Key result
Hydrochlorothiazide linked to ~36% greater prevention of nonfatal CVD vs chlorthalidone.
Why the study?
The pragmatic DCP trial showed no difference between chlorthalidone and hydrochlorothiazide in intent-to-treat analysis, motivating this per-protocol analysis to estimate adherence effects in older patients with hypertension.
Does chlorthalidone reduce major adverse cardiovascular events compared to hydrochlorothiazide in older patients with hypertension?
Does chlorthalidone reduce major adverse cardiovascular events compared to hydrochlorothiazide in older patients with hypertension?
A per-protocol analysis of the Diuretic Comparison Project found no statistically significant difference in cardiovascular events between chlorthalidone and hydrochlorothiazide in older patients with hypertension.
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Per-protocol suggestion of hydrochlorothiazide benefit does not alter practice; leaves open adherence effects on diuretic outcomes.
Background The DCP (Diuretic Comparison Project), a pragmatic trial, evaluated whether chlorthalidone compared with hydrochlorothiazide would reduce the risk of nonfatal cardiovascular disease or noncancer‐related death. The intent‐to‐treat analysis found no difference in such comparison (hazard ratio, 1.04 [95% CI, 0.94–1.16]). The objective of the current study is to estimate the per‐protocol effect of chlorthalidone (12.5/25 mg daily) compared with hydrochlorothiazide (25/50 mg daily) in preventing major adverse cardiovascular events among older patients with hypertension. Methods The effect of adhering to treatment strategies was assessed by censoring at first instance of nonadherence, defined as a gap (>90‐day gap in drug coverage), switch (switching between study medications), and discontinuation (stop taking chlorthalidone/hydrochlorothiazide altogether for >90 days before the end of the study). The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and noncancer‐related death. Using inverse probability weighting, we evaluated the per‐protocol effect of chlorthalidone and hydrochlorothiazide using DCP trial data. Results Nonadherence was found in 5476 (40%) participants; among 8047 (60%) adherents, 3905 (49%) were randomized to chlorthalidone and 4142 (51%) to hydrochlorothiazide. After censoring time when participants deviated from the assigned treatments, the estimated 5‐year risk ratio of the composite primary outcome of nonfatal cardiovascular disease and noncancer‐related death was 1.36 (95% CI, 0.96–2.12) in chlorthalidone compared with hydrochlorothiazide. Conclusions The per‐protocol analysis indicated a lower risk with hydrochlorothiazide compared with chlorthalidone in preventing nonfatal cardiovascular disease and noncancer‐related death; however, this difference was not statistically significant using dispensation data to identify adherence. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02185417.
Anand et al. (2026) studied this question. In the per-protocol analysis, hydrochlorothiazide was associated with a risk ratio of 1.36 for preventing nonfatal cardiovascular disease compared to chlorthalidone, indicating a potential benefit.
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