Hypertension in the Elderly: A Review of the Importance of Systolic Blood Pressure Elevation

Abstract

The elderly, those 65 years of age and older, will account for 20% of the population by the year 2040. Hypertension affects more than one half of the elderly and its prevalence continues to increase with age. The presence of hypertension confers an increased risk of stroke, congestive heart failure, coronary heart disease, end‐stage renal disease, and death. Although both diastolic and systolic blood pressure elevations are independently associated with increased cardiovascular risk in the younger individual, as vascular compliance becomes reduced at age 60, an increasing systolic blood pressure and lower diastolic blood pressure (or wider pulse pressure) increase cardiovascular risk in the elderly. Isolated systolic hypertension is the most common form of hypertension seen in the elderly. Lifestyle modification, including weight loss and salt restriction, reduces blood pressure, and may decrease the need for pharmacologic therapy. When the systolic blood pressure is 160 mm Hg or more and the diastolic blood pressure is <90 mm Hg, the initial use of a diureticbased or calcium channel blocker‐based regimen improves outcome. Alpha blocker therapy should not be used as initial monotherapy. Most elderly hypertensives will require two to three drugs to achieve the present blood pressure goal of <140 mm Hg. Caution should be exercised when lowering diastolic pressure to <55 mm Hg in those with isolated systolic hypertension. Although side effects of therapy are no more likely to occur in the elderly than in the younger individual with hypertension, blood pressure reduction should be accomplished gradually.

The elderly, defined as individuals 65 years of age and older, represent the most rapidly growing segment of the population. In 1990, they accounted for 13% of the US population and are expected to account for 20% of the population by the year 2040. ¹ The percentage of “old elderly” (i.e., those over age 85) is also growing, and is projected to reach 16 million by the middle of the 21st century. Hypertension, defined as a systolic blood pressure (SBP) of 140 mm Hg or higher and a diastolic blood pressure (DBP) of 90 mm Hg or higher, affects approximately 50 million adult Americans, 75% of whom are not adequately controlled (i.e., blood pressure (BP) of <140/90 mm Hg). Control rates are even worse in those at highest risk, including the elderly, in whom only one in five (20%) has BP controlled. Hypertension affects more than one half of those aged 65 and older, and its prevalence continues to increase with age. ² High BP in the elderly confers a three‐ to four‐fold increase in risk for cardiovascular disease, compared to younger individuals. It is a significant risk factor for stroke, congestive heart failure, coronary heart disease, end‐stage renal disease, and death. ¹ , ²

ISOLATED SYSTOLIC HYPERTENSION

Isolated systolic hypertension (ISH) is defined as a SBP of ≥140 mm Hg and a DBP of <90 mm Hg. It represents the most common form of hypertension in the elderly and its prevalence increases with age; two thirds of individuals 60 years of age and older, and three fourths of those over 75 years of age, have ISH. ³ More than 25% of adults 60 years of age or older have stage 1ISH (SBP of 140–159 mm Hg with DBP of <90 mm Hg). It is the predominant form of hypertension in the elderly, and often goes untreated.

Age‐related physiologic changes explain the frequent development of ISH. While DBP elevation is caused by constriction of the smaller arterioles, ISH is caused by the loss of distensibility of the larger arteries, especially the aorta. ⁴ In younger patients, the aorta is highly distensible, expanding during systole to minimize the rise in BP. The majority of elderly individuals, however, develop progressive stiffening of their arterial tree with age, reducing the compliance of the aorta during systole, which leads to a progressive elevation in SBP. Because the smaller arterioles are not involved in this process, the DBP remains normal or tends to decrease, contributing to a higher pulse pressure (SBP‐DBP) with age. ⁴ Accordingly, the elevated systolic pressure increases both left ventricular work and the risk for left ventricular hypertrophy, while the decreased DBP may compromise coronary blood flow, upon which it is dependent. ⁵

SBP is not only easier to determine than DBP in the elderly, but also it allows more appropriate risk stratification. In a recent analysis of the Framingham Heart Study, ⁶ knowing only the SBP correctly classified the stage of BP in 99% of adults over the age of 60, while knowing only the DBP allowed 66% to be correctly classified.

In younger populations, both DBP and SBP are independently associated with the cardiovascular event risk. At age 60, however, as vascular compliance is reduced, an increasing SBP and a lower DBP increases cardiovascular risk. Accordingly, the pulse pressure is a stronger predictor of cardiovascular risk than SBP or DBP. ⁷ As there is a lack of trial‐based evidence utilizing pulse pressure narrowing as a means of lessening risk, SBP will continue to be targeted for evidencebased event‐rate reduction.

APPROPRIATE GOALS OF THERAPY IN THE ELDERLY

Treatment Benefits.

The optimal BP level in the elderly has not yet been conclusively defined. ¹ In general, BP goals depend on the type of elevation and presence of concomitant conditions. Several large, prospective clinical trials conducted several decades ago, focusing on DBP as well as SBP elevation, demonstrated the benefits of treating hypertension in the elderly (Table I). Based on diastolic entry criteria, they showed significant decreases in morbidity and mortality when treating to a DBP goal of less than 90 mm Hg. Treatment benefits are more marked in older than younger individuals, due to their greater absolute risk for cardiovascular disease. ⁸ Even though cardiovascular events have been favorably decreased by treatment of hypertension in the elderly, the demonstrated benefit has been largest for the prevention of stroke and stroke‐related mortality. ¹

Table I.

Percentage of Event Reduction in Clinical Hypertension Trials in Older Patients: Average 12/5 mm Hg Systolic/Diastolic Reduction

	Stroke	CAD	CHF	All CVD
Systolic/diastolic
Australian	33	18	‐	31
EWPHE	36	20	22	29*
STOP	47*	13†	51*	40*
MRC	25*	19	‐	17*
HDFP	44*	15*	‐	16*
Isolated systolic
SHEP	33*	27*	55*	32*
Syst‐Eur	42*	30	29	31*
Syst‐China	38*	27	‐	25*
CAD=coronary artery disease; CHF=congestive heart failure; CVD=cardiovascular disease; EWPHE=European Working Party on High Blood Pressure in the Elderly; STOP=Swedish Trial in Old Patients with Hypertension; MRC=Medical Research Council; HDFP=Hypertension Detection and Follow‐up Program Cooperative Group; SHEP=Systolic Hypertension in the Elderly Program; Syst‐Eur=Systolic Hypertension‐Europe trial; Syst‐China=Systolic Hypertension‐China trial; *statistically significant; † myocardial infarction only

Several recent randomized, placebo‐controlled trials demonstrated significant benefit from drug treatment in elderly patients with ISH (Table II). In those with an SBP of ≥160 mm Hg and a DBP of <90–95 mm Hg, they found a 35%–40% reduction in stroke, up to a 50% reduction in heart failure, a 30% reduction in coronary events, and a 10%–15% reduction in mortality. In order to achieve this benefit, SBP was reduced by at least 20 mm Hg from baseline, to a level below either 150 or 160 mm Hg. In none of the trials was an average SBP of <140 mm Hg achieved (Table III).

Table II.

Major Clinical Trials Showing Benefit of Treating Isolated Systolic Hypertension

	SHEP (n=4736)	Syst‐Eur (n=4695)	Syst ‐China (n=2394)
Baseline BP	160‐219/<90	160‐219/<95	160‐219/<95
SBP/DBP (mm Hg)
BP reduction:	27/9	23/7	20/5
SBP/DPB (mm Hg)
Drug therapy	Chlorthalidone Atenolol	Nitrendipine Enalapril HCTZ	Nitrendipine Captopril HCTZ
Outcomes (%↓)
Stroke	33	42	38
CAD	27	30	27
CHF	55	29	‐
All CVD	32	31	25
BP=blood pressure; SBP/DBP=systolic/diastolic BP; CAD=coronary artery disease; CHF=congestive heart failure; CVD=cardiovascular disease; HCTZ=hydrochlorothiazide; SHEP=Systolic Hypertension in the Elderly Program; Syst‐Eur=Systolic Hypertension‐Europe trial; Syst‐China=Systolic Hypertension‐China trial

Table III.

Blood Pressure Reductions in SHEP and Syst‐Eur (mm Hg)

	SHEP	Syst‐Eur
Entry	160‐219/<90	160‐219/<95
Goal (SBP)	<160 +≥21 ↓	<150 +≥20 ↓
Baseline	170/77	174/86
Achieved: Rx	143/68	151/79
Achieved: Placebo	155/72	161/84
SHEP=Systolic Hypertension in the Elderly Program; Syst‐Eur=Systolic Hypertension‐Europe Trial; SBP=systolic blood pressure

Although the vascular risk of stage 1 ISH (140–159 mm Hg) is well established, no outcome‐based trial has been completed to test whether treatment reduces clinical event rates. A large trial is currently ongoing to evaluate this question. Nevertheless, the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) ⁹ and a recent consensus statement ³ based on epidemiologic and not trial‐based data recommend achieving an SBP of <140 mm Hg.

Clinical trials in those with hypertension, including the elderly, tend to underestimate the actual benefit of treatment for several reasons. First, patients with severe hypertension, who stand to benefit the most from treatment because of their greater absolute risk, are often excluded from the studies. In addition, many study protocols follow an “intention to treat” design, where patients in the placebo group are treated once their BP reaches a designated threshold, thus minimizing the ability to accurately measure treatment benefits in the active therapy group. In the Systolic Hypertension in the Elderly Program (SHEP), for example, by the end of the study, 44% of patients in the placebo group were receiving active treatment. Finally, a short trial duration may not allow cardiovascular end point differences to be realized, since cerebrovascular end point benefits may occur sooner than coronary heart disease event reductions. ¹ Accordingly, the actual results achieved in practice may be greater than those shown in the clinical trials.

Lifestyle (Nonpharmacologic) and Pharmacologic Goals and Options.

Lifestyle changes–in particular, reduced sodium intake and weight loss–are beneficial in controlling BP and are associated with less need for pharmacologic therapy in the elderly hypertensive. The Trial of Nonpharmacologic Interventions in the Elderly (TONE), ¹¹ showed that restricting salt to 80 mmol per day reduced SBP by 4.3 mm Hg and DBP by 2 mm Hg. Further, the combination of weight loss and salt restriction reduced BP more than either strategy by itself. In addition, it was found that weight loss and salt restriction may decrease the need for antihypertensive therapy in the elderly.

The majority of elderly patients with hypertension will require at least two to three drugs to achieve the SBP goal of <140 mm Hg recommended in JNC VI. In both the SHEP ¹⁰ and the Systolic Hypertension‐Europe (Syst‐Eur) trial, ¹² 40%‐50% of participants required at least two or more drugs to achieve a final SBP that was actually >140 mm Hg, while DBP was <80 mm Hg (Table III). As stated, lowering of DBP to goal is generally easier than lowering SBP to goal. If one focuses on achieving the SBP goal, the DBP goal will almost always be reached. For this reason, in the elderly, we need to focus more on SBP to achieve effective BP reduction.

The usual dose of the initial agent is often one half that used in the non‐elderly. This allows for the altered pharmacokinetic renal or hepatic metabolism that often occurs in the elderly. The dose should be up‐titrated slowly until the maximum BP reduction occurs at the dose with the fewest side effects. Agents are added until the BP goal is attained.

The initial (preferred) drug or drug class for use in elderly patients with ISH has been addressed in several outcome‐based trials. The SHEP trial, ¹⁰ performed in 4736 subjects at least 60 years of age with an SBP of ≥160 mm Hg and a DBP of <90 mm Hg, showed a favorable reduction in stroke and cardiovascular events using a diuretic‐based strategy with or without a β blocking agent (Table II). More recently, the Syst‐Eur trial, ¹² including 4695 patients older than 60 years of age over a median follow‐up of 2 years, has shown a benefit when using a long‐acting dihydropyridine calcium channel blocker (CCB) as initial therapy. A meta‐analysis of eight placebo‐controlled trials in 15,693 patients 60 years of age and older and followed for an average of 3.8 years found that active treatment reduced coronary events by 23%, stroke by 30%, cardiovascular death by 18%, and total death by 13%. ¹³ In those patients older than 70 years of age, the absolute benefit was particularly high. Treating 19 patients for 5 years prevented one major fatal or nonfatal cardiovascular event. Although most of these trials were performed in patients over 60 years of age, a recent meta‐analysis ¹⁴ supported the benefit of antihypertensive therapy even in patients over 80 years of age, as the oldest of the elderly seem to benefit the most from active treatment.

A recent retrospective analysis of SHEP, ¹⁵ which proved the benefit of initial diuretic‐based therapy, found that 7% of the participants in the active treatment group on chlorthalidone had developed hypokalemia (K⁺ of <3.5 mEq/L) by the 1‐year visit. The individuals who developed hypokalemia had an event rate similar to that of the placebo group, while those with levels >3.5 mEq/L had significantly fewer cardiovascular events, suggesting that K⁺ should be kept to a level of ≥3.5 mEq/L. If not used initially, a thiazide diuretic, based on outcome‐based trials, should be included in most regimens to enhance the efficacy of other BP‐lowering agents as well as to reduce the risk of developing ischemic stroke. ¹⁶

Although they have been used as single‐agent therapy in no more than 60% of the patients treated, diuretics and CCBs are the only drug classes that have so far been tested as initial therapy in outcome‐based trials in elderly patients with ISH. If a diuretic is used, potassium levels should be kept as close to normal as possible. ¹⁵

The Playing Field Appears Level.

Although all classes of antihypertensive agents effectively lower combined SBP/DBP elevation in the elderly, the majority of outcome‐based trials showing a reduction in vascular morbidity and mortality have used diuretics and, when necessary, additive therapy with β blockade. Since JNC VI in 1997, several therapeutic trials in elderly hypertensives with combined SBP and DBP elevation have suggested that the initial agent chosen for treatment may not have a unique status for event rate reduction and that the BP level achieved appears more important.

The open‐label Second Swedish Trial in Old Patients with Hypertension (STOP‐2) ¹⁷ compared the use of angiotensin‐converting enzyme (ACE) inhibitors and CCBs with diuretic and/or β blocker therapy. It included 6628 elderly hypertensives 70–84 years of age. With similar BP reduction, there was no difference in cardiovascular mortality (the primary outcome) among the three randomized groups. The ongoing Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ¹⁸ enrolled hypertensives at least 55 years of age (mean age, 67). It stopped the α blocker (doxazosin) arm early because of a 25% greater cardiovascular event rate as well as a two‐fold greater risk of heart failure when compared to the diuretic chlorthalidone. ¹⁸ This suggests that although doxazosin therapy can be used as additive therapy, it should not be used as initial monotherapy in the treatment of the elderly hypertensive.

The open‐label Nordic Diltiazem (NORDIL) trial, ¹⁹ enrolling patients with an average age of 60 years, found a similar rate for the primary outcome of combined fatal and nonfatal stroke, myocardial infarction, and cardiovascular disease death in comparing the CCB diltiazem with diuretic and/or β blocker therapy. Although fewer strokes occurred in the diltiazem arm, there was a trend toward more myocardial infarctions and congestive failure with diltiazem. The double‐blinded International Nifedipine GITS (INSIGHT) trial ²⁰ enrolled men and women 55–80 years of age, 75% of whom were above the age of 60. It found that nifedipine GITS (gastrointestinal treatment system) and diuretic therapy resulted in similar overall cardiovascular disease outcomes.

Presently, the degree of BP reduction–not the individual drug used for lowering BP–appears more important for improving outcome, even in the older individual. ²¹ The still‐to‐be‐completed ALLHAT trial, comparing the ACE inhibitor lisinopril, the CCB amlodipine, and the diuretic chlorthalidone, will help to clarify, in the 42,448 high‐risk hypertensives, whether newer‐generation agents are superior, similar, or inferior to the diuretic chlorthalidone in older individuals with hypertension. ²²

J‐Curve Phenomenon.

The J‐curve hypothesis describes the observational concern that lowering DBP below a certain critical value increases the risk of cardiovascular death in elderly hypertensives. Prospective data validating this hypothesis are lacking. It is important to remember that the bulk of the evidence available is from retrospective trials, which are associated with inherent observational bias. As this phenomenon has been prospectively observed in both placebo and actively treated patients, a low DBP is thought to serve more as a marker than as the cause of events in those with underlying coronary disease.

The Hypertension Optimal Treatment (HOT) study ²³ was designed to test this question. This prospective, randomized, open with blinded end point evaluation (PROBE) trial randomly assigned 18,790 hypertensive patients (mean age, 61.5 years) in 26 countries to a target DBP of 80 mm Hg, 85 mm Hg, or 90 mm Hg and followed them for an average of 3.8 years. It found no increased risk for the DBP goal of <80 mm Hg vs. <90 mm Hg.

A retrospective analysis of the SHEP trial, ²⁴ however, suggested that in the few patients whose DBP was lowered to <55 mm Hg, there was no benefit in outcome, compared to the placebo group. Although this may reflect a higher risk in those with the widest pulse pressure, it suggests we exercise caution in lowering DBP to <55 mm Hg when treating older individuals with ISH.

General Guidelines for Antihypertensive Treatment.

• •Hypertension therapy in older individuals should begin with lifestyle modification.
• •Weight loss and sodium restriction may decrease the need for antihypertensive medication in this population.
• •The starting dose of medication should be one half of that used in younger patients.
• •In the uncomplicated elderly patient with hypertension, a diuretic with or without a β blocker is a reasonable approach, based on outcome data.
• •In the elderly patient with ISH, a diuretic is preferred as initial therapy; however, a longacting dihydropyridine CCB may be used as alternative therapy.
• •ACE inhibitor therapy continues to be recommended in the elderly hypertensive with diabetes or systolic heart failure, and after myocardial infarction.
• •Although not specifically evaluated in elderly hypertension trials, an angiotensin‐receptor blocker may be recommended when a cough or other adverse effect precludes the use of an ACE inhibitor. There is, at present, no evidence to support the use of an ACE inhibitor and angiotensin receptor blocker together.
• •Alpha blocker therapy should not be used as initial monotherapy in the elderly hypertensive. It can be used as additive therapy to further reduce BP.
• •The treatment goal should be determined by the underlying concomitant hypertensive disorder. In systolic/diastolic hypertension, the goal should remain <140/90 mm Hg, with lower goals in diabetics and subjects with renal disease. Patients with ISH should have a minimal SBP goal of <140 mm Hg.
• •With the risk of more side effects, smaller doses of two tolerated agents are more desirable than high‐dose monotherapy.
• •Although BP reduction should occur more gradually in elderly patients, the goals of therapy should be similar to those in younger patients.

This paper was presented at the National Heart, Lung, and Blood Institute Symposium on Hypertension; April 25, 2001; Atlanta, GA.