Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published December 28, 2022


Was chlorthalidone superior to hydrochlorothiazide in the trial by Ishani et al.?

Ishani et al. conducted a comparative effectiveness trial that evaluated whether chlorthalidone, as compared with hydrochlorothiazide, reduced the risk of major nonfatal cardiovascular disease outcomes and non–cancer-related deaths in older patients with hypertension who were receiving hydrochlorothiazide at baseline. Read the NEJM Original Article here.

Clinical Pearls

Q: What was the design of this large pragmatic trial?

A: The authors conducted this large pragmatic trial within the Department of Veteran’s Affairs (VA) point-of-care program. The trial was embedded within the VA electronic health records system, which allowed centralized identification and recruitment. The trial was conducted in the context of usual care with no trial-specific procedures (including case-report forms) or trial-specific visits. All data were extracted from administrative databases, which dramatically reduced the total cost of the trial. Centralized recruitment allowed participation from many smaller VA sites that traditionally have been excluded from clinical trials owing to lack of research infrastructure.

Q: Was chlorthalidone superior to hydrochlorothiazide in the trial by Ishani et al.?

A: The primary outcome of this trial was the first occurrence of a composite outcome consisting of a nonfatal cardiovascular disease event or non–cancer-related death, assessed in a time-to-event analysis. Nonfatal cardiovascular disease events were nonfatal myocardial infarction, stroke, hospitalization for heart failure, or urgent coronary revascularization for unstable angina. At a median follow-up of 2.4 years, a primary composite outcome event had occurred in 1377 patients — 702 (10.4%) in the chlorthalidone group and 675 (10.0%) in the hydrochlorothiazide group (hazard ratio, 1.04; 95% confidence interval [CI], 0.94 to 1.16; P = 0.45). There was no difference between the groups in the individual components of the primary outcome.

Morning Report Questions 

Q: Did treatment outcomes differ in any of the prespecified subgroups?

A: There was a qualitative interaction in a prespecified subgroup that was defined according to the history of myocardial infarction or stroke and treatment-group assignment. Patients in the chlorthalidone group who had no history of myocardial infarction or stroke had a modestly higher risk of a primary-outcome event than patients in the hydrochlorothiazide group, but patients who had a history of myocardial infarction or stroke and were assigned to receive chlorthalidone had a lower risk of a primary outcome event than patients with this history in the hydrochlorothiazide group. Because the trial did not show a difference in the risk of the primary outcome between treatment groups overall, this difference is probably a chance finding and should not be overinterpreted.

Q: Describe a limitation of the trial by Ishani et al.

A: The dose levels of the two diuretics are an important limitation of this pragmatic trial. Previous trials that showed the benefits of these medications on cardiovascular outcomes used higher target doses (≥50 mg of hydrochlorothiazide or ≥25 mg of chlorthalidone). However, most patients currently treated with hydrochlorothiazide, including the VA population, receive 12.5 to 25 mg, and only 5% of the patients in this trial had been receiving 50 mg of hydrochlorothiazide at baseline. Therefore, the primary comparison in this trial was between 25 mg of hydrochlorothiazide and 12.5 mg of chlorthalidone. These results should not be extrapolated to other doses of these medications.

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