Chlorthalidone no better than hydrochlorothiazide for hypertension

Reference

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

Synopsis

There has been mixed evidence that chlorthalidone may do a better job at reducing cardiovascular events than hydrochlorothiazide (HCTZ); it has also been associated with a higher likelihood of adverse events. This pragmatic trial used the Department of Veterans Affairs' (VA) electronic health records to identify eligible patients, 65 years and older, who were currently taking HCTZ at a dose of 25 mg or 50 mg daily. If participation was approved by their primary care physician, the patients were randomized to either continuing to take HCTZ or switching to chlorthalidone. Patients in the HCTZ group continued at their usual dose, and those randomized to receive chlorthalidone received a dose half as large as their usual HCTZ dose (eg, if they usually took 25 mg HCTZ, they received 12.5 mg chlorthalidone). Almost all patients in the HCTZ group were taking the 25-mg dose. 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 (it was a VA study, after all), 15% were Black, and 44% had comorbid type 2 diabetes. 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 (MI), stroke, hospitalization for heart failure, urgent revascularization, or non-cancer-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 MI or stroke at baseline, patients with that history had fewer primary outcome events with chlorthalidone (14.3% vs 19.4%; hazard ratio [HR] 0.73; 95% CI 0.57 - 0.94; number needed to treat = 20), while those without that history had a slightly higher likelihood of the primary outcome with chlorthalidone (9.9% vs 8.9%; HR 1.12; 1.0 - 1.26). The authors note that they believe this difference was mostly likely a chance finding. Chlorthalidone use was associated with a slightly higher risk of hypokalemia (6.0% vs 4.4%; HR 1.38; 1.19 - 1.60; number needed to treat to harm [NNTH] = 62), including severe hypokalemia of less than 3.1 mmol/L (5.0% vs 3.6%; HR 1.39; 1.18 - 1.64; NNTH = 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.