treating hypertension in the primary care population

REVIEW
TREATING HYPERTENSION IN THE PRIMARY CARE POPULATION
—
Joseph L. Izzo, Jr, MD*
ABSTRACT
Hypertension is the most important modifiable
risk factor that can be treated medically, and better overall cardiovascular and renal outcomes
are directly dependent on better control of systolic hypertension by primary care physicians.
Systolic blood pressure (BP) increases with age in
all gender and ethnic groups in industrialized
societies. An individual with normotensive BP
who is 55 to 65 years of age still has a 94% likelihood of developing hypertension (BP ≥140/90
mm Hg) if he/she lives an additional 20 years.
Isolated systolic hypertension is the predominant
type of hypertension, occurring in all age groups,
especially in those patients older than 65 years.
Cardiovascular risk is related logarithmically to
systolic BP: each increment of 20 mm Hg in systolic BP (or 10 mm Hg in diastolic BP) above the
range of 115/75 to 185/115 mm Hg is associated with a 2-fold increase in mortality from
ischemic heart disease or stroke. Drugs to treat
hypertension partially correct inappropriate balances among the 3 major interacting pathophysiologic systems that control BP: the sympathetic
nervous system, the renin-angiotensin-aldosterone system, and the kidneys. The Seventh
Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure provides a streamlined
management approach to hypertension for the
primary care physician. The report’s general
principles of care emphasize lifestyle modifications and combination antihypertensive drug
therapy, including the initial use of combinations
*Professor of Medicine, SUNY, Buffalo, New York.
Address correspondence to: Joseph L. Izzo, Jr, MD,
Professor of Medicine, SUNY, 462 Grider Street, Buffalo,
NY 14215. E-mail: [email protected].
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for stage 2 hypertension. Special therapeutic
considerations are recommended for high-risk
individuals with “compelling indications” (eg,
diabetes mellitus, chronic kidney disease, heart
failure, coronary heart disease/high coronary
risk, or recurrent stroke).
(Adv Stud Med. 2005;5(6B):S531-S536)
HYPERTENSION AS A PUBLIC HEALTH ISSUE
BLOOD PRESSURE AND AGE
Systolic blood pressure (BP) inexorably increases
with age in all gender and ethnic groups in industrialized
societies.1 In contrast, a patient’s diastolic BP increases
steadily until approximately age 55 years, then decreases.
The result is increased pulse pressure (systolic-diastolic
pressure difference) in older patients, a manifestation of
increased central arterial stiffness. The overall prevalence
of hypertension thus increases with a patient’s age
because of the increasing prevalence of isolated systolic
hypertension. In the Framingham Heart Study, the lifetime risk of developing hypertension (BP ≥140/90 mm
Hg) was more than 90% for men or women who lived
for 20 years after the age of 55 or 65 years, even if they
had not yet developed hypertension by middle age.2
Overall, these trends indicate the importance of routine
BP screening and the recommendation of healthy
lifestyle habits for all patients to help reduce their overall
risk of developing hypertension.
BENEFITS OF TARGET BLOOD PRESSURE IN
REDUCING STROKE AND VASCULAR MORTALITY
Hypertension is the most important risk factor for
cardiovascular disease and stroke. Data from the
Prospective Studies Collaboration (a meta-analysis of
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61 prospective studies evaluating data from 1 million
adults without previous vascular disease) show that
throughout a patient’s middle and older years, elevated
BP is directly related to increases in cardiovascular mortality.3 Among men and women in this study age 40 to
69 years, each increment of 20 mm Hg in systolic BP
(or 10 mm Hg in diastolic BP) above the range of
115/75 to 185/115 was associated with a 2-fold or
greater increase in death rate caused by stroke, ischemic
heart disease, and other vascular causes. These data dramatically demonstrate the potential benefits of achieving BP targets in reducing stroke and vascular mortality
in patients who are middle-aged or older.
SYSTOLIC BLOOD PRESSURE CONTROL RATES
Isolated systolic hypertension is the most common
type of uncontrolled hypertension. In patients age 50 to
59 years, the prevalence of isolated systolic hypertension
is 87%.4 Therefore, older patients need greater reductions in systolic BP to reach the target of less than
140/90 mm Hg. In the Framingham Heart study cohort
involving 1959 men and women with hypertension who
were middle-aged and older, poor overall BP control was
overwhelmingly caused by the lack of systolic BP control, whether the subjects were or were not receiving
medications.5 Improved awareness of the prevalence and
importance of systolic hypertension and more aggressive
pharmacologic therapy to attain target systolic BPs are
needed, particularly for patients age 50 years and older
and those patients with diabetes mellitus, kidney disease,
or hypertensive target organ damage.6
this article but is covered in detail elsewhere.8 In secondary and primary (essential) hypertension, there is a
multifactorial web of mechanisms that sustains the BP
elevation over time. The components of this pathophysiologic web are not yet fully elucidated, but it is
clear that 3 key factors play at least a permissive role:
hyperactivity of the sympathetic nervous system
(SNS), hyperactivity of the renin-angiotensin-aldosterone system (RAAS), and abnormal renal salt-volume regulation (Figure). These 3 systems are major
Table 1. Identifiable Causes of Secondary
Hypertension or Drug Resistance*
Sleep apnea
Chronic kidney disease
Primary aldosteronism
Side effects of prescription or nonprescription drugs
Renovascular disease
Chronic steroid therapy/Cushing syndrome
Thyroid or parathyroid disease
Pheochromocytoma
Coarctation of the aorta
*Causes in probable order of prevalence.
Modified from Chobanian et al. JAMA. 2003;289:2560-2572.7
PATHOPHYSIOLOGY OF CHRONIC HYPERTENSION
Most patients with hypertension (estimated at >95%)
have primary (ie, “essential”) hypertension. The precise
prevalence rate of secondary hypertension is difficult to
establish, mostly because of the close association of obesity, sleep apnea, and hypertension (Table 1).7 Selection
bias in case series published by specialists also inflates the
prevalence rate of secondary forms of hypertension. In
patients with secondary forms of hypertension, standard
drug treatment is often relatively ineffective and the presence of “resistant hypertension” (BP not controlled by 3
or more agents, 1 of which is a diuretic) is an important
clue to the practitioner to perform additional diagnostic
studies to rule out secondary forms of hypertension.
A full discussion of the complex pathophysiology
of chronic hypertension is well beyond the scope of
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Figure. Pathophysiologic Mechanisms Contributing to
Chronic Hypertension
INAPPROPRIATELY HIGH
SYMPATHETIC OUTFLOW
Increased large
arterial stiffness
INCREASED
CARDIAC OUTPUT
INCREASED
PRELOAD
Abnormal venoconstriction
and high venous return
INAPPROPRIATELY HIGH
RENIN RELEASE
INCREASED
AFTERLOAD
Increased heart rate
Increased
systemic
resistance
ABNORMAL RENAL
SALT/WATER HANDLING
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targets of antihypertensive drug therapy. The SNS regulates BP physiologically by causing venoconstriction
and by increasing heart rate, cardiac contractility
(inotropy), and systemic vascular resistance. In chronic hypertension, the SNS is never fully suppressed and
the inappropriately high SNS output interacts with
inappropriately high RAAS activity to maintain inappropriate BP levels. These pressor interactions are further exacerbated by the tendency of the hypertensive
kidney to cause volume expansion through excess salt
and water retention that occurs despite increased renal
perfusion pressure.
Pathologic remodeling of blood vessels also contributes to chronic hypertension. At the large vessel
level, the cumulative damage of a lifetime of increased
pulsatile load causes stiffening of the aorta and central
arteries, thus increasing systolic pressure and pulse
pressure. The importance of arterial stiffening in the
pathogenesis of systolic hypertension is also covered in
detail in other publications.9 At the level of the microcirculation, hypertrophy of arteriolar smooth muscle
sustains the increase in systemic vascular resistance.
Therefore, from an overall hemodynamic perspective,
chronic hypertension is a blend of inappropriately
increased preload, cardiac output, and afterload.
Ultimately, hypertension-induced damage to target
organs causes overt disease consequences, such as
chronic kidney disease, stroke, angina, myocardial
infarction, left ventricular hypertrophy, cardiac failure,
peripheral arterial disease, retinopathy, and dementia.9
HYPERTENSION TREATMENT
The Joint National Committee practice guidelines
have been revised periodically over the past 30 years.
The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure (JNC 7) represents a major
attempt to update and to streamline the management
of hypertension. Each of the 4 new BP categories in
JNC 7 is coupled with a different set of therapeutic
recommendations that become increasingly aggressive
as the overall cardiovascular risk level increases.
PREHYPERTENSION
Patients with prehypertension (BP 120–139/80–89
mm Hg) or hypertension (BP >140/90 mm Hg) are recommended to pursue lifestyle modifications—primarily
reducing excess caloric intake and increasing physical
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activity to promote weight loss—to provide primary prevention and treatment of chronic hypertension.7
STAGE 1 HYPERTENSION
Stage 1 hypertension is defined by chronic BPs in the
range of 140 to 159/90 to 99 mm Hg. For many patients
in this group, lifestyle modifications can be effective.
Even if patients require drug therapy, lifestyle modifications can decrease the amount of medications needed to
reach target BP levels. Unfortunately, few patients actually achieve significant lifestyle modifications. In fact, in
most patients, therapy with single antihypertensive agents
is not enough to cause an effective sustained systolic BP
lowering of 20 mm Hg or more. Optimal treatment in
most patients usually requires 2 or more antihypertensive
agents, including fixed-dose combinations.7
STAGE 2 HYPERTENSION
In stage 2 hypertension (BP >160/100 mm Hg),
the increased urgency for BP control is exemplified by
the recommendation to begin therapy with 2 agents in
combination. One of the most important issues
underpinning this rationale is that a delay in BP control is associated with poorer overall outcomes, as was
amply demonstrated in the large Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT) and Valsartan Antihypertensive
Long-Term Use Evaluation (VALUE) trial.10,11
It is also noteworthy that the JNC-7 group omitted
the classifications of stage 3 and stage 4 hypertension
that were identified in earlier JNC reports. The JNC-7
group thought that the use of these categories deflected
attention from the importance of the overall BP lowering in the larger group of patients who already had lower
BPs and that the therapy for those patients with systolic
BPs above 180 mm Hg did not differ substantially from
those patients in the 160 to 180 mm Hg range.
COMPELLING INDICATIONS
A separate group of complex patients with hypertension is characterized as having a “compelling indication” for a particular class of agents (ie, a high-risk
condition associated with hypertension for which
there is 1 or more clinical trials demonstrating that a
particular class of antihypertensive agents improves the
natural history of the condition, not just lowers BP
levels). JNC 7 lists compelling indications as heart failure, postmyocardial infarction, high coronary risk,
diabetes mellitus, chronic kidney disease, and recur-
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rent stroke. The treatment philosophy of JNC 7 is to
treat the compelling indication first, then add or
adjust other antihypertensive agents as indicated clinically. Target BPs in these conditions remain less than
140/90 mm Hg, except in patients with diabetes mellitus and chronic kidney disease, in which target BPs
are less than 130/80 mm Hg.
Patients with congestive heart failure should be
treated with a regimen that includes at least one of the
following classes: angiotensin-converting enzyme
(ACE) inhibitors, angiotensin receptor blockers
(ARBs), β-blocking agents, or aldosterone antagonists.
Diuretic therapy is necessary to reduce the symptoms
of later-stage heart failure.7 Target BPs are not well
established for this group of patients; however, to minimize the work of the failing heart, an increasing number of medical experts are attempting to achieve BP
values well below 120/80 mm Hg.
In patients with ischemic heart disease (especially
postinfarction), physicians recommend β-blocking
agents, along with ACE inhibitors and aldosterone
antagonists.7 Diuretics, ACE inhibitors, and calcium
antagonists are effective in reducing morbidity and
mortality in those patients at high risk for ischemic
heart disease. In any patient at significant risk for
ischemic heart disease, effective antihypertensive therapy should be combined with intensive lipid management and low-dose aspirin therapy.7
Physicians advise patients with diabetes mellitus or
chronic kidney disease to begin therapy with an appropriate drug combination that includes an ACE
inhibitor or, alternatively, an ARB. Both classes of
drugs reduce mortality and slow the progression of
renal disease in these patient groups.7
ADDITIONAL FACTORS IN DRUG CHOICES
Other factors may be considered in a physician’s
treatment choice of antihypertensive drugs. A patient’s
ethnic background has some influence on therapeutic
choices when monotherapy is used. In general, race is
not a determining factor in antihypertensive drug choices because of the need for rational drug combinations in
the treatment of hypertension. Although AfricanAmerican patients may not respond as quickly as white
patients to monotherapy with ACE inhibitors, ARBs, or
β blockers, a combination of any of these classes of
agents with a thiazide diuretic or calcium antagonist
eliminates any racial difference in responses.12
Older patients may require additional consideration,
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but every attempt should be made to achieve a target BP.
If older patients begin antihypertensive therapy slowly,
the clinician must continue to titrate drugs as aggressively as can be tolerated by the patient. The appearance of
orthostatic hypotension can be a limiting factor in treating hypertension in older patients, especially with volume-depleting agents or venodilators (eg, nitrates,
β blockers, and phosphodiesterase inhibitors).7
The current consensus is that women who develop
hypertension during pregnancy are best treated with
methyldopa, β blockers, or hydralazine,7 but there are
no large-scale clinical trials to underpin this recommendation. Women who are pregnant or likely to
become pregnant should not receive treatment with
ACE inhibitors or ARBs, as use of these agents is associated with increased rates of birth defects.7
In the pediatric population, hypertension is a growing health concern that is associated overwhelmingly
with the epidemic of overweight and obese children in
the United States. In children and adolescents, hypertension is defined as BP that is, upon repeated measurement, at the 95th percentile or greater, as adjusted for
patient age, height, and gender.13 JNC 7 recommends
that regular BP screening for children should commence
around 3 years of age, with possible secondary causes of
hypertension considered in children who are of normal
weight but have BPs above the age-related 95th percentile. Nonpharmacologic therapy, especially diet and
exercise, is the preferred treatment for hypertension in
the pediatric population. Drug therapy, if indicated,
involves agents similar to those used in adults; however,
effective doses for children are often smaller and should
be adjusted carefully, and ACE inhibitors and ARBs
should not be prescribed for teenage girls who are sexually active.7
ANTIHYPERTENSIVE DRUGS
Many different antihypertensive drugs are available. For the most part, these agents target the major
BP regulatory mechanisms (Figure) or the blood vessels themselves. Each class has unique properties and
displays advantages and disadvantages. Skillful clinicians can often use these differences to individualize a
patient’s therapy (Table 2).14
Thiazide diuretics are highly effective but may cause
hyperglycemia in patients with impaired glucose tolerance. The long-term impact of this effect is the subject
of much current debate.15 However, thiazide diuretics
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are useful in patients with osteoporosis, as these agents
slow calcium resorption from bone.7
β-blocking agents, in addition to lowering BP, exert
favorable influences on mortality from ischemic heart
disease and heart failure. β blockers can be used in
patients with diabetes mellitus and patients with
chronic lung disease, but these agents should be used
with caution in those patients with severe bronchospastic disease.
Calcium antagonists are also highly effective in lowering a patient’s BP and may improve symptoms and
survival in patients with ischemic heart disease. These
agents rarely precipitate congestive heart failure in
some patients.16 However, only long-acting calcium
antagonists are currently recommended for the treatment of hypertension because short-acting calcium
antagonists have been implicated in increased cardiovascular mortality.
Angiotensin-converting enzyme inhibitors, as mentioned earlier in this article, are considered to be firstline therapy for patients with hypertension and
concurrent diabetes mellitus or impaired renal function. In addition to lowering BP, ACE inhibitors slow
the progression of renal disease7 and are first-line
agents for patients with heart failure because they
improve symptoms and survival in patients with this
condition.17 ACE inhibitors occasionally may increase
serum potassium levels in patients with renal dysfunction, type 4 renal tubular acidosis, or low renal blood
flow, but small increases in serum potassium
(<6 mEq/L) are rarely problematic and may actually
protect patients against cardiac arrhythmias. The combination of ACE inhibitors with adequate amounts of
diuretics, especially the combination of a loop agent
and a thiazide, assists in maintaining potassium balance. ACE inhibitors also inhibit the degradation of
bradykinin; some patients may develop a dry hacking
cough with these agents that is a class effect and generally not dose-dependent.
Angiotensin receptor blockers have a spectrum of
response and benefits that qualitatively are similar to
those observed with ACE inhibitors, but they do not
tend to cause a dry cough. ARBs are effective in maintaining renal and cardiac function and should be considered as alternative first-choice agents for patients
with hypertension and concurrent diabetes mellitus,
chronic kidney disease, or heart failure.
Older antihypertensive drug classes are used less often
than the 4 major classes of antihypertensive agents
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described earlier in this article. In addition, there is less
clinical trial evidence of benefit with these drug classes regarding morbidity and mortality.
Table 2. Major Antihypertensive Drug Classes
Drugs Acting on the Renin-Angiotensin-Aldosterone System
Angiotensin Receptor Antagonists
Candesartan (Atacand)
Eprosartan (Teveten)
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar)
Telmisartan (Micardis)
Valsartan (Diovan)
Angiotensin-Converting Enzyme Inhibitors
Benazepril (Lotensin)
Captopril
Enalapril
Lisinopril (Prinivil, Zestril)
Moxeripril (Univasc)
Perindopril (Aceon)
Quinapril (Accupril)
Ramipril (Altace)
Trandolapril (Mavik)
β Adrenergic Antagonists
Acebutolol
Atenolol (Tenormin)
Esmolol (Breviblock)
Metoprolol (Toprol XL)
Nadolol (Corgard)
Propanolol (Inderal, Innopran XL)
Timolol (Blocadren)
Thiazide and Thiazide-Type Diuretics
Chlorothiazide (Diuril)
Chlorthalidone (Clorpres)
Hydrochlorothiazide (Hydrodiuril)
Indapamide
Metazolone (Zaroxolyn)
Calcium Channel Antagonists
Amlodipine (Caduet, Norvasc)
Diltiazem (Cardizem, Tiazac, Dilacar XL)
Felodipine (Plendil)
Isradipine (DynaCirc)
Nicardipine (Cardene)
Nifedipine (Adalat, Procardia XL)
Nimodipine (Nimotop)
Nisoldipine (Sular)
Verapamil (Covera, Verelan, Isoptin SR)
Adapted from 2005 Physicians’ Desk Reference. 59th ed. Montvale, NJ:
Thomson Healthcare; 2005.14
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A variety of fixed-dose combination products are now
available. The JNC-7 report does not recommend which
agents should be used in combination, but many medical experts now follow similar lines of thought regarding
optimal 2-drug combinations: one of the agents should
be a direct vasodilator (thiazide or calcium antagonist);
the other agent, an “antineurohumoral” agent that
blocks the SNS or RAAS (ACE inhibitor, ARB, or β
blocker). Some patients with stage 2 hypertension will
require more than 2 drugs. Fixed-dose combination
agents, which are well tolerated by patients and aid in
improved BP control, are also underutilized.
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