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Cardiovascular Events With Chlorthalidone vs. Hydrochlorothiazide

Older adults taking chlorthalidone for hypertension did not have a lower occurrence of major cardiovascular events or non–cancer-related deaths than those on hydrochlorothiazide in the pragmatic, open-label Diuretic Comparison Project (DCP), researchers report. The DCP sought to evaluate the relative risks and benefits of the drugs given the discrepancy between guidelines (chlorthalidone is recommended for first-line treatment) and use in the real world (in 2020, hydrochlorothiazide was prescribed for hypertension in 11.5 million Medicare Part D beneficiaries, while chlorthalidone was prescribed for only 1.5 million beneficiaries).

Adults aged 65 years or older in the Veterans Affairs health system and taking hydrochlorothiazide 25 mg or 50 mg for blood pressure control were randomized to continue on that drug or change to chlorthalidone 12.5 mg or 25 mg. Based on a primary outcome of a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non–cancer-related death, the investigators found: “A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P <0.001).”

Editorial: “All told, will this trial change clinical care?” asks an editorialist. “Uniquely, the DCP is the first head-to-head comparison of hydrochlorothiazide and chlorthalidone in a randomized, prospective outcome trial. Without an apparent difference in the hazard ratios for the primary outcome in the two groups over the median follow-up of 2.4 years, results suggest that chlorthalidone therapy remains a good choice for hypertension despite the secondary observation that hypokalemia was more common with chlorthalidone than with hydrochlorothiazide. Although a subgroup analysis suggested that chlorthalidone was better than hydrochlorothiazide for participants with a history of myocardial infarction or stroke, that result may have been by chance. Currently, clinicians generally prefer using hydrochlorothiazide in their patients; these DCP results suggest similar benefits for the primary outcome with both agents but without any likely impetus for change. Furthermore, combined therapy and polypills may alter therapy beyond the results of this well-done, highly anticipated trial. Thus, its major effect may be as a model for other pragmatic study programs, which are greatly needed.”

Source: New England Journal of Medicine