Clinical Question

Is chlorthalidone or hydrochlorothiazide (HCTZ) associated with a difference in the rate of major adverse cardiovascular events when used to treat hypertension?

Bottom Line

There is no difference in cardiovascular outcomes when HCTZ is compared with chlorthalidone. There is a slightly higher risk of hypokalemia with chlorthalidone. (Level of Evidence = 1b)

Synopsis

There has been mixed evidence that chlorthalidone may do a better job at reducing cardiovascular events than HCTZ. Chlorthalidone has been associated with a higher likelihood of adverse events. The pragmatic trial used the U.S. Department of Veterans Affairs electronic health records to identify eligible patients 65 years and older who were currently taking HCTZ at a dosage of 25 or 50 mg daily. If participation was approved by their primary care physician, patients were randomized to continue taking HCTZ or switch to chlorthalidone. Patients in the HCTZ group continued their usual dose, and those randomized to receive chlorthalidone received a dose at one-half of their usual HCTZ dose (e.g., if they usually took 25 mg of HCTZ, they received 12.5 mg of chlorthalidone). Most patients in the HCTZ group were taking 25 mg. This was an open-label trial, although outcome assessors were masked for some outcomes. At baseline, the mean age of the 13,523 participants was 72 years, 97% were men, 15% were Black, and 44% had comorbid type 2 diabetes mellitus.

After a median of 2.4 years, blood pressure and medication adherence (79%) were similar between groups. The primary outcome was a composite of nonfatal myocardial infarction, stroke, hospitalization for heart failure, urgent revascularization, or noncancer-related death. There was no difference between groups for this primary outcome (10.4% for chlorthalidone and 10.0% for HCTZ) and no difference for any of the individual elements of the composite. When the analysis was stratified by history of myocardial infarction or stroke at baseline, patients with this history had fewer primary outcome events with chlorthalidone (14.3% vs. 19.4%; hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.94; number needed to treat = 20), whereas those without this history had a slightly higher likelihood of the primary outcome with chlorthalidone (9.9% vs. 8.9%; HR = 1.12; 95% CI, 1.0 to 1.26). The authors note that they believe this difference was most likely a chance finding. Chlorthalidone use was associated with a slightly higher risk of hypokalemia (6.0% vs. 4.4%; HR = 1.38; 95% CI, 1.19 to 1.60; number needed to harm = 62), with a potassium level of less than 3.10 mEq per L (3.1 mmol per L; 5.0% vs. 3.6%; HR = 1.39; 95% CI, 1.18 to 1.64; number needed to harm = 71). Although 15.4% of patients in the chlorthalidone group were switched back to HCTZ at some point, this kind of crossover only occurred for 3.8% in the HCTZ group.

Study design: Randomized controlled trial (nonblinded)

Funding source: Government

Allocation: Concealed

Setting: Outpatient (any)

Reference: Ishani A, Cushman WC, Leatherman SM, et al.; Diuretic Comparison Project Writing Group. Chlorthalidone vs. hydrochlorothiazide for hypertension–cardiovascular events. N Engl J Med. 2022;387(26):2401-2410.

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.