Clinical trial NCT02185417: Diuretic Comparison Project
Official title: CSP #597 - Diuretic Comparison Project
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension
Keywords: Hypertension
Cardiovascular outcomes
Pragmatic clinical trial
Point of care research
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2014-07-09
Enrollment: 20723
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Time From Randomization to Composite Primary Outcome
timeFrame: 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).
measure: Proportion of Participants Had a Composite Primary Outcome
timeFrame: 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:
measure: Proportion of Participants Had Nonfatal Myocardial Infarction
timeFrame: 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).
measure: Proportion of Participants Had Nonfatal Stroke
timeFrame: 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).
measure: Proportion of Participants Had Hospitalization for Heart Failure
timeFrame: 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).
measure: Proportion of Participants Had Unstable Angina Leading to Urgent Coronary Revascularization
timeFrame: 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).
measure: Proportion of Participants Deceased and Not Related to Cancer
timeFrame: 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).
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham VA Medical Center, Birmingham, AL
state: Alabama
city: Anchorage
country: United States
facility: Alaska VA Healthcare System, Anchorage, AK
state: Alaska
city: Fayetteville
country: United States
facility: Veterans Health Care System of the Ozarks, Fayetteville, AR
state: Arkansas
city: Little Rock
country: United States
facility: Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
state: Arkansas
city: Fresno
country: United States
facility: VA Central California Health Care System, Fresno, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: West Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System, West Los Angeles, CA
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: Grand Junction
country: United States
facility: Grand Junction VA Medical Center, Grand Junction, CO
state: Colorado
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: Wilmington
country: United States
facility: Wilmington VA Medical Center, Wilmington, DE
state: Delaware
city: Washington
country: United States
facility: Washington DC VA Medical Center, Washington, DC
state: District of Columbia
city: Bay Pines
country: United States
facility: Bay Pines VA Healthcare System, Pay Pines, FL
state: Florida
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Honolulu
country: United States
facility: VA Pacific Islands Health Care System, Honolulu, HI
state: Hawaii
city: Boise
country: United States
facility: Boise VA Medical Center, Boise, ID
state: Idaho
city: Danville
country: United States
facility: VA Illiana Health Care System, Danville, IL
state: Illinois
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: North Chicago
country: United States
facility: Captain James A. Lovell Federal Health Care Center, North Chicago, IL
state: Illinois
city: Indianapolis
country: United States
facility: Richard L. Roudebush VA Medical Center, Indianapolis, IN
state: Indiana
city: Des Moines
country: United States
facility: VA Central Iowa Health Care System, Des Moines, IA
state: Iowa
city: Iowa City
country: United States
facility: Iowa City VA Health Care System, Iowa City, IA
state: Iowa
city: Togus
country: United States
facility: Maine VA Medical Center, Augusta, ME
state: Maine
city: Baltimore
country: United States
facility: Rehabilitation R&D Service, Baltimore, MD
state: Maryland
city: Bedford
country: United States
facility: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA
state: Massachusetts
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Saginaw
country: United States
facility: Aleda E. Lutz VA Medical Center, Saginaw, MI
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Saint Cloud
country: United States
facility: St. Cloud VA Health Care System, St. Cloud, MN
state: Minnesota
city: Biloxi
country: United States
facility: VA Gulf Coast Veterans Health Care System, Biloxi, MS
state: Mississippi
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis VA Medical Center John Cochran Division, St. Louis, MO
state: Missouri
city: Omaha
country: United States
facility: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
state: Nebraska
city: Manchester
country: United States
facility: Manchester VA Medical Center, Manchester, NH
state: New Hampshire
city: Albuquerque
country: United States
facility: New Mexico VA Health Care System, Albuquerque, NM
state: New Mexico
city: Albany
country: United States
facility: Albany VA Medical Center Samuel S. Stratton, Albany, NY
state: New York
city: New York
country: United States
facility: Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
state: New York
city: Syracuse
country: United States
facility: Syracuse VA Medical Center, Syracuse, NY
state: New York
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Fargo
country: United States
facility: Fargo VA Healthcare System, Fargo, ND
state: North Dakota
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Dayton
country: United States
facility: Dayton VA Medical Center, Dayton, OH
state: Ohio
city: Muskogee
country: United States
facility: Jackson C. Montgomery VA Medical Center, Muskogee, OK
state: Oklahoma
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Roseburg
country: United States
facility: VA Roseburg Healthcare System, Roseburg, OR
state: Oregon
city: White City
country: United States
facility: VA Southern Oregon Rehabilitation Center and Clinics, White City, OR
state: Oregon
city: Coatesville
country: United States
facility: Coatesville VA Medical Center, Coatesville, PA
state: Pennsylvania
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Wilkes-Barre VA Medical Center, Wilkes-Barre, PA
state: Pennsylvania
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
city: Columbia
country: United States
facility: Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC
state: South Carolina
city: Sturgis
country: United States
facility: VA Black Hills Health Care System Fort Meade Campus, Fort Meade, SD
state: South Dakota
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
city: White River Junction
country: United States
facility: White River Junction VA Medical Center, White River Junction, VT
state: Vermont
city: Hampton
country: United States
facility: Hampton VA Medical Center, Hampton, VA
state: Virginia
city: Huntington
country: United States
facility: Huntington VA Medical Center, Huntington, WV
state: West Virginia
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
city: Milwaukee
country: United States
facility: Clement J. Zablocki VA Medical Center, Milwaukee, WI
state: Wisconsin
city: Tomah
country: United States
facility: Tomah VA Medical Center, Tomah, WI
state: Wisconsin
city: Sheridan
country: United States
facility: Sheridan VA Medical Center, Sheridan, WY
state: Wyoming
city: San Juan
country: Puerto Rico
facility: VA Caribbean Healthcare System, San Juan, PR
Study officials:
affiliation: Minneapolis VA Health Care System, Minneapolis, MN
name: Areef Ishani, MD MS
role: STUDY_CHAIR
affiliation: Memphis VA Medical Center, Memphis, TN
name: William C Cushman, MD
role: STUDY_CHAIR
References:
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.
citation: 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.
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 Events. N Engl J Med. 2022 Dec 29;387(26):2401-2410. doi: 10.1056/NEJMoa2212270. Epub 2022 Dec 14.
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 Diuretic Comparison Project. JAMA Netw Open. 2023 Sep 5;6(9):e2332049. doi: 10.1001/jamanetworkopen.2023.32049.