Systemic hypertension
Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes

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Diuretic-based antihypertensive therapy is associated with the development of diabetes but with improved clinical outcomes. It has been proposed that the duration of clinical trials has been too short to detect the adverse effects of diabetes. We assessed the long-term mortality rate of subjects in the Systolic Hypertension in the Elderly Program (n = 4,732) who were randomized to stepped-care therapy with 12.5 to 25.0 mg/day of chlorthalidone or matching placebo. If blood pressure remained above the goal, atenolol or matching placebo was added. At a mean follow-up of 14.3 years, cardiovascular (CV) mortality rate was significantly lower in the chlorthalidone group (19%) than in the placebo group (22%; adjusted hazard ratio [HR] 0.854, 95% confidence interval [CI] 0.751 to 0.972). Diabetes at baseline (n = 799) was associated with increased CV mortality rate (adjusted HR 1.659, 95% CI 1.413 to 1.949) and total mortality rate (adjusted HR 1.510, 95% CI 1.347 to 1.693). Diabetes that developed during the trial among subjects on placebo (n = 169) was also associated with increased CV adverse outcome (adjusted HR 1.562, 95% CI 1.117 to 2.184) and total mortality rate (adjusted HR 1.348, 95% CI 1.051 to 1.727). However, diabetes that developed among subjects during diuretic therapy (n = 258) did not have significant associations with CV mortality rate (adjusted HR 1.043, 95% CI 0.745 to 1.459) or total mortality rate (adjusted HR 1.151, 95% CI 0.925 to 1.433). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term CV mortality rate (adjusted HR 0.688, 95% CI 0.526 to 0.848) and total mortality rate (adjusted HR 0.805, 95% CI 0.680 to 0.952). Thus, chlorthalidone-based treatment improved long-term outcomes, especially among subjects who had diabetes. Subjects who had diabetes associated with chlorthalidone had no significant increase in CV events and had a better prognosis than did those who had preexisting diabetes.

Section snippets

Methods

The SHEP was a placebo-controlled, double-blind, randomized, multicenter clinical trial that tested the efficacy of diuretic-based stepped-care antihypertensive management of isolated systolic hypertension in subjects ≥60 years of age.4, 8 The major inclusion criterion was the presence of isolated systolic hypertension, which was defined as a systolic blood pressure of 160 to 219 mm Hg with a diastolic blood pressure <90 mm Hg. Patients who had insulin-dependent diabetes mellitus and those who

Results

Baseline characteristics of the active treatment and placebo groups at randomization have been previously reported.4, 18 Mean age was 71.6 ± 6.7 years, 58% were women, 14% were African-American, 16.9% had diabetes, 4.9% had a history of myocardial infarction, 49.8% were current or previous smokers, and mean blood pressures were 170.3 ± 9.4 mm Hg (systolic) and 77.0 ± 8.0 mm Hg (diastolic).

Discussion

This long-term study of older patients who had isolated systolic hypertension yielded 3 conclusions of clinical significance. First, chlorthalidone-based antihypertensive therapy was associated with a significantly lower rate of CV mortality during long-term follow-up (14.3 years). This was not observed during the double-blind phase of the study. Second, in contrast to diabetes present at baseline, diabetes diagnosed during diuretic therapy was rather mild and not associated with a significant

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    This study was supported in part by contracts with the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and the National Institute on Aging, Bethesda, Maryland; and a grant from the Robert Wood Johnson Foundation, Princeton, New Jersey.

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