Diuretic Comparison Project (DCP)

CSP #597 - 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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Hydrochlorothiazide (HCTZ); Drug: Chlorthalidone (CTD)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20723
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00921
    • VA Caribbean Healthcare System, San Juan, PR
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Birmingham VA Medical Center, Birmingham, AL
  • Alaska
    • Anchorage, Alaska, United States, 99504
      • Alaska VA Healthcare System, Anchorage, AK
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Veterans Health Care System of the Ozarks, Fayetteville, AR
    • Little Rock, Arkansas, United States, 72205-5484
      • Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
  • California
    • Fresno, California, United States, 93703
      • VA Central California Health Care System, Fresno, CA
    • Long Beach, California, United States, 90822
      • VA Long Beach Healthcare System, Long Beach, CA
    • Palo Alto, California, United States, 94304-1290
      • VA Palo Alto Health Care System, Palo Alto, CA
    • West Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System, West Los Angeles, CA
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Rocky Mountain Regional VA Medical Center, Aurora, CO
    • Grand Junction, Colorado, United States, 81501
      • Grand Junction VA Medical Center, Grand Junction, CO
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System West Haven Campus, West Haven, CT
  • Delaware
    • Wilmington, Delaware, United States, 19805
      • Wilmington VA Medical Center, Wilmington, DE
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington DC VA Medical Center, Washington, DC
  • Florida
    • Bay Pines, Florida, United States, 33744
      • Bay Pines VA Healthcare System, Pay Pines, FL
    • Gainesville, Florida, United States, 32608
      • North Florida/South Georgia Veterans Health System, Gainesville, FL
  • Hawaii
    • Honolulu, Hawaii, United States, 96819-1522
      • VA Pacific Islands Health Care System, Honolulu, HI
  • Idaho
    • Boise, Idaho, United States, 83702
      • Boise VA Medical Center, Boise, ID
  • Illinois
    • Danville, Illinois, United States, 61832
      • VA Illiana Health Care System, Danville, IL
    • Hines, Illinois, United States, 60141-5000
      • Edward Hines Jr. VA Hospital, Hines, IL
    • North Chicago, Illinois, United States, 60064
      • Captain James A. Lovell Federal Health Care Center, North Chicago, IL
  • Indiana
    • Indianapolis, Indiana, United States, 46202-2884
      • Richard L. Roudebush VA Medical Center, Indianapolis, IN
  • Iowa
    • Des Moines, Iowa, United States, 50310-5774
      • VA Central Iowa Health Care System, Des Moines, IA
    • Iowa City, Iowa, United States, 52246-2208
      • Iowa City VA Health Care System, Iowa City, IA
  • Maine
    • Togus, Maine, United States, 04330
      • Maine VA Medical Center, Augusta, ME
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Rehabilitation R&D Service, Baltimore, MD
  • Massachusetts
    • Bedford, Massachusetts, United States, 01730
      • Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA
    • Boston, Massachusetts, United States, 02130
      • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
  • Michigan
    • Saginaw, Michigan, United States, 48602
      • Aleda E. Lutz VA Medical Center, Saginaw, MI
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Minneapolis VA Health Care System, Minneapolis, MN
    • Minneapolis, Minnesota, United States, 55417-2309
      • Minneapolis VA Health Care System, Minneapolis, MN
    • Saint Cloud, Minnesota, United States, 56303
      • St. Cloud VA Health Care System, St. Cloud, MN
  • Mississippi
    • Biloxi, Mississippi, United States, 39531
      • VA Gulf Coast Veterans Health Care System, Biloxi, MS
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • Kansas City VA Medical Center, Kansas City, MO
    • Saint Louis, Missouri, United States, 63106
      • St. Louis VA Medical Center John Cochran Division, St. Louis, MO
  • Nebraska
    • Omaha, Nebraska, United States, 68105-1873
      • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
  • New Hampshire
    • Manchester, New Hampshire, United States, 03104
      • Manchester VA Medical Center, Manchester, NH
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108-5153
      • New Mexico VA Health Care System, Albuquerque, NM
  • New York
    • Albany, New York, United States, 12208
      • Albany VA Medical Center Samuel S. Stratton, Albany, NY
    • New York, New York, United States, 10010
      • Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
    • Syracuse, New York, United States, 13210
      • Syracuse VA Medical Center, Syracuse, NY
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center, Durham, NC
  • North Dakota
    • Fargo, North Dakota, United States, 58102
      • Fargo VA Healthcare System, Fargo, ND
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • Cincinnati VA Medical Center, Cincinnati, OH
    • Cleveland, Ohio, United States, 44106
      • Louis Stokes VA Medical Center, Cleveland, OH
    • Dayton, Ohio, United States, 45428
      • Dayton VA Medical Center, Dayton, OH
  • Oklahoma
    • Muskogee, Oklahoma, United States, 74401
      • Jackson C. Montgomery VA Medical Center, Muskogee, OK
  • Oregon
    • Portland, Oregon, United States, 97239
      • VA Portland Health Care System, Portland, OR
    • Roseburg, Oregon, United States, 97471
      • VA Roseburg Healthcare System, Roseburg, OR
    • White City, Oregon, United States, 97503
      • VA Southern Oregon Rehabilitation Center and Clinics, White City, OR
  • Pennsylvania
    • Coatesville, Pennsylvania, United States, 19320
      • Coatesville VA Medical Center, Coatesville, PA
    • Philadelphia, Pennsylvania, United States, 19104
      • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Wilkes-Barre VA Medical Center, Wilkes-Barre, PA
  • South Carolina
    • Charleston, South Carolina, United States, 29401-5799
      • Ralph H. Johnson VA Medical Center, Charleston, SC
    • Columbia, South Carolina, United States, 29209
      • Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
  • South Dakota
    • Sturgis, South Dakota, United States, 57741
      • VA Black Hills Health Care System Fort Meade Campus, Fort Meade, SD
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • Memphis VA Medical Center, Memphis, TN
    • Memphis, Tennessee, United States, 38104-2127
      • Memphis VA Medical Center, Memphis, TN
    • Nashville, Tennessee, United States, 37212-2637
      • Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
  • Texas
    • Dallas, Texas, United States, 75216
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center, Houston, TX
    • San Antonio, Texas, United States, 78229
      • South Texas Health Care System, San Antonio, TX
  • Vermont
    • White River Junction, Vermont, United States, 05009-0001
      • White River Junction VA Medical Center, White River Junction, VT
  • Virginia
    • Hampton, Virginia, United States, 23667
      • Hampton VA Medical Center, Hampton, VA
  • West Virginia
    • Huntington, West Virginia, United States, 25704
      • Huntington VA Medical Center, Huntington, WV
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • William S. Middleton Memorial Veterans Hospital, Madison, WI
    • Milwaukee, Wisconsin, United States, 53295-1000
      • Clement J. Zablocki VA Medical Center, Milwaukee, WI
    • Tomah, Wisconsin, United States, 54660
      • Tomah VA Medical Center, Tomah, WI
  • Wyoming
    • Sheridan, Wyoming, United States, 82801
      • Sheridan VA Medical Center, Sheridan, WY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydrochlorothiazide; Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg).	Drug: Hydrochlorothiazide (HCTZ); Trial activities following study randomization were considered as usual care. Prescriptions of the allocated drug were managed by the primary care providers and patients would receive the prescribed mediations through the VA outpatient pharmacy services.; Other Names: HCTZ
Active Comparator: Chlorthalidone; Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg).	Drug: Chlorthalidone (CTD); Trial activities following study randomization were considered as usual care. Prescriptions of the allocated drug were managed by the primary care providers and patients would receive the prescribed mediations through the VA outpatient pharmacy services.; Other Names: CTD
No Intervention: Providers; Providers were enrolled in order to contact their potentially eligible patients and were not included in the results

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From Randomization to Composite Primary Outcome	Time to study primary outcome was defined as years from randomization to the first occurrence of a composite endpoint, 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. For participants who had a primary outcome, time to event was determined as the earliest admission or death date. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).
Proportion of Participants Had a Composite Primary Outcome	The primary outcome was the first occurrence of a composite endpoint 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. Time to the first event was computed based on the earliest hospital admission or death dates. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Had Nonfatal Myocardial Infarction	Secondary outcomes were the individual components of the primary outcome. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).
Proportion of Participants Had Nonfatal Stroke	Secondary outcomes were the individual components of the primary outcome. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).
Proportion of Participants Had Hospitalization for Heart Failure	Secondary outcomes were the individual components of the primary outcome. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).
Proportion of Participants Had Unstable Angina Leading to Urgent Coronary Revascularization	Secondary outcomes were the individual components of the primary outcome. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Collection of outcome data were performed from randomization until participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).
Proportion of Participants Deceased and Not Related to Cancer	Secondary outcomes were the individual components of the primary outcome. Ascertainment of study outcomes was made with the use of administrative and clinical data obtained from VA EHRs through June 1, 2022, from records of Medicare claims obtained from the Centers for Medicare and Medicaid Services through 2021, and from National Death Index records through 2019. Trial outcomes were ascertained with the use of validated EHR phenotypes and, when needed, manual adjudication. Manually adjudicated outcomes were evaluated by investigators and staff who were unaware of group assignment.	Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Study Chair: Areef Ishani, MD MS, Minneapolis VA Health Care System, Minneapolis, MN; Study Chair: William C Cushman, MD, Memphis VA Medical Center, Memphis, TN

Publications and helpful links

General Publications

• Ishani A, Leatherman SM, Woods P, Hau C, Klint A, Lew RA, Taylor AA, Glassman PA, Brophy MT, Fiore LD, Ferguson RE, Cushman WC. Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project. Contemp Clin Trials. 2022 May;116:106754. doi: 10.1016/j.cct.2022.106754. Epub 2022 Apr 4.
• Ishani A, Cushman WC, Leatherman SM, Lew RA, Woods P, Glassman PA, Taylor AA, Hau C, Klint A, Huang GD, Brophy MT, Fiore LD, Ferguson RE; Diuretic Comparison Project Writing Group. Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events. N Engl J Med. 2022 Dec 29;387(26):2401-2410. doi: 10.1056/NEJMoa2212270. Epub 2022 Dec 14.
• Ferguson RE, Leatherman SM, Woods P, Hau C, Lew R, Cushman WC, Brophy MT, Fiore L, Ishani A. Practical issues in pragmatic trials: the implementation of the Diuretic Comparison Project. Clin Trials. 2023 Jun;20(3):276-283. doi: 10.1177/17407745231160553. Epub 2023 Mar 29.
• Hau C, Efird JT, Leatherman SM, Soloviev OV, Glassman PA, Woods PA, Ishani A, Cushman WC, Ferguson RE. A Centralized EHR-Based Model for the Recruitment of Rural and Lower Socioeconomic Participants in Pragmatic Trials: A Secondary Analysis of the Diuretic Comparison Project. JAMA Netw Open. 2023 Sep 5;6(9):e2332049. doi: 10.1001/jamanetworkopen.2023.32049.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2016
• Primary Completion (Actual): October 15, 2022
• Study Completion (Actual): December 29, 2022

Study Registration Dates

• First Submitted: June 30, 2014
• First Submitted That Met QC Criteria: July 3, 2014
• First Posted (Estimated): July 9, 2014

Study Record Updates

• Last Update Posted (Actual): May 22, 2024
• Last Update Submitted That Met QC Criteria: May 21, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Hypertension; Pragmatic clinical trial; Cardiovascular outcomes; Point of care research
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide; Chlorthalidone
• Other Study ID Numbers: 597

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no IPD sharing plan description

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No