Diuretic Comparison Project

The Diuretic Comparison Project aimed to evaluate whether chlorthalidone, as compared with hydrochlorothiazide, would reduce the risk of major nonfatal cardiovascular disease outcomes and non-cancer-related deaths in older patients with hypertension who were receiving hydrochlorothiazide at baseline. The investigators incorporated the pragmatic methods used by the Department of Veterans Affairs (VA) Healthcare System to provide a real-world assessment of the effectiveness of chlorthalidone as compared with hydrochlorothiazide in routine clinical care.

Thiazide-type diuretics have been in use for more than 50 years and are considered as the first-line treatment for hypertension. Of the more than 1 million Veterans prescribed a thiazide-type diuretic each year, more than 95% receive hydrochlorothiazide, and fewer than 2.5% receive chlorthalidone. However, indirect evidence has been accumulating for many years that chlorthalidone may be more effective than hydrochlorothiazide at preventing cardiovascular events.

The Diuretic Comparison Project was conducted with a clinically integrated design (termed a "point of care" or "pragmatic embedded" trial). The key feature of our design was that, instead of employing local investigators, the investigators developed centralized trial procedures and implemented into the VA electronic health record (EHR) and healthcare delivery systems. This approach enabled us to conduct trial-related interactions and randomization with the use of data in the EHRs, centralize recruitment efforts without the use of site staff, eliminate the need for trial-related visits and procedures, and centralize data capture from administrative databases.

This study was performed to answer a question of whether chlorthalidone is more effective than hydrochlorothiazide at preventing cardiovascular outcomes. Consent was obtained from eligible participants who were willing to participate and their primary care providers. With provider assented to the patient undergoing randomization, 3,523 older patients with hypertension were randomized across 72 VA health care systems. Patients across the US (including Puerto Rico and District of Columbia) were enrolled. Participants were randomly assigned to continue with existing hydrochlorothiazide treatment regimen (25/50mg daily) or switch to a dose equivalent chlorthalidone (12.5/25 mg daily).

The primary outcome was the first occurrence of a composite outcome consisting of a nonfatal cardiovascular event or non-cancer related death. Nonfatal cardiovascular events included nonfatal myocardial infarction, stroke, hospitalization for heart failure, or urgent coronary revascularization for unstable angina.

Eligibility Criteria:
Inclusion criteria

* over age 65 years
* receiving hydrochlorothiazide from the VA pharmacy at a daily dose of 25 or 50 mg
* most recent SBP ≥120 mm Hg and no records of SBP \<120 mm Hg in the past 90 days

Exclusion criteria:

* impaired decision-making capacity rendering the patient unable to provide informed consent (i.e., if there is any question during the nurse's EHR chart review that the individual does not have the ability to make an autonomous decision or the PCP declines permission to randomize)
* death expected within 6 months (inferred by PCP permission to randomize)
* blood potassium level \<3.1 or 3.5 (if taking digoxin) meq/L in the past 90 days
* blood sodium level \<130 meq/L in the past 90 days
* enrolled in Medicare Part C (This exclusion only applied if there might be insufficient EHR data available to the study team)