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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hydrochlorothiazide | Active Comparator | Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg). |
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| Chlorthalidone | Active Comparator | Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg). |
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| Providers | No Intervention | Providers were enrolled in order to contact their potentially eligible patients and were not included in the results |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion criteria
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Birmingham VA Medical Center, Birmingham, AL | Birmingham | Alabama | 35233 | United States | ||
| Alaska VA Healthcare System, Anchorage, AK |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35390512 | Background | 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. | |
| 36992530 |
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After participants provided verbal informed consent, the patient's provider was sent an electronic order to sign if the provider assented to the patient undergoing study randomization. Provider participation involved agreeing to have their patients approached for trial recruitment by study staff, signing the study drug order, and managing their patient per usual care after randomization. Providers were not randomized.
A total of 72 VA health care systems were enlisted in the trial. A total of 6188 primary care providers were approached for participation in the trial and 4128 (69%) consented. Patients managed by the consented provider were electronically screened for study eligibility. Centralized study recruiters telephoned potential participants and obtained oral informed consent if the patient agreed to participate (n=16595). Of these, 13523 patients were randomized (started participant flow).
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| ID | Title | Description |
|---|---|---|
| FG000 | Hydrochlorothiazide | Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg). |
| FG001 | Chlorthalidone | Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg). |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 26, 2022 | Jul 26, 2023 |
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| 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. |
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| 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 | 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). |
| 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). |
| 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). |
| 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). |
| Anchorage |
| Alaska |
| 99504 |
| United States |
| Veterans Health Care System of the Ozarks, Fayetteville, AR | Fayetteville | Arkansas | 72703 | United States |
| Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR | Little Rock | Arkansas | 72205-5484 | United States |
| VA Central California Health Care System, Fresno, CA | Fresno | California | 93703 | United States |
| VA Long Beach Healthcare System, Long Beach, CA | Long Beach | California | 90822 | United States |
| VA Palo Alto Health Care System, Palo Alto, CA | Palo Alto | California | 94304-1290 | United States |
| VA Greater Los Angeles Healthcare System, West Los Angeles, CA | West Los Angeles | California | 90073 | United States |
| Rocky Mountain Regional VA Medical Center, Aurora, CO | Aurora | Colorado | 80045 | United States |
| Grand Junction VA Medical Center, Grand Junction, CO | Grand Junction | Colorado | 81501 | United States |
| VA Connecticut Healthcare System West Haven Campus, West Haven, CT | West Haven | Connecticut | 06516 | United States |
| Wilmington VA Medical Center, Wilmington, DE | Wilmington | Delaware | 19805 | United States |
| Washington DC VA Medical Center, Washington, DC | Washington D.C. | District of Columbia | 20422 | United States |
| Bay Pines VA Healthcare System, Pay Pines, FL | Bay Pines | Florida | 33744 | United States |
| North Florida/South Georgia Veterans Health System, Gainesville, FL | Gainesville | Florida | 32608 | United States |
| VA Pacific Islands Health Care System, Honolulu, HI | Honolulu | Hawaii | 96819-1522 | United States |
| Boise VA Medical Center, Boise, ID | Boise | Idaho | 83702 | United States |
| VA Illiana Health Care System, Danville, IL | Danville | Illinois | 61832 | United States |
| Edward Hines Jr. VA Hospital, Hines, IL | Hines | Illinois | 60141-5000 | United States |
| Captain James A. Lovell Federal Health Care Center, North Chicago, IL | North Chicago | Illinois | 60064 | United States |
| Richard L. Roudebush VA Medical Center, Indianapolis, IN | Indianapolis | Indiana | 46202-2884 | United States |
| VA Central Iowa Health Care System, Des Moines, IA | Des Moines | Iowa | 50310-5774 | United States |
| Iowa City VA Health Care System, Iowa City, IA | Iowa City | Iowa | 52246-2208 | United States |
| Maine VA Medical Center, Augusta, ME | Togus | Maine | 04330 | United States |
| Rehabilitation R&D Service, Baltimore, MD | Baltimore | Maryland | 21202 | United States |
| Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA | Bedford | Massachusetts | 01730 | United States |
| VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA | Boston | Massachusetts | 02130 | United States |
| Aleda E. Lutz VA Medical Center, Saginaw, MI | Saginaw | Michigan | 48602 | United States |
| Minneapolis VA Health Care System, Minneapolis, MN | Minneapolis | Minnesota | 55417-2309 | United States |
| Minneapolis VA Health Care System, Minneapolis, MN | Minneapolis | Minnesota | 55417 | United States |
| St. Cloud VA Health Care System, St. Cloud, MN | Saint Cloud | Minnesota | 56303 | United States |
| VA Gulf Coast Veterans Health Care System, Biloxi, MS | Biloxi | Mississippi | 39531 | United States |
| Kansas City VA Medical Center, Kansas City, MO | Kansas City | Missouri | 64128 | United States |
| St. Louis VA Medical Center John Cochran Division, St. Louis, MO | St Louis | Missouri | 63106 | United States |
| Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE | Omaha | Nebraska | 68105-1873 | United States |
| Manchester VA Medical Center, Manchester, NH | Manchester | New Hampshire | 03104 | United States |
| New Mexico VA Health Care System, Albuquerque, NM | Albuquerque | New Mexico | 87108-5153 | United States |
| Albany VA Medical Center Samuel S. Stratton, Albany, NY | Albany | New York | 12208 | United States |
| Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY | New York | New York | 10010 | United States |
| Syracuse VA Medical Center, Syracuse, NY | Syracuse | New York | 13210 | United States |
| Durham VA Medical Center, Durham, NC | Durham | North Carolina | 27705 | United States |
| Fargo VA Healthcare System, Fargo, ND | Fargo | North Dakota | 58102 | United States |
| Cincinnati VA Medical Center, Cincinnati, OH | Cincinnati | Ohio | 45220 | United States |
| Louis Stokes VA Medical Center, Cleveland, OH | Cleveland | Ohio | 44106 | United States |
| Dayton VA Medical Center, Dayton, OH | Dayton | Ohio | 45428 | United States |
| Jackson C. Montgomery VA Medical Center, Muskogee, OK | Muskogee | Oklahoma | 74401 | United States |
| VA Portland Health Care System, Portland, OR | Portland | Oregon | 97239 | United States |
| VA Roseburg Healthcare System, Roseburg, OR | Roseburg | Oregon | 97471 | United States |
| VA Southern Oregon Rehabilitation Center and Clinics, White City, OR | White City | Oregon | 97503 | United States |
| Coatesville VA Medical Center, Coatesville, PA | Coatesville | Pennsylvania | 19320 | United States |
| Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA | Philadelphia | Pennsylvania | 19104 | United States |
| VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA | Pittsburgh | Pennsylvania | 15240 | United States |
| Wilkes-Barre VA Medical Center, Wilkes-Barre, PA | Wilkes-Barre | Pennsylvania | 18711 | United States |
| Ralph H. Johnson VA Medical Center, Charleston, SC | Charleston | South Carolina | 29401-5799 | United States |
| Wm. Jennings Bryan Dorn VA Medical Center, Columbia, SC | Columbia | South Carolina | 29209 | United States |
| VA Black Hills Health Care System Fort Meade Campus, Fort Meade, SD | Sturgis | South Dakota | 57741 | United States |
| Memphis VA Medical Center, Memphis, TN | Memphis | Tennessee | 38104-2127 | United States |
| Memphis VA Medical Center, Memphis, TN | Memphis | Tennessee | 38104 | United States |
| Tennessee Valley Healthcare System Nashville Campus, Nashville, TN | Nashville | Tennessee | 37212-2637 | United States |
| VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX | Dallas | Texas | 75216 | United States |
| Michael E. DeBakey VA Medical Center, Houston, TX | Houston | Texas | 77030 | United States |
| South Texas Health Care System, San Antonio, TX | San Antonio | Texas | 78229 | United States |
| White River Junction VA Medical Center, White River Junction, VT | White River Junction | Vermont | 05009-0001 | United States |
| Hampton VA Medical Center, Hampton, VA | Hampton | Virginia | 23667 | United States |
| Huntington VA Medical Center, Huntington, WV | Huntington | West Virginia | 25704 | United States |
| William S. Middleton Memorial Veterans Hospital, Madison, WI | Madison | Wisconsin | 53705 | United States |
| Clement J. Zablocki VA Medical Center, Milwaukee, WI | Milwaukee | Wisconsin | 53295-1000 | United States |
| Tomah VA Medical Center, Tomah, WI | Tomah | Wisconsin | 54660 | United States |
| Sheridan VA Medical Center, Sheridan, WY | Sheridan | Wyoming | 82801 | United States |
| VA Caribbean Healthcare System, San Juan, PR | San Juan | 00921 | Puerto Rico |
| 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. |
| 36516076 | Result | 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. |
| 37656456 | 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. |
| 41614323 | Derived | 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 Feb 3;15(3):e046142. doi: 10.1161/JAHA.125.046142. Epub 2026 Jan 30. |
| 40269774 | 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. |
| 39656458 | 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. |
| 38743423 | 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. |
| 37244366 | 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. |
| 37137378 | 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. |
| 37031794 | 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. |
| FG002 | Providers | Providers were enrolled in order to contact their potentially eligible patients and were not included in the results |
| COMPLETED |
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| NOT COMPLETED |
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Analysis and report of baseline information according to the intention-to-treat principle. Baseline characteristics were not collected for providers.
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| ID | Title | Description |
|---|---|---|
| BG000 | Hydrochlorothiazide | Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg) |
| BG001 | Chlorthalidone | Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg) |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Age | Mean | Standard Deviation | years |
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| Body mass index | Mean | Standard Deviation | kg/m2 |
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| Systolic blood pressure | Mean | Standard Deviation | mm Hg |
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| Current smoker | Count of Participants | Participants |
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| Resided in rural area | Count of Participants | Participants |
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| History of diabetes | Count of Participants | Participants |
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| History of heart failure | Count of Participants | Participants |
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| History of myocardial infarction | Count of Participants | Participants |
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| History of stroke | Count of Participants | Participants |
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| History of myocardial infarction or stroke | Count of Participants | Participants |
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| Estimated GFR<60 ml/min/1.73 m2 | Count of Participants | Participants |
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| Receiving hydrochlorothiazide at a daily dose of 25 mg | Based on the latest prescription received before study randomization | Count of Participants | Participants |
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| Number of antihypertensive drugs prescribed | Based on prescriptions received within 182 day before randomization | Mean | Standard Deviation | drugs |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. | Analysis of primary outcome was performed according to the intention-to-treat principle. | Posted | Mean | Standard Deviation | Years | 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). |
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| 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. | Analysis of secondary outcome was performed according to the intention-to-treat principle. | Posted | Count of Participants | Participants | 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). |
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| 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. | Analysis of secondary outcome was performed according to the intention-to-treat principle. | Posted | Count of Participants | Participants | 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). |
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| 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. | Analysis of secondary outcome was performed according to the intention-to-treat principle. | Posted | Count of Participants | Participants | 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). |
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| 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. | Analysis of secondary outcome was performed according to the intention-to-treat principle. | Posted | Count of Participants | Participants | 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). |
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| 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. | Analysis of secondary outcome was performance according to the intention-to-treat principle. | Posted | Count of Participants | Participants | 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). |
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| 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. | Analysis of primary outcome was performed according to the intention-to-treat principle. | Posted | Count of Participants | Participants | 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). |
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Safety 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).
Adverse events (AE) were collected based on the 21 CFR 312.32, International Conference on Harmonisation (ICH) for Clinical Safety Data Management (ICH-E2A), and Cooperative Studies Program (CSP) Global standard operating procedure definitions. All-cause mortality and hospitalization were monitored and reported as serious adverse events. Expected adverse events of interest were specified in the study protocol and captured from VA electronic medical records. AEs were not collected for providers.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Hydrochlorothiazide | Hydrochlorothiazide daily dose of 50 mg or 25 mg for duration of study Hydrochlorothiazide (HCTZ): Thiazide-type diuretic. Daily dose of 50 or 25 mg for duration of the study. | 448 | 6,767 | 1,977 | 6,767 | 1,229 | 6,767 |
| EG001 | Chlorthalidone | Chlorthalidone daily dose of 25 mg or 12.5 mg for duration of study Chlorthalidone: Thiazide-type diuretic. Daily dose of 25 or 12.5 mg for duration of the study. | 446 | 6,756 | 1,990 | 6,756 | 1,397 | 6,756 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| All-cause hospitalization | General disorders | Systematic Assessment |
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| All-cause mortality | General disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| New allergic or adverse reaction to thiazide-type diuretic | General disorders | Systematic Assessment |
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| Hypokalemia | General disorders | Systematic Assessment |
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| Hyponatremia | General disorders | Systematic Assessment |
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| Renal failure | General disorders | Systematic Assessment |
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| New onset of diabetes | General disorders | Systematic Assessment |
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| Acute gout episode | General disorders | Systematic Assessment |
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| Hospitalization for acute kidney injury | General disorders | Systematic Assessment |
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This trial had several important limitations:
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Sarah Leatherman | Boston VAHCS | 857-364-4201 | sarah.leatherman@va.gov |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 27, 2022 | Nov 15, 2023 | SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | Feb 19, 2021 | Jan 17, 2024 | ICF_004.pdf |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D006852 | Hydrochlorothiazide |
| D002752 | Chlorthalidone |
| ID | Term |
|---|---|
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D049971 | Thiazides |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000096926 | Benzenesulfonamides |
| D000577 | Amides |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D001577 | Benzophenones |
| D010797 | Phthalimides |
| D007094 | Imides |
| D007659 | Ketones |
| D054833 | Isoindoles |
Not provided
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| United States |
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Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg). |
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