Hypertension in the elderly

,
Cardiology Review® Online, September 2006, Volume 23, Issue 9

More important than the choice of pharmaceutical agent in the treatment of elderly hypertensive patients is the achievement of goal blood pressure. Low-dose diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers are equally effective in reducing cardiovascular end points. Most patients will require 2 or more drugs to achieve target blood pressure, and physicians should feel comfortable prescribing 3 to 4 agents to a significant proportion of patients.

Readers wishing to see the figures and/or tables for this paper should consult the print version of this paper.

The proportion of elderly persons is increasing in most industrialized countries, and this trend is expected to continue in the coming decades. Hypertension affects approximately 60 million patients in the United States and nearly a billion individuals worldwide. Blood pressure increases markedly with age, and in this country, the majority of individuals over the age of 60 are hypertensive. Data from the Framingham Study suggest that an individual who is 55 years of age or older and remains normotensive still has an approximately 90% lifetime risk of developing hypertension.1 Although men are more likely to develop hypertension compared with women in younger age groups, the proportion of elderly women with increased blood pressure equals or exceeds that of men. As the population ages, the number of elderly patients with hypertension will continue to increase unless broad and effective preventive measures are used to control blood pressure.

Elderly patients with hypertension are often treated less intensively than younger individuals, and not surprisingly, the Third National Health and Nutrition Examination Survey (NHANES III) found that hypertensive patients older than 60 years of age had lower rates of blood pressure control compared with younger individuals.2 This may reflect poor patient understanding regarding the significance of high blood pressure or may be caused by the fact that health care providers are often hesitant to start or aggressively titrate antihypertensive medications in their older patients. In a study of elderly patients visiting their physicians for the treatment of hypertension, approximately 40% were found to have blood pressures greater than 160/90 mm Hg, despite averaging more than 6 visits per year.3

A meta-analysis by Lewington et al showed that the absolute benefits of treatment are actually much greater in older vs younger hypertensive patients.4 For individuals aged 40 to 80 years, each increment of 20 mm Hg in systolic blood pressure or 10 mm Hg in diastolic blood pressure approximately doubles the risk of stroke and ischemic heart disease mortality across the blood pressure range of 115/75 to 185/115 mm Hg. Because the baseline risk is so much higher in older patients, however, the total number of preventable events is as much as 10-fold higher in patients older than 70 years of age. Thus, the necessity and cost effectiveness of aggressive blood pressure management in older patients with hypertension cannot be overemphasized.

Age is a continuous variable, and there is no distinct demarcation among young, middle-aged, and elderly hypertensive patients. Nevertheless, there are sufficient differences in the clinical characteristics of older individuals with hypertension to justify a specific focus on this segment of the hypertensive population. This article highlights the differences in the physiologic basis, natural history, and approaches to treatment in elderly patients with hypertension, emphasizing issues that have the potential to reduce cardiovascular end points, improve survival, and enhance quality of life.

Clinical characteristics

Systolic blood pressure increases inexorably with age in industrialized societies. This age-related increase in systolic blood pressure is experienced by both sexes and all ethnic groups. In contrast, diastolic blood pressure increases only until about age 55 and then declines. The result is a high prevalence of isolated systolic hypertension (ISH) and increased pulse pressure (systolic blood pressure minus diastolic blood pressure) in older patients. Whereas diastolic blood pressure is a potent cardiovascular risk factor in hypertensive patients younger than 50 years of age, in older patients, systolic blood pressure plays the predominant role.

The results of several large epidemiologic studies have documented that increased systolic blood pressure is a potent risk factor for stroke, congestive heart failure, and end-stage renal disease. In the Multiple Risk Factor Intervention Trial (MRFIT), systolic blood pressure was a much stronger predictor of death due to coronary artery disease (CAD) than diastolic blood pressure.2 A recent clinical advisory statement issued by the National High Blood Pressure Education Program recommended that systolic blood pressure become the major criterion for diagnosis, staging, and therapeutic management of hypertension for individuals older than 50 years of age.5 Isolated systolic hypertension is defined in the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) as a systolic blood pressure > 140 mm Hg in the presence of normal diastolic blood pressure.6 Isolated systolic hypertension accounts for approximately two thirds of the hypertension seen in patients older than 60 years of age. Among elderly patients with uncontrolled hypertension, 80% have ISH, and an additional 14% have increased systolic and diastolic blood pressure. The presence of ISH doubles all-cause mortality, triples cardiovascular mortality, and increases cardiovascular morbidity 2.5-fold.

Much of the morbidity associated with hypertension in elderly patients consists of stroke, a particularly devastating complication that often signals the end of independent living. With advancing age, stroke accounts for an increasing proportion of nonfatal outcomes associated with hypertension. In most studies of older hypertensive patients, stroke is a more frequent complication than myocardial infarction (MI). A meta-regression analysis, which included 27 clinical trials of antihypertensive drugs, showed that reduction of high blood pressure decreases the risk of death and morbidity from stroke and that the level of protection achieved against stroke is directly related to the degree of blood pressure reduction.7

The increased pulse pressure regularly seen in elderly hypertensive patients is itself an independent risk factor for cardiovascular events. Large population-based studies and a meta-analysis pooling the results of 3 major international trials have found that pulse pressure is a better predictor of cardiovascular outcomes in older persons than is systolic or diastolic blood pressure. Data derived from the Framingham Study indicate that for a patient with a blood pressure of 170/60 mm Hg, the risk of developing a clinical manifestation of CAD is double that of a patient with an identical systolic blood pressure and an increased diastolic pressure of 110 mm Hg.8 The effect of pulse pressure on cardiovascular outcome extends to patients receiving antihypertensive therapy. In the Systolic Hypertension in the Elderly Program (SHEP), patients who showed an increase of 10 mm Hg or more in pulse pressure while receiving therapy experienced significant increases in the risk of stroke and heart failure.9

Another distinguishing feature of hypertension in the elderly is the high frequency of comorbid conditions, which amplify the cardiovascular risks associated with blood pressure elevation. The prevalence of diabetes mellitus, CAD, renal disease, and cerebrovascular disease are all age-dependent, and these conditions frequently coexist with hypertension. The presence of these independent cardiovascular risk factors increases the absolute risk of hypertension-associated cardiovascular complications. In patients with diabetes, for example, the cardiovascular mortality associated with a systolic blood pressure of 120 to 140 mm Hg exceeds that seen in nondiabetic patients with systolic blood pressure in the 160- to 180 mm Hg range. As discussed earlier, the higher the absolute risk, the greater will be the number of complications that are preventable by effective antihypertensive treatment in a given population. In patients with diabetes and renal disease, evidence from clinical trials indicates that treating hypertension more aggressively to lower blood pressure goals (< 130/80 mm Hg) further reduces cardiovascular end points beyond that which can be achieved by conventional blood pressure targets (< 140/90 mm Hg).

Pathophysiology

The predominance of the increased systolic blood pressure and increased pulse pressure seen in elderly hypertensive patients is the direct result of structural and functional changes that occur in the aging vasculature. Dilatation of the aorta and large conduit arteries, thickening of the arterial walls, an increased number of collagen fibers in the arterial wall, and increased mineralization (calcium deposition) of elastin are all seen with increasing age. These changes, which appear to be associated with aging per se, also occur as a result of hypertension.10 Hypertension, in effect, accelerates the vascular aging process.

There is evidence that high salt consumption, endothelial dysfunction, and activation of the renin-angiotensin-aldosterone system (RAAS) are important factors in the development of these structural changes. A positive correlation has been observed between urinary sodium excretion, which is an estimate of sodium consumption, and the upward slope of systolic blood pressure with aging. Sodium consumption and pulse pressure are also statistically associated, particularly in men. A high-salt diet induces phenotypic changes in vascular smooth muscle cells, which favor the development of secretory properties leading to collagen accumulation within the walls of large arteries. Increased sodium intake or endothelium-dependent nitric oxide deficiency, or both, promotes increased aortic collagen accumulation. Both are also thought to contribute to arteriolar hypertrophy, leading to increased vascular resistance and an augmented physiologic response to vasoconstrictor agents, including angiotensin II and norepinephrine. Angiotensin II itself causes endothelial dysfunction and makes an important independent contribution to the development of vascular hypertrophy and remodeling.11

Increased central arterial stiffness (reduced compliance) is largely responsible for the rise in systolic blood pressure and widened pulse pressure seen in elderly patients. Compliant, normally functioning arteries can instantaneously accommodate the blood ejected from the heart, storing part of the stroke volume during systole and draining this volume during diastole. This process promotes continuous perfusion of organs and tissues. Loss of large-vessel elasticity compromises this cushioning role of arteries in dampening pressure oscillations. The result is higher systolic and lower diastolic pressure.

before

Central arterial stiffness also increases systolic blood pressure and pulse pressure by increasing pulse wave velocity (PWV). 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 PWV 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 PWV (eg, 20 m/sec) results in the reflective wave reaching the left ventricle aortic valve closure. The resulting pressure in the ascending aorta is the sum of the incident and reflected waves, and the effect is augmentation of systolic blood pressure (Figure 1).

Elevated systolic blood pressure increases ventricular afterload—the tension that must be developed in the left ventricle to eject blood into the aorta. This increased afterload contributes to the development of left ventricular hypertrophy (LVH), which occurs frequently in elderly patients with hypertension. Other than age, LVH is the most potent predictor of adverse cardiovascular outcomes in the hypertensive population. It is an independent risk factor for CAD, sudden death, heart failure, and stroke.

Changes in left ventricular diastolic function are regularly seen in patients with LVH. Approximately 40% of clinical episodes of heart failure requiring hospitalization in the United States occur in patients with normal or near-normal left ventricular systolic function. The majority of these patients have hypertension, LVH, and left ventricular diastolic dysfunction. Increased myocardial stiffness, delayed myocardial relaxation, and impaired coronary flow reserve lead to increased left ventricular filling pressures, which are reflected back into the pulmonary capillaries. These high pressures increase further with exercise, limiting cardiac reserve and exercise capacity. As a result, congestive heart failure characterized by fatigue, dyspnea, and pulmonary congestion often develops.

Therapy

The goal of treating hypertension in elderly patients is to reduce cardiovascular end points without adversely affecting quality of life. In designing a comprehensive treatment regimen, cardiovascular risk factors other than blood pressure should be addressed. The most common associated risk factors in hypertensive patients are obesity, dyslipidemia, and insulin resistance. The single most important objective with regard to blood pressure management is the achievement of goal blood pressure. Lifestyle modification should be undertaken whenever feasible. In the majority of patients, drug therapy will be required.

Lifestyle modification

The JNC 7 recommendations advocate lifestyle interventions as an important component of treating patients with hypertension. Weight reduction in overweight persons, limitation of alcohol and sodium intake, increased physical activity, and adequate potassium intake are all recommended to reduce blood pressure. However, the role of these strategies in older persons has not been adequately tested. Lifestyle modification is easy to prescribe but difficult to implement. Effective behavioral change requires a motivated patient. It is important for the treating physician to convey the value of lifestyle modification in a convincing manner to patients and their families. Sufficient time must be devoted to this endeavor if it is to produce meaningful results. Effective drug therapy should not be delayed significantly while awaiting the results of lifestyle modification.

The most important lifestyle interventions are salt restriction and weight loss. Sodium intake correlates with blood pressure in both populations and individual patients. A meta-analysis of 22 trials of salt restriction in hypertensive patients showed a mean blood pressure reduction of 4.8/2.5 mm Hg in association with a median reduction in sodium excretion of 76 mmol/day.12 Subgroup analysis suggested that dietary sodium restriction was more effective in older hypertensive individuals (≥ 45 years). There is a direct correlation between body mass index (BMI) and blood pressure; BMI is also an independent risk factor for the development of LVH. Weight reduction in overweight persons is associated with a significant decrease of approximately 0.9 mm Hg in systolic blood pressure for every kilogram of weight loss.

The Trial of Nonpharmacological Interventions in the Elderly (TONE) showed that reduced sodium intake and weight loss were safe, effective, and feasible in elderly, obese patients with mild hypertension.13 A total of 875 patients aged 60 to 80 years with mild hypertension controlled by a single agent were randomly assigned to receive sodium restriction, weight loss, both, or usual care. In most subjects, drug therapy was withdrawn during the trial. A larger proportion (44%) of patients receiving both sodium restriction and weight loss were able to avoid reinstitution of drug therapy after a follow-up period of 30 months compared with the usual-care group (16%) not receiving these lifestyle modifications.

Drug therapy

Placebo-controlled trials

The value of antihypertensive therapy in elderly patients has been clearly shown in placebo-controlled trials. Three studies compared diuretic or beta-blocker therapy, or both, with placebo in older patients with systolic/diastolic hypertension. All showed a significant reduction in stroke incidence of 25% to 47%. Cardiac event reductions of a lesser magnitude were also documented.14-16

Recent data analyses suggest that diuretics may be superior to beta blockers (in particular, atenolol [Tenormin]) as first-line drugs in uncomplicated hypertension. Messerli and colleagues examined data derived from more than 16,000 elderly patients randomly assigned to receive diuretic therapy or beta blockers, or both.17 Diuretic therapy was found to be superior in preventing strokes, CAD, and mortality from all causes, including cardiovascular causes. Other studies indicate that treatment with beta blockers results in reduced brachial blood pressure but does not lower central aortic blood pressure as much as treatment with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and calcium antagonists. As discussed later, beta blockers remain the preferred agents for patients with CAD who constitute a significant proportion of the elderly hypertensive population.

The SHEP trial was the first study to show the benefit of treating ISH in older adults.15 In this study, 4736 patients older than 60 years of age with a systolic blood pressure > 160 mm Hg and a diastolic blood pressure < 90 mm Hg were randomly assigned to receive placebo or antihypertensive treatment with low-dose chlorthalidone (Thalitone) and atenolol. The average systolic blood pressure during treatment was 155 mm Hg in the placebo group and 143 mm Hg in the active-treatment group. The 5-year incidence of total stroke was reduced by 36%, the incidence of heart failure by 54%, and the risk of nonfatal MI plus coronary death by 27%. It is noteworthy that these impressive results were obtained with modest blood pressure reduction and that the mandated treatment goals in the study were less aggressive than the current JNC 7 systolic blood pressure targets (< 140 mm Hg for most patients; < 130 mm Hg for diabetic patients and patients with renal disease). In the SHEP study, the benefit of active treatment compared with placebo increased with age, reaching its maximum in the oldest age group. The Syst-Eur and Syst-China studies showed similar results using a dihydropyridine calcium channel blocker as first-line therapy for ISH.18,19

P

P

P

A meta-analysis of 8 trials, including 15,693 patients with ISH followed for 8 years, was recently published. Hazard ratios associated with a 10-mm-Hg higher initial systolic blood pressure were 1.26 ( = .001) for total mortality and 1.22 ( = .02) for stroke, but only 1.07 ( = .37) for coronary events. Active treatment reduced total mortality by 13%, cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30%, and coronary events by 23%. The number of patients needed to treat for 5 years to prevent 1 major cardiovascular event was lower for patients at or above age 70 (19 vs 39) and for patients with previous cardiovascular complications (16 vs 37).20

Comparative studies

A number of long-term end point trials have been conducted with the goal of determining which drugs or drug classes are the most effective agents for reducing cardiovascular complications in patients with hypertension. Many of these studies have included a large proportion of elderly patients.

In the Swedish Trial in Old Patients with Hypertension (STOP) 2 trial, 6614 patients aged 70 to 84 years with hypertension (blood pressure, ≥ 180/105 mm Hg) were followed for 5 years.14 They were randomly assigned to 1 of 3 treatment groups: conventional agents (diuretics, beta blockers), ACE inhibitors, or calcium antagonists. The blood-pressure—lowering effects were similar in all groups. The total mortality was not significantly different among the 3 groups, but ACE inhibitors were associated with significantly less MI and congestive heart failure compared with calcium antagonists.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included 33,357 participants aged 55 years or older (mean age, 67 years) with hypertension and at least 1 other CAD risk factor.21 Participants were randomly assigned to receive chlorthalidone, amlodipine (Norvasc), or lisinopril (Prinivil, Zestril). The mean follow-up period was 4.9 years. (An arm of the study evaluating first-line therapy with the peripheral alpha blocker doxazosin [Cardura] was dropped because of an excess of cardiovascular events.) There was no difference among treatments with regard to the primary end point (fatal CAD or nonfatal MI) and all-cause mortality. The results were no different when patients older than 65 years of age were compared with younger patients. Higher rates of stroke in the ACE inhibitor group in ALLHAT were the result of an increased incidence in the large black subgroup, whose blood pressure was less well-controlled. This finding was not seen in nonblack subjects, suggesting that the effect was related to the difference in blood pressure rather than inferiority of the ACE inhibitor. The overall conclusion of the study was that, in this relatively high-risk cohort of older hypertensive patients, a diuretic, a dihydropyridine calcium channel blocker, and an ACE inhibitor were about equally effective with regard to long-term end point reduction. Peripheral alpha blockers are no longer considered first-line antihypertensive agents.

P

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study compared cardiovascular outcomes in 13,449 high-risk hypertensive patients (average age, 67 years) randomly assigned to receive valsartan (Diovan) or amlodipine as first-line therapy.22 The achieved blood pressure was, on average, 2.2 mm Hg systolic and 1.7 mm Hg diastolic lower in the amlodipine-treated group compared with the valsartan-treated group. The primary composite end point (cardiac morbidity and mortality) occurred in 10.6% of valsartan-treated patients and 10.4% of amlodipine-treated patients (hazard ratio = 1.04; 95% confidence interval [CI], 0.94-1.15; = .49). Although there appeared to be some advantage in the amlodipine group with regard to the occurrence of MI and stroke, it was probably related to the lower achieved blood pressure in the amlodipine group. Interestingly, achievement of goal blood pressure (systolic < 140 mm Hg) by 6 months, independent of drug assignment, was associated with significant benefits for all major end points (Figure 2). Blood pressure reduction after only 1 month of treatment predicted events and survival.

Taken in aggregate, the results of these and other comparative trials and meta-analyses strongly support the view that blood pressure reduction per se is the most potent determinant of outcome in elderly patients with hypertension. Diuretics, long-acting dihydropyridine calcium channel blockers, and RAAS blockers (ACE inhibitors or angiotensin receptor blockers [ARBs]) appear to be equally effective in preventing major cardiovascular end points in unselected elderly hypertensive populations. In the absence of compelling indications to the contrary, a first-line agent should be selected from among these drug classes. Achievement of target blood pressure within a few months (by any means) is the most important objective of therapy.

The necessity of combination therapy

In most patients, combination therapy will be required to achieve blood pressure goals. In ALLHAT, about two thirds of patients achieved the goal blood pressure of < 140/90 mm Hg using an average of 2 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 1 drug would be required to meet blood pressure goals in approximately 80% of the ALLHAT cohort. To facilitate rapid blood pressure control, JNC 7 recommends that therapy be initiated with 2 agents in patients in whom baseline blood pressure is > 20/10 mm Hg above the treatment goal.

Rational combinations include drugs that work by different but complementary pharmacologic mechanisms. The best combinations include a low-dose diuretic with an ACE inhibitor or ARB, or a dihydropyridine calcium channel blocker added to an ACE inhibitor. These combinations produce additive blood pressure reduction and also have advantages in terms of side effect occurrence. Thus, combining an RAAS blocker with a diuretic reduces the risk of hypokalemia. Adding an ACE inhibitor to a calcium channel blocker decreases the incidence of calcium channel blocker—induced peripheral edema. In the Anglo-Scandinavian Cardiac Outcome Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), a combination strategy including a calcium channel blocker (amlodipine) and an ACE inhibitor (perindopril erbumine [Aceon]) proved to be superior to a beta blocker (atenolol) and a diuretic in controlling blood pressure and reducing total mortality and long-term cardiovascular end points.23

Special populations and compelling indications

There are a number of clinical circumstances in which specific agents and drug classes confer significant advantage. These conditions constitute what are termed by JNC 7 as “compelling indications” for specific drug classes and are listed in the Table.

Coronary artery disease

In patients with a prior (ST-segment elevation) MI, beta blockers reduce recurrent infarction and improve survival. In a meta-analysis of 15 prospective trials involving 18,995 patients randomized to receive a beta blocker or placebo, overall mortality was reduced by 22%, sudden cardiac death by 33%, and nonfatal MI by 20%.24 In a subsequent meta-analysis, only 4 of the beta blockers studied were found to achieve a statistically significant reduction in mortality: propranolol (Inderal), timolol (Betimol, Blocadren), metoprolol (Lopressor), and acebutolol (Sectral). In patients who had sustained a non-Q wave MI or who had angina pectoris, the data regarding the benefits of beta-blocker therapy were less definitive. However, most national guidelines recommend the use of beta blockers as preferred antihypertensive agents in all or almost all CAD patients. The same applies to patients with hypertension and heart failure related to systolic dysfunction (left ventricular ejection fraction [LVEF] < 40%). In these patients, the beta blockers carvedilol (Coreg), metoprolol-extended release (Toprol-XL), and bisoprolol (Zebeta) have been shown to reduce mortality by approximately 33%.

Blockade of the RAAS reduces ventricular remodeling and improves survival in patients with reduced systolic function following acute MI. The Survival and Ventricular Enlargement (SAVE) trial included 2231 patients within 3 to 16 days following an MI who had an LVEF of ≤ 40%. Patients were randomly assigned to receive placebo or captopril (Capoten). After an average of 42 months of follow-up, captopril therapy was associated with a 19% decrease in mortality, a 37% reduction in the development of clinical heart failure, and a 22% reduction in hospitalization for heart failure. A 25% reduction in the incidence of recurrent MI was also observed.25 Subsequent trials in post-MI populations with other ACE inhibitors showed similar results. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), also conducted in post-MI patients with left ventricular systolic dysfunction, the ARB valsartan was found to be equivalent to captopril with regard to all major end points.26 In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), mortality reduction was also seen post-MI with the aldosterone antagonist eplerenone (Inspra).27 In the Heart Outcomes Prevention and Evaluation (HOPE)28 and European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease (EUROPA)29 studies, ACE inhibitor therapy reduced recurrent MI in post-MI patients regardless of baseline systolic function. The conclusion is that most, if not all, patients with hypertension and CAD should receive an RAAS blocker—either an ACE inhibitor or an ARB.

Cerebrovascular disease

The use of an ACE inhibitor for secondary stroke prevention was evaluated in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).30 In this trial, 6105 individuals (mean age, 64 years) with a prior history of stroke or transient ischemic attacks were randomly assigned to receive active treatment with the ACE inhibitor perindopril (4 mg daily) or placebo. In perindopril-treated patients, the diuretic indapamide (Lozol) could be added at the discretion of the investigator regardless of blood pressure. Over the 4-year follow-up period, active treatment reduced blood pressure by 9/4 mm Hg. Ten percent of patients (307) assigned to receive active treatment had a stroke, compared with 14% (420) assigned to receive placebo, a risk reduction of 28%. Interestingly, there were similar reductions in the risk of stroke in hypertensive and nonhypertensive subgroups. The blood-pressure lowering regimen also resulted in a 34% reduction in post-stroke dementia and a 45% reduction in cognitive decline as assessed by the Mini-Mental State Examination. Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43%. In the absence of secondary stroke prevention data with other drug classes, JNC 7 adopted the recommendation that combination therapy with an ACE inhibitor and a diuretic be preferred treatment in patients with prior cerebrovascular events.

Left ventricular hypertrophy

RAAS blockade, using an ARB, was also found to be effective in preventing strokes in patients with LVH. In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, 9193 patients with hypertension and LVH were randomly assigned to receive losartan (Cozaar) or atenolol as first-line therapy, with hydrochlorothiazide (Microzide) as add-on therapy, followed by additional agents as needed.31 Although on-treatment blood pressure was almost identical in the 2 treatment groups, losartan-treated patients had a 25% reduction in the occurrence of stroke. Among the LIFE study participants, there were 1326 patients with ISH (mean age, 70 years). In this subset, there was a 25% reduction in the combined primary end point of cardiovascular mortality, stroke, and MI in patients who received losartan. Significantly more electrocardiogram-LVH 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. More than 90% of patients in both treatment arms required more than 1 antihypertensive drug. On the basis of the LIFE data, the Food and Drug Administration approved losartan for stroke prevention in patients with hypertension and LVH.

Diabetic nephropathy

Systolic blood pressure is a critical determinant of the rate of progression in patients with diabetic renal disease. In patients with hypertension, diabetes, and proteinuria, RAAS blockade reduces the progression of nephropathy independent of blood pressure reduction. In patients with adult-onset diabetes, losartan and irbesartan (Avapro) have been shown to reduce the rate of progression of renal insufficiency in major clinical trials.32,33 An earlier study with captopril in patients with type 1 diabetes showed similar results. In patients with proteinuria and hypertension, either an ACE inhibitor or an ARB should be included in the antihypertensive regimen.34 Based on earlier studies, multiple agents (average, 3.5 per patient) will be required to reach the lower target blood pressure (< 130/80 mm Hg) recommended by JNC 7 for patients with these 2 conditions.35

Special considerations

Accurate measurement of blood pressure in older persons can be challenging because of the cardiovascular changes associated with aging. Measurements may be inaccurate because of pseudohypertension, in which the blood pressure cuff fails to compress a calcified artery. This should be considered in patients with resistant hypertension (ie, patients with inadequate blood pressure control despite treatment with an appropriate 3-drug regimen), especially if these patients have symptoms of orthostatic hypotension.36

Central sympatholytic agents and reserpine should generally be avoided in elderly patients, as they may adversely affect cognition. In general, drugs should be initiated at a low dose and titrated gradually to effect a slow reduction in elevated blood pressure.

Special attention should be paid to renal function, as 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 elderly patients and may contribute to a lack of blood pressure control. These agents cause sodium retention, increase blood pressure, 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 may improve medication compliance.

Because age-related decreases in baroreflex response may lead to orthostatic hypotension, blood pressure should be monitored in sitting and standing positions. Orthostatic hypotension is defined as being present when the patient’s systolic blood pressure decreases by ≥ 20 mm Hg or diastolic blood pressure decreases by ≥ 10 mm Hg within 3 minutes of standing or in the passive head-up tilt position at 60 degrees. Readings in the sitting position may miss the diagnosis of orthostatic hypotension. Patients with diabetes, those on diuretics or vasodilators, and patients with ISH 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 blockers (doxazosin, terazosin [Hytrin]) and direct-acting vasodilators (minoxidil [Loniten], hydralazine [Apresoline]) should be avoided or used with caution, as they may cause or exacerbate orthostatic hypotension.

Conclusions

Systolic blood pressure increases with age, and hypertension as currently defined is present in a majority of individuals over the age of 65. Because the baseline risk of cardiovascular events is much higher in elderly versus younger patients, the potential of effective antihypertensive therapy to reduce cardiovascular outcomes is greatly enhanced. Systolic blood pressure is the chief determinant of risk in elderly hypertensive patients and constitutes the primary target of therapy. The necessity of treating ISH cannot be overemphasized.

The most important objective of therapy is the achievement of goal blood pressure, and this, more than the choice of pharmaceutical agents, determines outcome. Results of long-term clinical trials indicate that low-dose diuretics, ACE inhibitors, ARBs, and calcium channel blockers are about equally effective in reducing cardiovascular end points in broad populations of elderly hypertensive patients. Beta blockers are less appropriate choices for first-line therapy in uncomplicated patients. ACE inhibitors and ARBs have the advantage of reducing the future development of diabetes. Most patients will require 2 or more drugs to achieve target blood pressure, and physicians should feel comfortable in prescribing 3 to 4 agents to a significant proportion of patients. Lifestyle modification, particularly salt restriction and weight loss, can be a useful adjunct to drug therapy in motivated patients.

Many elderly patients with hypertension have comorbid conditions that reflect target-organ damage. Included in this category are patients with CAD, previous MI, LVH, left ventricular systolic dysfunction, cerebrovascular disease, and diabetic nephropathy. Beta blockers constitute preferred therapy for patients with CAD and should be a component of any antihypertensive regimen. In all of these conditions, blockade of the renin-angiotensin system with ACE inhibitors or ARBs is required and improves long-term benefits over and above blood pressure reduction.