From the Division of Cardiovascular Diseases, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania
Americans older than 60 years of age represent the fastest growing segment of the population. The prevalence of hypertension increases with age, and elderly persons are particularly prone to the cardiovascular morbidity and mortality resulting from hypertension-associated conditions, including coronary artery disease, peripheral artery disease, stroke, renal disease, and heart failure. In the Third National Health and Nutrition Examination Survey (NHANES III), hypertension was present in 65.4% of the population aged 65 years and older.1 Other risk factors associated with increased rates of hypertension are increased body mass index and non-Hispanic African American race/ethnicity.2 Elderly African American women have the highest prevalence rates of hypertension in the general population.
Isolated systolic hypertension, defined as systolic blood pressure of 140 mm Hg or above with a diastolic blood pressure of 90 mm Hg or below, is the most common form of hypertension in older Americans. It is present in approximately two thirds of hypertensive individuals older than 60 years of age.3 Diastolic blood pressure is a potent cardiovascular risk factor for patients younger than 50 years of age, but this changes for patients older than age 50, in whom systolic blood pressure plays a more important role. The results of several large epidemiologic studies indicate that increased systolic blood pressure is strongly associated with a greater risk of cardiovascular morbidity, stroke, and transient ischemic attacks. In the Multiple Risk Factor Intervention Trial (MRFIT), systolic blood pressure was a much stronger predictor of death due to coronary artery disease than diastolic blood pressure. The presence of isolated systolic hypertension doubles overall mortality and increases cardiovascular morbidity 2.5-fold. A recent clinical advisory statement issued by the National High Blood Pressure Education Program recommended that systolic blood pressure be made the major criterion for diagnosis, staging, and therapeutic management of hypertension for individuals older than 50 years of age.4
In NHANES III, hypertensive patients older than age 60 had significantly lower rates of blood pressure control compared with younger individuals and non-Hispanic whites. In a study of elderly patients visiting their physicians for hypertension, approximately 40% had a blood pressure higher than 160/90 mm Hg, despite more than six visits per year to their physicians. Clinicians frequently achieve better success with controlling diastolic than systolic blood pressure,5 probably reflecting the misconception among many physicians that diastolic blood pressure control is more important than systolic blood pressure control in the elderly. As shown in table 1, there are substantial risks associated with undertreatment; for example, treated hypertensive men with a residual increase in systolic blood pressure of between 140 and 160 mm Hg exhibit a 68% increase in mortality compared with individuals who achieve a systolic goal blood pressure of below 140 mm Hg.6
Several pathophysiologic features have been identified in the elderly hypertensive population, including increased sympathetic nervous system activity, overproduction of vasoconstrictors and salt-retaining hormones, chronic high-sodium dietary intake, and decreased renin secretion.7 Structural abnormalities of large conduit arteries as well as endothelial dysfunction from aging contribute to increased arterial stiffness and increased blood pressures. Aortic elasticity and distensibility decline with age, with an increased collagen-to-elastin ratio resulting from fragmentation of elastin and increased collagen deposition.8
Increased central arterial stiffness leads to the increased systolic blood pressure and the wide pulse pressure seen in elderly hypertensive patients by causing the pulse wave velocity to increase. With each ejection of blood from the heart, a pulse wave travels from the heart to the peripheral vessels and is reflected at branching points back to the aorta and the left ventricle. In younger persons, a pulse wave velocity of approximately 5 m/sec is slow enough that the reflected wave reaches the aortic valve after closure, augmenting diastolic blood pressure and enhancing coronary perfusion. In the elderly hypertensive patient, an increased pulse wave velocity (eg, 20 m/sec) results in the reflective wave reaching the left ventricle before
aortic valve closure, leading to an
increased systolic blood pressure,
increased afterload, and decreased diastolic blood pressure. A widened pulse pressure is, in itself, a powerful independent predictor of cardiovascular end points in the elderly.9 The increased left ventricular systolic pressure, wall tension, and blood volume result in the left ventricular hypertrophy commonly seen in elderly hypertensive patients. This important structural change predisposes to the development of heart failure and increases the risk of myocardial infarction (MI), stroke, and sudden death.
Hypertension is the most common risk factor for the develop-
ment of congestive heart failure.10 Changes in myocardial diastolic function are regularly seen with
the development of left ventricular hypertrophy. Myocardial contrac-tility is generally preserved, but diastolic dysfunction due to increased myocardial stiffness and impaired coronary flow reserve results in increased left ventricular filling pressures. These high pressures increase further with exercise and are reflected into the pulmonary capillaries. As a result, congestive heart failure with pulmonary congestion and dyspnea may develop. Data from the Framingham Heart Study indicate that a wide pulse pressure and increased systolic blood pressure confer a greater risk for the development of heart failure compared with diastolic blood pressure.11 Although most of the mortality from heart failure occurs in patients with a significant degree of systolic dysfunction (ejection fraction below 40%), morbidity is high for patients with diastolic dysfunction, and approximately 40% of clinical episodes requiring hospitalization occur in patients with normal or near-normal left ventricular systolic function. The pathogenesis of hypertension in elderly patients is summarized in table 2.
Clinical trials on the therapy for hypertension
Nonpharmacologic treatment of hypertension remains a useful therapeutic adjunct for all patients, including the elderly. The Trial of Nonpharmacological Interventions in the Elderly (TONE) showed that reduced sodium intake, weight loss, or both, were safe, effective, and feasible in elderly, obese patients with mild hypertension.12
Several placebo-controlled trials have shown that treatment of elderly patients with increased systolic, diastolic, or both systolic and dia-stolic blood pressure greatly reduces cardiovascular morbidity and mortality. The Systolic Hypertension in the Elderly Program (SHEP) study showed the benefit of treating isolated systolic hypertension in older adults. In this study, 4,736 patients older than 60 years of age, with a systolic blood pressure above 160 mm Hg and a diastolic blood pressure below 90 mm Hg, were randomly assigned to receive placebo or antihypertensive stepped-care drug treatment with low-dose chlorthalidone and atenolol. The 5-year incidence of total stroke was 5.2 per 100 participants receiving treatment and 8.2 per 100 participants receiving placebo, a statistically significant reduction of 36%. After a mean of 4.5 years, the incidence of left ventricular failure was reduced by 54% in the diuretic-based therapy group.13 Chlorthalidone-based treatment also had favorable effects on the hypertrophied myocardium, reducing left ventricular mass by 13% over 3 years.14 There also was a trend toward lower depression and dementia scores with diuretic-based therapy.
Angiotensin-converting enzyme (ACE) inhibitors (lisinopril or enalapril), as well as calcium antagonists (isradipine or felodipine), were noted to have efficacy similar to conventional treatment with diuretics or beta blocking agents in elderly patients with hypertension. In the Swedish Trial in Old Patients with Hypertension-2 (STOP-2), 6,614 patients with hypertension (blood pressure ≥ 180/105 mm Hg), aged 70 to 84 years, were followed up for 5 years.15 They were randomly assigned to receive one of three treatments: conventional agents (diuretics, beta blocking agents), ACE inhibitors, or calcium antagonists. The blood pressure—lowering effects were similar for all groups. The total mortality was not significantly different among the groups, but ACE inhibitors were associated with significantly fewer MIs and less congestive heart failure compared with calcium antagonists.
Long-acting nifedipine also decreased the number of strokes and arrhythmias in elderly hypertensive patients, as shown in the Shanghai Trial of Nifedipine in the Elderly (STONE), which included 1,632 patients randomly assigned to receive placebo or twice-daily dosing of slow-release nifedipine.16 The Sys-
tolic Hypertension in Elderly in Europe (Syst-Eur) trial also showed the benefit of calcium antagonist—
based therapy (nitrendipine) in reducing cardiovascular and cerebrovascular events in patients older than 60 years of age with isolated systolic hypertension.17 Nitrendipine with added enalapril and hydrochlorothiazide as required reduced systolic blood pressure by 23 mm Hg and diastolic blood pressure by
7 mm Hg after 2 years of follow-up. There was a 42% reduction in stroke rate and a 26% reduction in cardiac end points, including heart failure, fatal and nonfatal MI, and sudden death. The benefits of antihypertensive therapy were seen despite a target blood pressure that was higher than current recommendations.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) consisted of 42,418 patients with hypertension aged 55 years or older, with at least one other coronary artery disease risk factor. Patients received chlorthalidone, amlodipine, lisinopril, or doxazosin as first-line therapy.18 Doxazosin treatment was associated with a higher risk of cardiac events, particularly heart failure, and was dropped midway through the study. The final results showed that chlorthalidone, amlodipine, and lisinopril were equally effective in preventing fatal coronary artery
disease or nonfatal MI. There was
no difference in overall mortality among the three treatment groups. The results were consistent for all major prespecified subgroups, including patients older than 65 years. Higher rates of stroke in the ACE inhibitor group in ALLHAT were the result of an increased incidence of stroke in the large African American subgroup, whose blood pressures were less well controlled. This finding was not seen in non-African American subjects, suggesting that the effect was related to the difference in blood pressure rather than to an intrinsic inferiority of the ACE inhibitor. Chlorthalidone was superior in preventing heart failure compared with either amlodipine or lisinopril. The diuretic-based regimen reduced occurrence of heart failure by 22% compared with an amlodipine-based treatment program. Patients randomly assigned to receive chlorthalidone achieved a statistically significant lower systolic blood pressure (by 3 mm Hg) than the lisinopril group, probably because of protocol-derived constraints in the selection of add-on medications. About two thirds of the elderly patients achieved a goal blood pressure below 140/90 mm Hg with the use of an average of two antihypertensive drugs per patient. Given current recommendations for lower blood pressure targets (< 130/80 mm Hg) in patients with diabetes (who constituted 36% of the ALLHAT population), it is likely that more than one drug would be required to meet blood pressure goals in approximately 80% of the ALLHAT cohort.
The benefits of angiotensin-receptor blockade in elderly patients with isolated systolic hypertension were shown in the Losartan Intervention for Endpoint Reduction (LIFE) substudy.19 In that trial, 1,326 patients (mean age, 70 years) with isolated systolic hypertension were randomly assigned to receive losartan or atenolol with hydrochloro-
thiazide as add-on therapy, followed by additional agents as needed. Despite a similar decrease in blood pressure of 28/9 mm Hg, there was a 25% reduction in the combined primary end point of cardiovascular mortality, stroke, and MI in patients assigned to losartan. Significantly more electrocardiographic left ventricular hypertrophy regression occurred with losartan treatment, and there was a striking 40% reduction in nonfatal and fatal stroke, a 38% reduction in new-onset diabetes, and a 38% reduction in total mortality compared with atenolol.
The relatively poor performance of atenolol in the LIFE isolated systolic hypertension substudy raises questions regarding the suitability of beta blocking agents as first-line therapy for hypertension in elderly patients. In a previous meta-analysis of 10 hypertension trials, Messerli and colleagues examined data derived from over 16,000 patients randomly assigned to receive diuretics or beta blocking agents, or both.20 According to this analysis, two thirds of patients on diuretic monotherapy were well controlled compared with only a third of those receiving beta blocking agents. Furthermore, diuretic therapy was found to be superior in preventing strokes, coronary artery disease, cardiovascular mortality, and all-cause mortality.20 It should be emphasized, however, that beta blocking agents remain the preferred agents in patients with coronary artery disease, who constitute a significant fraction of the elderly hypertensive population. Table 3 lists treatment recommendations for patients with isolated systolic hypertension. The figure shows the pooled analysis of the outcome of eight trials of older patients with isolated systolic hypertension.21
The exciting concept of secondary stroke prevention with antihypertensive therapy was shown in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). In that study, 6,105 patients (mean age, 64 years) with a history of stroke or transient ischemic attack were randomly assigned to receive placebo or the ACE inhibitor perindopril (with the addition of indapamide at the discretion of the investigator). Blood pressure was reduced by 9/4 mm Hg in patients receiving perindopril alone and 12/5 mm Hg in those receiving both perindopril and indapamide. There was a 28% relative risk reduction in stroke in the active treatment group. The reduction in stroke risk did not depend on baseline blood pressure and was comparable in magnitude for hypertensive and nonhypertensive patients.22 Because the study de-
sign made it difficult to determine whether the ACE inhibitor or the diuretic was responsible for the beneficial effects, combination treatment is recommended for patients who have had a stroke.
Special issues with antihypertensive therapy for elderly patients According to recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), antihypertensive therapy is indicated for all elderly patients with systolic blood pressure above 140 mm Hg or diastolic pressure above 90 mm Hg. For patients with diabetes mellitus or renal impairment, a lower threshold for treatment of 130/80 mm Hg is indicated. The benefits of treatment are clearly established, yet surveys indicate that fewer than 25% of patients are at or below goal blood pressure. Clinical inertia is a hindrance to optimizing blood pressure control. Physicians are encouraged to titrate medications upward, combine different agents, and reinforce lifestyle modifications when the systolic or diastolic blood pressure is not at goal. Medical regimens should be tailored to the patient’s coexisting conditions. Certain comorbid illnesses are compelling reasons for the selection of particular agents, as shown in table 4.
Particular attention should be paid to the technique of blood pressure measurement in the elderly. A falsely increased brachial cuff blood pressure reading may be caused by diffuse arteriosclerosis and increased arterial stiffness, a phenomenon referred to as pseudohypertension. In these patients, measurement of blood pressure with automated devices that use oscillometric techniques will give more accurate readings. Postural hypotension despite antihypertensive therapy, treatment-resistant hypertension, and the absence of target organ damage in patients with long-standing “hypertension” are some of the clinical features suggestive of pseudohypertension.23
Central sympatholytic agents and reserpine should generally be avoided in elderly patients because they may adversely affect cognition. In general, drugs should be initiated at a low dose and titrated gradually to effect a slow reduction in increased blood pressure. Special attention should be paid to renal function because the dose may need to be adjusted for certain medications. Low-dose diuretic therapy is well tolerated. Nonsteroidal anti-inflammatory drugs are commonly used by the elderly and may contribute to difficult blood pressure control. These agents cause sodium retention and may adversely affect renal function. The use of fixed-drug combinations is an attractive option to reduce the number of pills a patient must take and therefore improve medication compliance.
The recommendations in JNC 7 state that all hypertensive patients older than 50 years of age should have lying and standing blood pressure recordings periodically. Readings in the sitting position may miss the diagnosis of orthostatic hypo-tension (a supine-to-standing blood pressure reduction of > 20 mm Hg systolic or > 10 mm Hg diastolic). Diabetic patients, patients taking diuretics or vasodilators, and patients with isolated systolic hypertension are particularly prone to this condition. Volume depletion, baroreflex dysfunction, and autonomic insufficiency may contribute to
the development of this difficult condition in elderly patients. Alpha blocking agents (doxazosin, terazosin) and direct-acting vasodilators (minoxidil, hydralazine) should be avoided or used with caution because they may cause or exacerbate orthostatic hypotension.
Hypertension is a major risk factor for the development of cardiovascular, cerebrovascular, and renal events in elderly patients. Because the baseline risk of cardiovascular events is so much higher in these patients, aggressive lowering of blood pressure reaps a much greater reduction in complications in this subgroup compared with the hypertensive population as a whole. The importance of treating isolated systolic hypertension cannot be overemphasized. Pharmacologic therapy, with an emphasis on low-dose diuretics, angiotensin-receptor blockers, ACE inhibitors, and calcium channel blocking agents should be initiated whenever the systolic blood pressure exceeds 140 mm Hg. An aggressive stance with African American patients should be adopted because this subgroup shows a higher risk of cerebrovascular and cardiovascular complications. Clinical inertia should be avoided, and active pursuit of a treatment goal of less than 140 mm Hg systolic blood pressure is imperative. Combination therapy with two or more antihypertensive agents will be needed to achieve this target in the majority of patients, and many will require three or more drugs. Heart failure, type 2 diabetes mellitus, chronic renal failure, previous stroke, and MI are frequent comorbid conditions in the elderly that warrant an individualized approach to blood pressure control and mandate the inclusion of specific drug agents in the therapeutic regimen. The presence of underlying endocrine disorders and renovascular disease may pose a therapeutic challenge, and early referral to a hypertension specialist is encouraged if goal blood pressure cannot be achieved with three medications. n