Diuretic Comparison Project

Hypertension Clinical Trial

— DCP  

Official title:

CSP #597 - Diuretic Comparison Project

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02185417
• Other study ID #: 597
• Status: Completed
• Phase: Phase 3
• Start date: June 15, 2016
• Est. completion date: December 29, 2022

Study information

• Verified date: May 2024
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20723
• Est. completion date: December 29, 2022
• Est. primary completion date: October 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Hypertension

Intervention

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.
• 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.

Locations

Country	Name	City	State
Puerto Rico	VA Caribbean Healthcare System, San Juan, PR	San Juan
United States	Albany VA Medical Center Samuel S. Stratton, Albany, NY	Albany	New York
United States	New Mexico VA Health Care System, Albuquerque, NM	Albuquerque	New Mexico
United States	Alaska VA Healthcare System, Anchorage, AK	Anchorage	Alaska
United States	Rocky Mountain Regional VA Medical Center, Aurora, CO	Aurora	Colorado
United States	Rehabilitation R&D Service, Baltimore, MD	Baltimore	Maryland
United States	Bay Pines VA Healthcare System, Pay Pines, FL	Bay Pines	Florida
United States	Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA	Bedford	Massachusetts
United States	VA Gulf Coast Veterans Health Care System, Biloxi, MS	Biloxi	Mississippi
United States	Birmingham VA Medical Center, Birmingham, AL	Birmingham	Alabama
United States	Boise VA Medical Center, Boise, ID	Boise	Idaho
United States	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts
United States	Ralph H. Johnson VA Medical Center, Charleston, SC	Charleston	South Carolina
United States	Cincinnati VA Medical Center, Cincinnati, OH	Cincinnati	Ohio
United States	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio
United States	Coatesville VA Medical Center, Coatesville, PA	Coatesville	Pennsylvania
United States	Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC	Columbia	South Carolina
United States	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas
United States	VA Illiana Health Care System, Danville, IL	Danville	Illinois
United States	Dayton VA Medical Center, Dayton, OH	Dayton	Ohio
United States	VA Central Iowa Health Care System, Des Moines, IA	Des Moines	Iowa
United States	Durham VA Medical Center, Durham, NC	Durham	North Carolina
United States	Fargo VA Healthcare System, Fargo, ND	Fargo	North Dakota
United States	Veterans Health Care System of the Ozarks, Fayetteville, AR	Fayetteville	Arkansas
United States	VA Central California Health Care System, Fresno, CA	Fresno	California
United States	North Florida/South Georgia Veterans Health System, Gainesville, FL	Gainesville	Florida
United States	Grand Junction VA Medical Center, Grand Junction, CO	Grand Junction	Colorado
United States	Hampton VA Medical Center, Hampton, VA	Hampton	Virginia
United States	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois
United States	VA Pacific Islands Health Care System, Honolulu, HI	Honolulu	Hawaii
United States	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas
United States	Huntington VA Medical Center, Huntington, WV	Huntington	West Virginia
United States	Richard L. Roudebush VA Medical Center, Indianapolis, IN	Indianapolis	Indiana
United States	Iowa City VA Health Care System, Iowa City, IA	Iowa City	Iowa
United States	Kansas City VA Medical Center, Kansas City, MO	Kansas City	Missouri
United States	Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR	Little Rock	Arkansas
United States	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California
United States	William S. Middleton Memorial Veterans Hospital, Madison, WI	Madison	Wisconsin
United States	Manchester VA Medical Center, Manchester, NH	Manchester	New Hampshire
United States	Memphis VA Medical Center, Memphis, TN	Memphis	Tennessee
United States	Memphis VA Medical Center, Memphis, TN	Memphis	Tennessee
United States	Clement J. Zablocki VA Medical Center, Milwaukee, WI	Milwaukee	Wisconsin
United States	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota
United States	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota
United States	Jackson C. Montgomery VA Medical Center, Muskogee, OK	Muskogee	Oklahoma
United States	Tennessee Valley Healthcare System Nashville Campus, Nashville, TN	Nashville	Tennessee
United States	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York
United States	Captain James A. Lovell Federal Health Care Center, North Chicago, IL	North Chicago	Illinois
United States	Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE	Omaha	Nebraska
United States	VA Palo Alto Health Care System, Palo Alto, CA	Palo Alto	California
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	VA Portland Health Care System, Portland, OR	Portland	Oregon
United States	VA Roseburg Healthcare System, Roseburg, OR	Roseburg	Oregon
United States	Aleda E. Lutz VA Medical Center, Saginaw, MI	Saginaw	Michigan
United States	St. Cloud VA Health Care System, St. Cloud, MN	Saint Cloud	Minnesota
United States	St. Louis VA Medical Center John Cochran Division, St. Louis, MO	Saint Louis	Missouri
United States	South Texas Health Care System, San Antonio, TX	San Antonio	Texas
United States	Sheridan VA Medical Center, Sheridan, WY	Sheridan	Wyoming
United States	VA Black Hills Health Care System Fort Meade Campus, Fort Meade, SD	Sturgis	South Dakota
United States	Syracuse VA Medical Center, Syracuse, NY	Syracuse	New York
United States	Maine VA Medical Center, Augusta, ME	Togus	Maine
United States	Tomah VA Medical Center, Tomah, WI	Tomah	Wisconsin
United States	Washington DC VA Medical Center, Washington, DC	Washington	District of Columbia
United States	VA Connecticut Healthcare System West Haven Campus, West Haven, CT	West Haven	Connecticut
United States	VA Greater Los Angeles Healthcare System, West Los Angeles, CA	West Los Angeles	California
United States	VA Southern Oregon Rehabilitation Center and Clinics, White City, OR	White City	Oregon
United States	White River Junction VA Medical Center, White River Junction, VT	White River Junction	Vermont
United States	Wilkes-Barre VA Medical Center, Wilkes-Barre, PA	Wilkes-Barre	Pennsylvania
United States	Wilmington VA Medical Center, Wilmington, DE	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (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. — View Citation

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 Diureti — View Citation

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 Eve — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).
Primary	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	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).