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Leaving a “Legacy Effect” on Hypertension: A 22-Year-Old Revisit to SHEP


A 22-year follow-up of the SHEP study cohort showed that each month of active treatment with chlorthalidone was associated with a 1-day extension of life.

Controversy existed in the 1980s regarding isolated systolic hypertension. Does blood pressure lowering lead to any benefits?

The Systolic Hypertension in the Elderly Program (SHEP) provided strong evidence that treating isolated systolic hypertension in the elderly was crucial.1 In that study, 4.5-year follow-up of chlorthalidone-based therapy prevented 1 of 2 admissions for heart failure, 1 of 3 fatal and nonfatal strokes, and 1 of 4 coronary heart disease events.

That was 1991 and now is now, however. How about revisiting those patients?

A 22-year follow-up has been published.2 Life expectancy gain, expressed as the area between active and placebo survival curves, was 105 days for all-cause mortality and 158 days for cardiovascular death. Framed another way, each month of active treatment with chlorthalidone was associated with a 1-day extension of life. These data are all the more amazing when one realizes that the baseline 22 years ago for this particular cohort was a mean age of 72 years!
The effect of longer survival after initial therapy in any trial has been called the legacy effect. After a trial ends, if an active drug’s benefit has been proved (in this instance with chlorthalidone for decreasing heart failure, strokes, and heart disease in the SHEP trial), all entrants are told to take the beneficial drug-including those who previously received placebo. When the original drug-treated individuals continue to do better over time, they are said have benefitted from a legacy effect.

This effect has been reported not only in hypertension but also in lipid disorders and diabetes. In the United Kingdom Prospective Diabetes Study (UKPDS), post-monitoring follow-up demonstrated that the initial active group maintained the benefit from earlier glucose lowering after 10 years.3 Early and intensive therapy with antihypertensives that block the renin-angiotensin-aldosterone system in diabetes might also have a benefit that persists over time.3

There are a number of things to take home from these studies.

First, the original value of the SHEP study regarding the lowering of isolated systolic blood pressure has been more durable than ever imagined. Despite a mean randomization age at entry of 72 years, 22 years later a benefit is still realized.

I will have no trouble recommending therapy for isolated systolic hypertension in the elderly.

Second, old drugs are still good drugs. There has been resurgence of chlorthalidone use-and for good reason. The many newer drugs on the market have not supplanted it. How many of them are buttressed by a 22-year follow-up?

Third, add the “legacy effect” to your clinical vocabulary. Although an exact explanation for the effect is not available, it is worth watching for. It may be a real phenomenon in the treatment of hypertension and diabetes. It says something about earlier active intervention.

You may be providing a legacy.       

1. SHEP Cooperative Research Group. Prevention of Stroke by Antihypertensive Treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264. 
2. Kostis JB, Cabrera J, Cheng JQ, et al. Association between chlorthalidone treatment of systolic hypertension and long-term survival. JAMA. 2011;306:2588-2593.
3. Volpe M, Cosentino F, Tocci G, et al. Antihypertensive therapy in diabetes: the legacy effect and RAAS blockade. Curr Hypertens Rep. 2011;13:318-324.

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