JAMA June 26, 1991

Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP)

SHEP Cooperative Research Group

Bottom Line

In older adults with isolated systolic hypertension, a stepped-care treatment approach starting with low-dose chlorthalidone significantly reduced the incidence of fatal and nonfatal strokes by 36% compared to placebo.

Key Findings

1. Stepped-care antihypertensive treatment reduced the incidence of total stroke by 36% compared to placebo (relative risk 0.64; 95% CI 0.50-0.82; P=.0003) [2.1.3].

2. The 5-year absolute benefit for total stroke was 30 fewer events per 1,000 participants.

3. Major cardiovascular events were significantly reduced by 32% (relative risk 0.68), yielding a 5-year absolute benefit of 55 fewer events per 1,000 participants.

4. The secondary endpoint of nonfatal myocardial infarction plus coronary death was reduced by 27% (relative risk 0.73; 95% CI 0.53-1.00).

Study Design

Design

RCT

Double-Blind

Sample

4,736

Patients

Duration

4.5 yr

Median

Setting

Multicenter, US

Population Men and women aged 60 years or older with isolated systolic hypertension, defined as systolic blood pressure between 160 and 219 mm Hg and diastolic blood pressure <90 mm Hg.

Intervention Antihypertensive stepped-care drug treatment with low-dose chlorthalidone (12.5-25 mg/day) as step 1 medication, followed by atenolol (25-50 mg/day) or reserpine (0.05 mg/day) as step 2.

Comparator Matching placebo for both step 1 and step 2 medications.

Outcome Incidence of nonfatal and fatal (total) stroke.

Study Limitations

• The trial excluded participants with major pre-existing cardiovascular conditions, potentially limiting the generalizability of the findings to more frail, higher-risk elderly populations [1.1.3].

• Substantial crossover occurred due to ethical safety triggers, with many participants in the placebo group receiving active antihypertensive therapy by the end of the trial, which likely attenuated the observed treatment effects.

• A 4.5-year average follow-up might be too short to observe definitive long-term mortality benefits or potential adverse metabolic effects of thiazide diuretics fully.

Clinical Significance

The SHEP trial provided definitive evidence that pharmacological treatment of isolated systolic hypertension in patients aged 60 years and older effectively reduces stroke and major cardiovascular morbidity. This proved that safely lowering systolic pressure does not intrinsically compromise organ perfusion in the elderly, leading to a paradigm shift in geriatric cardiovascular guidelines.

Historical Context

Prior to the publication of the SHEP trial in 1991, diastolic blood pressure was the primary focus of hypertension management. Isolated systolic hypertension was largely viewed as a normal physiological consequence of age-related arterial stiffening, and many physicians feared that aggressively lowering it could dangerously compromise cerebral and coronary perfusion. The compelling results of SHEP helped establish isolated systolic hypertension as a critical and modifiable cardiovascular risk factor.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pathophysiological mechanism underlying isolated systolic hypertension (ISH) in older adults, and how does chlorthalidone pharmacologically address it?

Key Response

ISH is driven by age-related arterial stiffening and decreased aortic compliance, leading to increased pulse wave velocity and early reflection of the pulse wave during systole. Chlorthalidone, a thiazide-like diuretic, lowers BP initially by reducing intravascular volume and later through vasodilation, effectively reducing systolic peaks.

Resident

The SHEP trial utilized a stepped-care approach starting with chlorthalidone. Based on this and subsequent trials, how does the management of ISH in a 75-year-old differ from a 45-year-old with essential hypertension regarding drug choice and target goals?

Key Response

For older adults with ISH, thiazide diuretics or long-acting calcium channel blockers are preferred first-line agents due to their efficacy in lowering systolic BP. Residents must balance reaching targets while monitoring for orthostasis, unlike younger patients where ACE inhibitors or ARBs are equally or more prominently used initially depending on comorbidities.

Fellow

In older adults with ISH, lowering systolic blood pressure inevitably lowers diastolic blood pressure. How does the SHEP trial data inform our understanding of the J-curve phenomenon, and what is the risk of excessive diastolic BP lowering in patients with underlying coronary artery disease?

Key Response

The J-curve hypothesis suggests that lowering diastolic BP too much (e.g., below 60 mmHg) impairs coronary perfusion, which occurs primarily during diastole. Fellows must critically weigh the stroke-reduction benefits of lowering systolic BP against the potential risk of inducing myocardial ischemia if diastolic BP drops excessively, a common clinical conundrum in severe ISH.

Attending

When applying the SHEP trial results to frail, multimorbid older adults in your clinic, how do you balance the 36 percent relative risk reduction in stroke against the iatrogenic risks of aggressive BP control, such as falls, acute kidney injury, and polypharmacy?

Key Response

Attendings must contextualize trial data, recognizing that SHEP enrolled relatively healthy older adults. The clinical art involves shared decision-making, weighing the number needed to treat for stroke prevention against the number needed to harm for falls or syncope in frail populations not perfectly represented in the trial.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The SHEP trial utilized a stepped-care algorithm rather than a strict monotherapy protocol. How does this pragmatic trial design impact the internal validity regarding the specific efficacy of chlorthalidone versus the overall strategy of BP reduction?

Key Response

Stepped-care designs mimic clinical practice but dilute the ability to attribute outcomes solely to the first-line drug. A researcher must critique how the addition of step-2 drugs introduces confounding by indication or co-interventions when analyzing the precise mechanism of cardiovascular protection.

Journal Editor

As a peer reviewer evaluating a long-term trial in an elderly population like SHEP, how would you scrutinize the handling of competing risks (e.g., non-cardiovascular mortality) and loss to follow-up in the statistical analysis plan?

Key Response

In elderly cohorts, competing risks of death can bias Kaplan-Meier estimates of cardiovascular events. An editor would demand a competing risk analysis (like Fine-Gray subdistribution hazards) and rigorous handling of informative censoring to ensure the treatment effect is not artificially inflated.

Guideline Committee

How did the findings of the SHEP trial fundamentally shift the paradigm of historical hypertension guidelines, and how do modern guidelines (e.g., 2017 ACC/AHA) reconcile the SHEP targets with more recent data from trials like SPRINT?

Key Response

Prior to SHEP, ISH was often considered a benign consequence of aging. SHEP provided Class I evidence that treating ISH reduces stroke risk. Modern ACC/AHA guidelines build on this by pushing systolic targets even lower (under 130 mmHg based on SPRINT), but committees must carefully adapt these recommendations for older adults, acknowledging the foundational evidence SHEP provided for treating isolated systolic elevations.

Clinical Landscape

Noteworthy Related Trials

1997

Syst-Eur Trial

n = 4,695 · Lancet

Tested

Nitrendipine step-up therapy

Population

Older adults with isolated systolic hypertension

Comparator

Placebo

Endpoint

Fatal and non-fatal stroke

Key result: Active treatment reduced the rate of total stroke by 42 percent and all cardiovascular endpoints by 31 percent.

2008

HYVET Trial

n = 3,845 · NEJM

Tested

Indapamide with or without perindopril

Population

Very elderly patients 80 years or older with hypertension

Comparator

Placebo

Endpoint

Fatal and non-fatal stroke

Key result: Active treatment resulted in a 30 percent reduction in the rate of fatal or nonfatal stroke and a 21 percent reduction in all-cause mortality.

2015

SPRINT Trial

n = 9,361 · NEJM

Tested

Intensive blood pressure control targeting systolic under 120 mmHg

Population

Adults 50 years or older with high cardiovascular risk but without diabetes

Comparator

Standard blood pressure control targeting systolic under 140 mmHg

Endpoint

Composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death

Key result: Intensive treatment significantly reduced the primary composite outcome by 25 percent and all-cause mortality by 27 percent.

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