Diuretic Comparison Project

NCT02185417 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 597
• Study Type: interventional
• Target: 20,723
• Locations: 2 countries
• Sites: 70

Brief Summary

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.

Conditions

Hypertension

Keywords

Hypertension; Cardiovascular outcomes; Pragmatic clinical trial; Point of care research

Outcome Measures

Primary Outcomes (2)

• 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  Outcome data collection was performed from study randomization until the participants deceased, withdrawn, or reached end of study (Up to 5.4 years for the first patient enrolled and an average of 2.4 years for all participants).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 Outcomes (5)

• Proportion of Participants Had Nonfatal Myocardial Infarction

  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

  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

  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

  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

  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).

Study Arms (3)

Hydrochlorothiazide

ACTIVE COMPARATOR

Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg).

Drug: Hydrochlorothiazide (HCTZ)

Chlorthalidone

ACTIVE COMPARATOR

Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg).

Drug: Chlorthalidone (CTD)

Providers

NO INTERVENTION

Providers were enrolled in order to contact their potentially eligible patients and were not included in the results

Interventions

Hydrochlorothiazide (HCTZ) DRUG

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.

Also known as: HCTZ

Hydrochlorothiazide

Chlorthalidone (CTD) DRUG

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.

Also known as: CTD

Chlorthalidone

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (70)

Birmingham VA Medical Center, Birmingham, AL

Birmingham, Alabama, 35233, United States

Location

Alaska VA Healthcare System, Anchorage, AK

Anchorage, Alaska, 99504, United States

Location

Veterans Health Care System of the Ozarks, Fayetteville, AR

Fayetteville, Arkansas, 72703, United States

Location

Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR

Little Rock, Arkansas, 72205-5484, United States

Location

VA Central California Health Care System, Fresno, CA

Fresno, California, 93703, United States

Location

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, 90822, United States

Location

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, 94304-1290, United States

Location

VA Greater Los Angeles Healthcare System, West Los Angeles, CA

West Los Angeles, California, 90073, United States

Location

Rocky Mountain Regional VA Medical Center, Aurora, CO

Aurora, Colorado, 80045, United States

Location

Grand Junction VA Medical Center, Grand Junction, CO

Grand Junction, Colorado, 81501, United States

Location

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, 06516, United States

Location

Wilmington VA Medical Center, Wilmington, DE

Wilmington, Delaware, 19805, United States

Location

Washington DC VA Medical Center, Washington, DC

Washington D.C., District of Columbia, 20422, United States

Location

Bay Pines VA Healthcare System, Pay Pines, FL

Bay Pines, Florida, 33744, United States

Location

North Florida/South Georgia Veterans Health System, Gainesville, FL

Gainesville, Florida, 32608, United States

Location

VA Pacific Islands Health Care System, Honolulu, HI

Honolulu, Hawaii, 96819-1522, United States

Location

Boise VA Medical Center, Boise, ID

Boise, Idaho, 83702, United States

Location

VA Illiana Health Care System, Danville, IL

Danville, Illinois, 61832, United States

Location

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, 60141-5000, United States

Location

Captain James A. Lovell Federal Health Care Center, North Chicago, IL

North Chicago, Illinois, 60064, United States

Location

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Indianapolis, Indiana, 46202-2884, United States

Location

VA Central Iowa Health Care System, Des Moines, IA

Des Moines, Iowa, 50310-5774, United States

Location

Iowa City VA Health Care System, Iowa City, IA

Iowa City, Iowa, 52246-2208, United States

Location

Maine VA Medical Center, Augusta, ME

Togus, Maine, 04330, United States

Location

Rehabilitation R&D Service, Baltimore, MD

Baltimore, Maryland, 21202, United States

Location

Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA

Bedford, Massachusetts, 01730, United States

Location

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, 02130, United States

Location

Aleda E. Lutz VA Medical Center, Saginaw, MI

Saginaw, Michigan, 48602, United States

Location

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, 55417-2309, United States

Location

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, 55417, United States

Location

St. Cloud VA Health Care System, St. Cloud, MN

Saint Cloud, Minnesota, 56303, United States

Location

VA Gulf Coast Veterans Health Care System, Biloxi, MS

Biloxi, Mississippi, 39531, United States

Location

Kansas City VA Medical Center, Kansas City, MO

Kansas City, Missouri, 64128, United States

Location

St. Louis VA Medical Center John Cochran Division, St. Louis, MO

St Louis, Missouri, 63106, United States

Location

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Omaha, Nebraska, 68105-1873, United States

Location

Manchester VA Medical Center, Manchester, NH

Manchester, New Hampshire, 03104, United States

Location

New Mexico VA Health Care System, Albuquerque, NM

Albuquerque, New Mexico, 87108-5153, United States

Location

Albany VA Medical Center Samuel S. Stratton, Albany, NY

Albany, New York, 12208, United States

Location

Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY

New York, New York, 10010, United States

Location

Syracuse VA Medical Center, Syracuse, NY

Syracuse, New York, 13210, United States

Location

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705, United States

Location

Fargo VA Healthcare System, Fargo, ND

Fargo, North Dakota, 58102, United States

Location

Cincinnati VA Medical Center, Cincinnati, OH

Cincinnati, Ohio, 45220, United States

Location

Louis Stokes VA Medical Center, Cleveland, OH

Cleveland, Ohio, 44106, United States

Location

Dayton VA Medical Center, Dayton, OH

Dayton, Ohio, 45428, United States

Location

Jackson C. Montgomery VA Medical Center, Muskogee, OK

Muskogee, Oklahoma, 74401, United States

Location

VA Portland Health Care System, Portland, OR

Portland, Oregon, 97239, United States

Location

VA Roseburg Healthcare System, Roseburg, OR

Roseburg, Oregon, 97471, United States

Location

VA Southern Oregon Rehabilitation Center and Clinics, White City, OR

White City, Oregon, 97503, United States

Location

Coatesville VA Medical Center, Coatesville, PA

Coatesville, Pennsylvania, 19320, United States

Location

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Philadelphia, Pennsylvania, 19104, United States

Location

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Pittsburgh, Pennsylvania, 15240, United States

Location

Wilkes-Barre VA Medical Center, Wilkes-Barre, PA

Wilkes-Barre, Pennsylvania, 18711, United States

Location

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, 29401-5799, United States

Location

Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC

Columbia, South Carolina, 29209, United States

Location

VA Black Hills Health Care System Fort Meade Campus, Fort Meade, SD

Sturgis, South Dakota, 57741, United States

Location

Memphis VA Medical Center, Memphis, TN

Memphis, Tennessee, 38104-2127, United States

Location

Memphis VA Medical Center, Memphis, TN

Memphis, Tennessee, 38104, United States

Location

Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Nashville, Tennessee, 37212-2637, United States

Location

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, 75216, United States

Location

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, 77030, United States

Location

South Texas Health Care System, San Antonio, TX

San Antonio, Texas, 78229, United States

Location

White River Junction VA Medical Center, White River Junction, VT

White River Junction, Vermont, 05009-0001, United States

Location

Hampton VA Medical Center, Hampton, VA

Hampton, Virginia, 23667, United States

Location

Huntington VA Medical Center, Huntington, WV

Huntington, West Virginia, 25704, United States

Location

William S. Middleton Memorial Veterans Hospital, Madison, WI

Madison, Wisconsin, 53705, United States

Location

Clement J. Zablocki VA Medical Center, Milwaukee, WI

Milwaukee, Wisconsin, 53295-1000, United States

Location

Tomah VA Medical Center, Tomah, WI

Tomah, Wisconsin, 54660, United States

Location

Sheridan VA Medical Center, Sheridan, WY

Sheridan, Wyoming, 82801, United States

Location

VA Caribbean Healthcare System, San Juan, PR

San Juan, 00921, Puerto Rico

Location

Related Publications (11)

• 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.

  PMID: 35390512 BACKGROUND

• 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.

  PMID: 36992530 BACKGROUND

• 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.

  PMID: 36516076 RESULT

• 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.

  PMID: 37656456 RESULT

• Anand ST, Hau C, Davenport MJ, Ishani A, Cushman WC, Glassman PA, Taylor AA, Lew RA, Ferguson RE, Leatherman SM. Per-Protocol Analysis of Chlorthalidone Versus Hydrochlorothiazide for Cardiovascular Event Prevention-Diuretic Comparison Project. J Am Heart Assoc. 2026 Jan 30:e046142. doi: 10.1161/JAHA.125.046142. Online ahead of print.

  PMID: 41614323 DERIVED

• 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.

  PMID: 40269774 DERIVED

• 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.

  PMID: 39656458 DERIVED

• 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.

  PMID: 38743423 DERIVED

• 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.

  PMID: 37244366 DERIVED

• 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.

  PMID: 37137378 DERIVED

• 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.

  PMID: 37031794 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Hydrochlorothiazide; Chlorthalidone

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzenesulfonamides; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Benzophenones; Phthalimides; Imides; Ketones; Isoindoles

Limitations and Caveats

This trial had several important limitations: * most patients treated with hydrochlorothiazide, including the VA population, received 12.5 to 25 mg, and only 5% in this trial had been receiving 50 mg of hydrochlorothiazide at baseline. * only a subset of follow-up data from Medicare and NDI were available at the time of reporting.

Results Point of Contact

• Title: Dr. Sarah Leatherman
• Organization: Boston VAHCS

sarah.leatherman@va.gov

857-364-4201

Study Officials

• Areef Ishani, MD MS

  Minneapolis VA Health Care System, Minneapolis, MN

  STUDY CHAIR

• William C Cushman, MD

  Memphis VA Medical Center, Memphis, TN

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 30, 2014
• First Posted: July 9, 2014
• Study Start: June 15, 2016
• Primary Completion: October 15, 2022
• Study Completion: December 29, 2022
• Last Updated: May 22, 2024
• Results First Posted: May 22, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (69); PR (1)