Association Between Chlorthalidone Treatment of Systolic Hypertension and Long-Term Survival

Study Questions:

What is the gain in life expectancy of participants randomized to chlorthalidone-based stepped care antihypertensive therapy at the 22-year follow-up?


A National Death Index ascertainment of death in the long-term follow-up of a randomized, placebo-controlled, clinical trial (SHEP) of patients ages 60 years or older with isolated systolic hypertension was performed. Recruitment was between March 1, 1985, and January 15, 1988. After the end of a 4.5-year randomized phase of the SHEP trial, all participants were advised to receive active therapy. The time interval between the beginning of recruitment and the ascertainment of death by National Death Index (December 31, 2006) was approximately 22 years (21 years 10 months). The primary outcome measure was cardiovascular death and all-cause mortality.


At the 22-year follow-up, life expectancy gain, expressed as the area between active (n = 2,365) and placebo (n = 2,371) survival curves, was 105 days (95% confidence interval [CI], −39 to 242; p = 0.07) for all-cause mortality and 158 days (95% CI, 36-287; p = 0.009) for cardiovascular death. Each month of active treatment was therefore associated with approximately 1-day extension in life expectancy. The active treatment group had higher survival free from cardiovascular death versus the placebo group (hazard ratio [HR], 0.89; 95% CI, 0.80-0.99; p = 0.03), but similar survival for all-cause mortality (HR, 0.97; 95% CI, 0.90-1.04; p = 0.42). There were 1,416 deaths (59.9%) in the active treatment group and 1,435 deaths (60.5%) in the placebo group (log-rank p = 0.38, Wilcoxon p = 0.24). Cardiovascular death was lower in the active treatment group (669 deaths [28.3%]) versus the placebo group (735 deaths [31.0%]; log-rank p = 0.03, Wilcoxon p = 0.02). Time to 70th percentile survival was 0.56 years (95% CI, −0.14 to 1.23) longer in the active treatment group versus the placebo group (11.53 vs. 10.98 years; p = 0.03) for all-cause mortality and 1.41 years (95% CI, 0.34-2.61; 17.81 vs. 16.39 years; p = 0.01) for survival free from cardiovascular death.


The authors concluded that in the SHEP trial, treatment of isolated systolic hypertension with chlorthalidone stepped-care therapy for 4.5 years was associated with longer life expectancy at 22 years of follow-up.


This long-term analysis of the SHEP trial shows that treating hypertension with chlorthalidone-based therapy for 4.5 years was associated with higher survival and a gain in life expectancy at 22 years of follow-up. The gain in life expectancy free from cardiovascular death corresponds with approximately 1 day gained for each month of treatment. Reporting that each month of antihypertensive therapy is associated with 1-day prolongation of life is a strong clinical message that will likely result in increased patient adherence to drug therapy, and also decrease the degree of therapeutic inertia by health care providers.

Clinical Topics: Prevention, Statins, Hypertension

Keywords: Outcome Assessment (Health Care), Incidence, Follow-Up Studies, Chlorthalidone, Cardiology, Life Expectancy, Cardiovascular Diseases, Hypertension

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