
practise to consume items (pickle, papad, sausages)
which are loaded with sodium.
c. Diet Changes: Role of diet has been proven in
DASH (Dietary Approaches to Stop Hypertension),
TONE16 (Trial of Nonpharmacological Interventions in the Elderly), and many more trials. The diet
should be rich in fruits, vegetables, low in saturated
and total fat and high in fibre content. It causes SBP
reduction by 8 -14 mm Hg.
d. Moderation of alcohol: Alcohol abuse is the commonest cause of reversible hypertension. Limit consumption to not more than 2 drinks per day in men
and one drink per day in women. It causes SBP reduction by 2 - 4 mm Hg. These are associated with
fewer coronary events and strokes in comparison to
teetotallers.
f. Avoidance of tobacco: Smoking is prevalent in urban and rural population. It is a significant contributory factor for ISH, along with other detrimental effects on other body systems.
g. Physical exercise: Regular aerobic physical activity
such as brisk walking at least 30 minutes daily for
most of the days of the week results in SBP reduction by 4 - 9 mm Hg.
h. Stress management: Relaxation techniques, yoga,
massage can reduce blood pressure and this can be
a part of their treatment.
i. Low caffeine: Discourage excessive consumption
of coffee and other caffeine rich products.
These lifestyle changes reduce the blood pressure and
Intervention as a Goal in Hypertension Treatment (INSIGHT)12
Study
The INSIGHT study was performed in hypertensive patients
with at least one additional risk factors such as hyperlipidemia
or diabetes mellitus. The study was not deliberately designed
to investigate ISH treatment, but it contained a subgroup of
patients with defined ISH which were analysed separately.
Treatment consisted of nifedipine (in the GITS form:
Adalat-OROS), versus hydrochlorothiazide. This subgroup
of patients appeared to be more responsive than those with
‘ordinary’ hypertension to treatment with nifedipine – GITS.
Interestingly, in these study patients with ISH whose DBP
significantly decreased with increasing therapy were smokers
with evidence of atherosclerosis.
Both types of treatment (calcium antagonist vs diuretic)
caused a significant and sustained reduction in blood pressure
(in particular SBP) and a significant reduction of the relevant
endpoint parameters, such as stroke and MI.
Losartan Intervention For Endpoint reduction (LIFE) 13 study
The ISH substudy of LIFE compared Losartan with atenolol
and demonstrated that losartan reduced the risk of stroke and
CV death to greater degree than atenolol.
Angiotensin II receptor antagonist telmisartan in isolated
systolic hypertension (ARAMIS)14 studies:
Telmisartan (20 – 80 mg) produce significant reduction in SBP
Valsartan in Isolated systolic hypertension (VALISH)15
This study showed a significant effect on ISH.
Smaller studies on ISH
ACE inhibitors like lisinopril, Enalpril, Periondopril are
also suitable for blood pressure control in ISH patients and
favourably influence cardiovascular risk factors.
In conclusion, it appears mandatory and possible to treat
ISH and there is sufficient evidence that has demonstrated
beneficial effects of this treatment.
Management of Isolated systolic hypertension
The management of ISH should start with lifestyle changes
followed by drug therapy.
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favourably affect other risk factors like obesity, lipid
disorders and diabetes.
2. Drug Treatment
regimen as more than one drug is required to control
blood pressure. Diuretics can be combined with most of
the other class of antihypertensives.17
General principles of drug therapy:
a. The therapy in ISH should begin with life style
changes which may decrease the need of medications.
b. The initial dose of drugs should be as low as possible to achieve the pharmacological effect and
gradually increase the dose to attain the target BP.
c. The minimum goal for BP control in ISH is < 140
mm Hg and in patients with diabetes and renal disorder, the goal is <130 mm of Hg.
d. Care should be taken to avoid DBP < 55 mm Hg in
older patients with ISH.
e. Avoid orthostatic hypotension in diabetics and in
immobile patients.
f.
g. Carefully consider all the pre-morbid conditions
like diabetes, kidney disease, lung disease, coronary artery disease, prostatomegaly before selecting
the agent
h. Select a drug which can give multiple benefits, add
on therapy can be given, if target BP in ISH is not
controlled
B. CALCIUM CHANNEL BLOCKERS
Most of the patients will require more than one drug
to achieve target BP control in ISH
Six major classes of antihypertensives which are most useful
in ISH:
B Calcium channel blockers
C Angiotensin Converting Enzyme (ACE) inhibitors
D Angiotensin Receptor Blockers (ARB’s)
E Beta adrenoreceptor blockers
Hypertensives with high renin are more prone to cardiovascular events and show maximum benefit with ACE
inhibitor therapy. The ACE inhibitor should be started in
low dose and to be increased gradually to prevent first
dose hypotension. ACEI are considered standard therapy in hypertension with renal disorders, diabetes, diabetic nephropathy and LV dysfunction. ACE inhibitors
are preferred in elderly because of end organ protection
in cardiac and renal patients. The ACE inhibitors often
induce a persistent dry cough and in rare instances, angioedema.19
D. ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)
A.DIURETICS
This group of drugs is effective in hypertensive diabetics, a combination very commonly seen in clinical
practice. A unique character of CCBs is that its antihypertensive efficacy is not blunted by non-steroidal antiinflammatory agents (NSAIDs) which can elevate BP by
3-6 mmHg. The commonly seen side effects of CCBs
are leg edema & constipation. Lercanidipine, a newer
long-acting dihydropyridine is promising to have lesser
incidence of leg oedema and has associated antiatherogenic properties. Its antihypertensive efficacy and tolerability has been established in recent ELYPSE trial.18
C.ANGIOTENSIVE CONVERTING ENZYME (ACE)
INHIBITORS
A Diuretics
F Alpha adrenoreceptor blockers
The New 2011 British hypertension guidelines commissioned by the National Institute for Clinical Excellence (NICE) and developed in conjunction with the
British Hypertension Society (BHS) highlights the use
of thiazide like diuretic, such as chlorthalidone (12.5-25
mg once daily) or indapamide (1.5-2.5 mg once daily)
in preference to a conventional thiazide diuretic such as
bendroflumethiazide or hydrochlorothiazide, if there is
high risk of heart failure. In presence of elevated serum
creatinine levels(S Cr > 2) the diuretic of choice would
be Furosemide, Toresemide or Metolazone.
The current Joint National Committee guidelines recommend thiazide diuretics as initial drug therapy for most
patients with isolated systolic hypertension on basis of
their efficacy of reducing blood pressure, cardiovascular
complications and their low cost.Thiazide diuretics induce glucose intolerance and hypokalemia resulting in
muscle fatigue, weakness, lethargy. The clinical importance of these adverse effects is uncertain. Most of the
patients will end up receiving diuretic as a part of their
ARBs may be especially useful in treating ISH. All the
ARBs are potent in reducing SBP levels as shown by
various clinical trials, and have a class effect.
This group of drugs was initially introduced as an alternative to ACEI, for those who are intolerant to them
due to severe dry cough. The ISH substudy of LIFE
demonstrated for the first time in patients with ISH that
losartan confers more CV benefits over atenolol at the
same level of BP control. The ARBs are used in the renal
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Isolated Systolic Hypertension
diseases, proteinuria, and heart failure. The compelling
contraindication is renovascular disease.
3. Eplerenone, a newer aldosterone antagonist results in
very low incidence of gynaecomastia.
A remarkable feature of ARBs is safety and tolerability
profile. 20 The combinations of ARBs and ACEI have
additive effect in lowering BP and proteinuria.
4. Bosentan, an endothelin receptor antagonist demonstrated BP-lowering effects. Drug toxicity (i.e., teratogenicity, testicular atrophy, and hepatotoxicity) has largely
limited the use of this drug, but new agents are in the
pipeline.
E. BETA ADRENORECEPTOR BLOCKERS
Beta- blockers are effective in reducing blood pressure
in ISH. The use of beta-blockers as first line therapy for
elderly patients has been controversial; a meta analysis
of trials for hypertension showed a 16% higher incidence of stroke among patients treated with atenolol as
compared to other antihypertensives. 21 It may be due
to small reductions in blood pressure. A recent study
showed that ISH is less responsive to beta blockers as
compared to patients with essential hypertension. The
rate lowering effects of beta blockers may result in increase in systolic and pulse pressure. 22 The use should
limit to those with compelling indications such as coronary artery disease, myocardial infarction, congestive
failure or certain arrhythmias, young patients, women
with child bearing potential. Beta blockers are associated with a number of chronic adverse effects like lethargy, fatigue, muscle weakness, cold extremities and
impotence in men.
F. ALPHA ADRENORECEPTOR BLOCKERS
Selective alpha blockers like Doxazocin, Prazosin have
been shown to be effective agents as monotherapy. Men
with ISH and prostatic hyperplasia may obtain dual benefit from these drugs. Postural hypotension and heart
failure are known side effects with them.
The centrally acting agents such as clonidine and methyldopa result in dry mouth, sedation and rebound
hypertension. Selective Imidazoline (Type I) agonists,
such as moxonidine and rilmenidinen are reasonably
effective and well tolerated.
Newer attempts to treat ISH:
It would be desirable to find new antihypertensive agents
which selectively decrease SBP without reducing DBP. Some
of these drugs are:
1. Nitrates as NO generator may be considered as a potential new agent to treat ISH. Isosorbide dinitrate took
eight weeks of treatment to show this effect on SBP.
Transdermal nitroglycerine and molsidomine demonstrated similar effect. 23
2. Spironolactone, an aldosterone antagonist is weak potassium sparing diuretic which also inhibit the enhanced
formation of collagen and vascular fibrosis provoked by
aldosterone. Spironolactone can control the arterial stiffness which is the basis of ISH.24
5. Aliskiren, recently released renin inhibitor, demonstrated antihypertensive efficacy similar to that of currently
available ACE inhibitors and ARBs. The advantage of
aliskiren is that it suppresses renin activity, unlike ACE
inhibitors and ARBs, which can lead to a reactive rise in
plasma renin activity.
All these agents require larger studies and investigations for
their widespread use in ISH.
ISH in the young
Little is known about isolated systolic hypertension (ISH)
in younger adults. ISH among young adults is increasing
in prevalence, and is more common than systolic/diastolic
hypertension. Obesity, smoking, and low socioeconomic
status appear to be important determinants of ISH among
young adults and have all increased over the last decade.
The onset of hypertension during early adulthood warrants
particular concern as even slight elevations in SBP during
early adulthood increase one’s risk for further cardiovascular
disease morbidity in later life.
Increased blood viscosity is associated with obesity and
might, by increasing the rheological component of peripheral
resistance, contribute to obesity-associated changes in arterial
blood pressure. Body fat has been shown to be a strong
predictor of aortic stiffness in both young and older adults,
which may account for the isolated elevation in SBP among
obese young adults.3
ISH in Hyperthyroidism
The secondary causes of isolated systolic hypertension include
anaemia, aortic insufficiency, Paget’s disease, beriberi, and
hyperthyroidism. They all share a common mechanism of an
increase in cardiac output.
The prevalence of ISH in thyrotoxicosis is 20–30%.
Triiodothyronine (T3) is the active form of thyroid hormone.
In hyperthyroidism, T3 dilates resistance arterioles, reducing
systemic vascular resistance, which stimulates renin release
and sodium reabsorption, resulting in an expansion of blood
volume by 5.5% and an increase in venous return to the heart.
Erythropoietin stimulation also contributes to blood volume.
Heart rate and cardiac contractility are also changed with
hyperthyroidism. Cardiac output is increased by >1 L/min.
The net effect of these hemodynamic changes is a rise in
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SBP and a widening of pulse pressure. Arterial stiffness is
increased. 25
Treatment with antithyroid drugs narrows the pulse pressure,
decreases heart rate, reduces cardiac output and improves the
ISH.
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