Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
20723 participants
INTERVENTIONAL
2016-06-15
2022-12-29
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Hydrochlorothiazide
Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg).
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.
Chlorthalidone
Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg).
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.
Providers
Providers were enrolled in order to contact their potentially eligible patients and were not included in the results
No interventions assigned to this group
Interventions
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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.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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)
65 Years
ALL
No
Sponsors
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VA Office of Research and Development
FED
Responsible Party
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Principal Investigators
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Areef Ishani, MD MS
Role: STUDY_CHAIR
Minneapolis VA Health Care System, Minneapolis, MN
William C Cushman, MD
Role: STUDY_CHAIR
Memphis VA Medical Center, Memphis, TN
Locations
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Birmingham VA Medical Center, Birmingham, AL
Birmingham, Alabama, United States
Alaska VA Healthcare System, Anchorage, AK
Anchorage, Alaska, United States
Veterans Health Care System of the Ozarks, Fayetteville, AR
Fayetteville, Arkansas, United States
Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
Little Rock, Arkansas, United States
VA Central California Health Care System, Fresno, CA
Fresno, California, United States
VA Long Beach Healthcare System, Long Beach, CA
Long Beach, California, United States
VA Palo Alto Health Care System, Palo Alto, CA
Palo Alto, California, United States
VA Greater Los Angeles Healthcare System, West Los Angeles, CA
West Los Angeles, California, United States
Rocky Mountain Regional VA Medical Center, Aurora, CO
Aurora, Colorado, United States
Grand Junction VA Medical Center, Grand Junction, CO
Grand Junction, Colorado, United States
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, United States
Wilmington VA Medical Center, Wilmington, DE
Wilmington, Delaware, United States
Washington DC VA Medical Center, Washington, DC
Washington D.C., District of Columbia, United States
Bay Pines VA Healthcare System, Pay Pines, FL
Bay Pines, Florida, United States
North Florida/South Georgia Veterans Health System, Gainesville, FL
Gainesville, Florida, United States
VA Pacific Islands Health Care System, Honolulu, HI
Honolulu, Hawaii, United States
Boise VA Medical Center, Boise, ID
Boise, Idaho, United States
VA Illiana Health Care System, Danville, IL
Danville, Illinois, United States
Edward Hines Jr. VA Hospital, Hines, IL
Hines, Illinois, United States
Captain James A. Lovell Federal Health Care Center, North Chicago, IL
North Chicago, Illinois, United States
Richard L. Roudebush VA Medical Center, Indianapolis, IN
Indianapolis, Indiana, United States
VA Central Iowa Health Care System, Des Moines, IA
Des Moines, Iowa, United States
Iowa City VA Health Care System, Iowa City, IA
Iowa City, Iowa, United States
Maine VA Medical Center, Augusta, ME
Togus, Maine, United States
Rehabilitation R&D Service, Baltimore, MD
Baltimore, Maryland, United States
Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA
Bedford, Massachusetts, United States
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Boston, Massachusetts, United States
Aleda E. Lutz VA Medical Center, Saginaw, MI
Saginaw, Michigan, United States
Minneapolis VA Health Care System, Minneapolis, MN
Minneapolis, Minnesota, United States
Minneapolis VA Health Care System, Minneapolis, MN
Minneapolis, Minnesota, United States
St. Cloud VA Health Care System, St. Cloud, MN
Saint Cloud, Minnesota, United States
VA Gulf Coast Veterans Health Care System, Biloxi, MS
Biloxi, Mississippi, United States
Kansas City VA Medical Center, Kansas City, MO
Kansas City, Missouri, United States
St. Louis VA Medical Center John Cochran Division, St. Louis, MO
St Louis, Missouri, United States
Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
Omaha, Nebraska, United States
Manchester VA Medical Center, Manchester, NH
Manchester, New Hampshire, United States
New Mexico VA Health Care System, Albuquerque, NM
Albuquerque, New Mexico, United States
Albany VA Medical Center Samuel S. Stratton, Albany, NY
Albany, New York, United States
Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
New York, New York, United States
Syracuse VA Medical Center, Syracuse, NY
Syracuse, New York, United States
Durham VA Medical Center, Durham, NC
Durham, North Carolina, United States
Fargo VA Healthcare System, Fargo, ND
Fargo, North Dakota, United States
Cincinnati VA Medical Center, Cincinnati, OH
Cincinnati, Ohio, United States
Louis Stokes VA Medical Center, Cleveland, OH
Cleveland, Ohio, United States
Dayton VA Medical Center, Dayton, OH
Dayton, Ohio, United States
Jackson C. Montgomery VA Medical Center, Muskogee, OK
Muskogee, Oklahoma, United States
VA Portland Health Care System, Portland, OR
Portland, Oregon, United States
VA Roseburg Healthcare System, Roseburg, OR
Roseburg, Oregon, United States
VA Southern Oregon Rehabilitation Center and Clinics, White City, OR
White City, Oregon, United States
Coatesville VA Medical Center, Coatesville, PA
Coatesville, Pennsylvania, United States
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Philadelphia, Pennsylvania, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Pittsburgh, Pennsylvania, United States
Wilkes-Barre VA Medical Center, Wilkes-Barre, PA
Wilkes-Barre, Pennsylvania, United States
Ralph H. Johnson VA Medical Center, Charleston, SC
Charleston, South Carolina, United States
Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
Columbia, South Carolina, United States
VA Black Hills Health Care System Fort Meade Campus, Fort Meade, SD
Sturgis, South Dakota, United States
Memphis VA Medical Center, Memphis, TN
Memphis, Tennessee, United States
Memphis VA Medical Center, Memphis, TN
Memphis, Tennessee, United States
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
Nashville, Tennessee, United States
VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
Dallas, Texas, United States
Michael E. DeBakey VA Medical Center, Houston, TX
Houston, Texas, United States
South Texas Health Care System, San Antonio, TX
San Antonio, Texas, United States
White River Junction VA Medical Center, White River Junction, VT
White River Junction, Vermont, United States
Hampton VA Medical Center, Hampton, VA
Hampton, Virginia, United States
Huntington VA Medical Center, Huntington, WV
Huntington, West Virginia, United States
William S. Middleton Memorial Veterans Hospital, Madison, WI
Madison, Wisconsin, United States
Clement J. Zablocki VA Medical Center, Milwaukee, WI
Milwaukee, Wisconsin, United States
Tomah VA Medical Center, Tomah, WI
Tomah, Wisconsin, United States
Sheridan VA Medical Center, Sheridan, WY
Sheridan, Wyoming, United States
VA Caribbean Healthcare System, San Juan, PR
San Juan, , Puerto Rico
Countries
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References
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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.
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.
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.
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.
Leatherman SM, Beaudette-Zlatanova B, Robben G, Glassman PA, Woods P, Ferguson RE, Cushman WC, Ishani A. Provider experiences with and attitudes about an embedded pragmatic clinical trial. BMC Prim Care. 2025 Apr 23;26(1):121. doi: 10.1186/s12875-025-02799-w.
Ishani A, Hau C, Raju S, Wise JK, Glassman PA, Taylor AA, Ferguson RE, Cushman WC, Leatherman SM. Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024 Dec 2;7(12):e2449576. doi: 10.1001/jamanetworkopen.2024.49576.
Ishani A, Hau C, Cushman WC, Leatherman SM, Lew RA, Glassman PA, Taylor AA, Ferguson RE. Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024 May 1;7(5):e2411081. doi: 10.1001/jamanetworkopen.2024.11081.
Klint AL, Leatherman SM, Taylor O, Glassman PA, Ferguson RE, Cushman WC, Ishani A. Telephone informed consent in a pragmatic point-of-care clinical trial embedded in primary care. Contemp Clin Trials. 2023 Aug;131:107239. doi: 10.1016/j.cct.2023.107239. Epub 2023 May 25.
Raju S, Hau C, Woods P, Flynn M, Sadatis C, McPherson J, Tella A, Ishani A, Ferguson RE, Leatherman SM. Ascertainment of stroke from administrative data to support a pragmatic embedded clinical trial. Contemp Clin Trials. 2023 Jul;130:107214. doi: 10.1016/j.cct.2023.107214. Epub 2023 May 1.
Leatherman SM, Hau C, Klint A, Glassman PA, Taylor AA, Ferguson RE, Cushman WC, Ishani A. The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care. Contemp Clin Trials. 2023 Jun;129:107179. doi: 10.1016/j.cct.2023.107179. Epub 2023 Apr 7.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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597
Identifier Type: -
Identifier Source: org_study_id
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