Chlorthalidone vs Hydrochlorothiazide for Hypertension-Associated CV Events

There is no difference in risk for CV events in patients with hypertension who receive chlorthalidone or hydrochlorothiazide.

In patients with hypertension who are treated with either chlorthalidone or hydrochlorothiazide at doses commonly used in clinical practice for the prevention of major adverse cardiovascular (CV) events, similar rates of major CV outcomes or noncancer-related deaths have been reported. These findings were published in The New England Journal of Medicine.

Recognizing that whether chlorthalidone is superior to hydrochlorothiazide for the prevention of major CV events remains unclear, investigators from the Diuretic Comparison Project Writing Group sought to provide a real-world assessment that compared treatment with the 2 diuretics. They conducted a pragmatic, comparative-effectiveness trial ( identifier: NCT02185417). The primary study outcome was a composite of nonfatal myocardial infarction (MI), stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and noncancer-related death. Safety was evaluated as well.

Patients (N=13,523) aged 65 years or older who were receiving treatment in the Department of Veterans Affairs health system and had been receiving a daily dose of hydrochlorothiazide 25 mg or 50 mg were randomly assigned either to continue hydrochlorothiazide treatment or to switch to a daily dose of chlorthalidone 12.5 mg or 25 mg.

Overall, 6756 patients were assigned to the chlorthalidone treatment group and 6767 were assigned to the hydrochlorothiazide treatment group. The mean participant age was 72 years. Overall, 97% of the patients were men, 15% were Black, 10.8% had a history of stroke or MI, and 45% resided in rural locations. At baseline, the mean systolic blood pressure was 139 mm Hg. The mean number of medications being received for blood pressure control at baseline was 2.6 and 94.5% of the participants were receiving a hydrochlorothiazide prescription at a daily dose of 25 mg.

We believe that this trial provides several lessons that can be used in the conduct of large pragmatic trials.

At a median follow-up of 2.4 years, little difference was observed in occurrence of the primary outcome events between the chlorthalidone group and the hydrochlorothiazide group (10.4% vs 10.0%, respectively; hazard ratio, 1.04; 95% CI, 0.94-1.16; P =.45). In fact, no between-group differences were reported in the occurrence of any components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group compared with the hydrochlorothiazide group (6.0% vs 4.4%, respectively; P <.001).

Some limitations of the study include it being open-label in design and including individuals who were receiving hydrochlorothiazide at baseline, which created a greater likelihood that the patients assigned to the chlorthalidone arm might switch back to the hydrochlorothiazide arm. The dose levels of the 2 diuretics compared were a key limitation as well, with prior studies having shown that the benefits of these medications require higher doses.

“We believe that this trial provides several lessons that can be used in the conduct of large pragmatic trials,” the study authors wrote. “Large, embedded trials are clinically and operationally feasible. They can be incorporated into the clinical workflow of providers by means of leveraging EHR [electronic health record] systems and other existing clinical and informatics infrastructure.”

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Disclosure forms provided by the authors are available with the full text of this article at

This article originally appeared on The Cardiology Advisor


Ishani A, Cushman WC, Leatherman SM, et al; on behalf of the Diuretic Comparison Project Writing Group. Chlorthalidone vs. hydrochlorothiazide for hypertension-cardiovascular events. N Engl J Med. Published online December 29, 2022. doi:10.1056/NEJMoa2212270