Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. Methods: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. Results: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. Conclusions: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. Clinical trial registration: NCT02185417 [].

Original languageEnglish (US)
Article number106754
JournalContemporary Clinical Trials
StatePublished - May 2022

Bibliographical note

Funding Information:
CSP 597 The Diuretic Comparison Project is sponsored by the Veterans Affairs Cooperative Studies Program

Publisher Copyright:
© 2022


  • Chlorthalidone
  • Design
  • Diuretics
  • Hydrochlorothiazide
  • Hypertension
  • Pragmatic

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.


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