Diuretic Comparison Project (DCP)

CSP #597 - Diuretic Comparison Project

The purpose of this study is to determine whether chlorthalidone is more effective than hydrochlorothiazide at preventing cardiovascular outcomes in Veterans over age 65 with hypertension. Both medications are thiazide-type diuretics that have been used for more than 50 years and are considered first-line treatment for hypertension. Patients currently prescribed hydrochlorothiazide will be randomized to either continue taking hydrochlorothiazide or to receive chlorthalidone, and followed for major cardiovascular events, such as myocardial infarction (MI) and stroke. The study will use a new, efficient and less expensive study design termed 'point of care', in which study operations will be conducted centrally and patient data will be collected passively through the electronic medical record.

Study Overview

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

Detailed Description

Over 1 million Veterans are prescribed a thiazide-type diuretic each year; over 95% receive hydrochlorothiazide, and fewer than 2.5% receive chlorthalidone. Both medications are thiazide-type diuretics that have been used for more than 50 years and are considered first-line treatment for hypertension. Indirect evidence has been accumulating, however, that chlorthalidone may be more effective than hydrochlorothiazide at preventing cardiovascular events. This will be the first randomized head-to-head comparison of the effectiveness of these two drugs. The study plans to enroll 13,500 Veterans over 3 years and follow them on average for 3 years, resulting in a total study duration of 4.5 years. Patients currently prescribed hydrochlorothiazide will be randomized to either continue taking hydrochlorothiazide or to receive an equivalent dose of chlorthalidone. The unique 'point of care' or 'clinically integrated' study design will identify, enroll and follow subjects using the electronic medical record system and national VA and non-VA databases. The primary outcome is an event composite consisting of: stroke, myocardial infarction, non-cancer death, urgent revascularization, and hospitalization for acute congestive heart failure. All patient care, including the study drug, will continue to be managed by the primary care provider.

Primary Care Providers will also be included as participants in this research study. Adding providers as subjects will allow us to study the implementation of the point of care protocol design in addition to the original research question. The study team will collect data on diuretic management within the study and may contact providers by phone or email to learn reasons for declining a particular patient or discontinuing a new chlorthalidone order or an ongoing diuretic prescription.

If cardiovascular events are reduced by even a small amount by chlorthalidone, the public health effect will be considerable because of the large number of patients who take diuretics. A randomized trial, now feasible due to the investigators' efficient and inexpensive design, will provide evidence needed to better inform practice throughout the VA.

• Study Type: Interventional
• Enrollment (Actual): 13523
• 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
    • Fort Meade, 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:

Veterans who:

• Are over age 65 years
• Are receiving hydrochlorothiazide from the VA pharmacy at a daily dose of 25 or 50 mg
• Have a most recent systolic blood pressure (SBP) in CPRS greater than or equal to 120 mm Hg, with no SBP less than 120 mm Hg recorded in CPRS in the previous 90 days

Primary Care Providers will also be included as participants in this research study.

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 EMR 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)
• K<3.1 meq/L (or K<3.5 meq/L if on digoxin) in the past 90 days
• Na<130 meq/L in the past 90 days
• Known to be enrolled in Medicare Part C (assessed on consent phone call). This exclusion will only be employed if the investigators determine that sufficient information from Part C data cannot obtained.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydrochlorothiazide; Hydrochlorothiazide daily dose of 50 mg or 25 mg for duration of study	Drug: Hydrochlorothiazide (HCTZ); Thiazide-type diuretic. Daily dose of 50 or 25 mg for duration of the study.; Other Names: HCTZ
Active Comparator: Chlorthalidone; Chlorthalidone daily dose of 25 mg or 12.5 mg for duration of study	Drug: Chlorthalidone; Thiazide-type diuretic. Daily dose of 25 or 12.5 mg for duration of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to major cardiovascular event	The Primary outcome measure will be time to a major cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, hospitalization for acute congestive heart failure, non-cancer death.	Randomization to time to event; average follow-up 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to event for each component of the composite primary outcome and additional cardiovascular events	The Secondary outcomes will include time to event for (1) each of the 5 components of the composite primary outcome, (2) all deaths, (3) the composite outcome substituting all deaths for non-cancer deaths, (4) "possibly vascular deaths," (5) the composite outcome substituting "possibly vascular deaths" for non-cancer deaths, (6) any revascularization of any artery.	Randomization to time to event; average follow-up 3 years
All Deaths	All Deaths	Randomization to time to event; average follow-up 3 years
The primary composite outcome substituting 'all deaths' for 'non-cancer deaths'	This secondary outcome measure will be time to a major cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, hospitalization for acute congestive heart failure, all deaths.	Randomization to time to event; average follow-up 3 years
Possibly Vascular Deaths	Defined as all deaths caused by vascular diseases, diabetes, external causes, and unknown causes.	Randomization to time to event; average follow-up 3 years
The primary composite outcome substituting 'possibly vascular deaths' for 'non-cancer deaths'	This secondary outcome measure will be time to a major cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, hospitalization for acute congestive heart failure, possibly vascular deaths. 'Possibly vascular deaths' are defined as all deaths caused by vascular diseases, diabetes, external causes, and unknown causes.	Randomization to time to event; average follow-up 3 years
Any revascularization of any artery	Any revascularization of any artery	Randomization to time to event; average follow-up 3 years
Erectile dysfunction (ED)	Defined as first prescription for phosphodiesterase Type 5 (PDE5) inhibitor or referral for ED	Randomization to time to event; average follow-up 3 years

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.

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): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 26, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Hypertension; Diuretic; Comparative Effectiveness Research; 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