Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events

Areef Ishani, William C. Cushman, Sarah M. Leatherman, Robert A. Lew, Patricia Woods, Peter A. Glassman, Addison A. Taylor, Cynthia Hau, Alison Klint, Grant D. Huang, Mary T. Brophy, Louis D. Fiore, Ryan E. Ferguson

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Background Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. Methods In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. Results 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). Conclusions In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; number, NCT02185417.)

Original languageEnglish (US)
Pages (from-to)2401-2410
Number of pages10
JournalNew England Journal of Medicine
Issue number26
StatePublished - Dec 29 2022

Bibliographical note

Funding Information:
The Supported by the Veterans Affairs Cooperative Studies Program through a grant to the Diuretic Comparison Project.

Publisher Copyright:
© 2022 Massachusetts Medical Society.


  • Cardiology
  • Cardiology General
  • Clinical Medicine
  • Clinical Medicine General
  • Geriatrics/Aging
  • Geriatrics/Aging General
  • Hypertension
  • Nephrology
  • Nephrology General
  • Prevention

PubMed: MeSH publication types

  • Comparative Study
  • Journal Article
  • Pragmatic Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.


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