Diuretic Comparison Project (DCP)

• ClinicalTrials.gov Identifier: NCT02185417
• Recruitment Status: Recruiting
• First Posted: July 9, 2014
• Last Update Posted: August 13, 2019
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

The purpose of this study is to determine whether chlorthalidone is more effective than hydrochlorothiazide at preventing cardiovascular outcomes in Veterans over age 65 with hypertension. Both medications are thiazide-type diuretics that have been used for more than 50 years and are considered first-line treatment for hypertension. Patients currently prescribed hydrochlorothiazide will be randomized to either continue taking hydrochlorothiazide or to receive chlorthalidone, and followed for major cardiovascular events, such as myocardial infarction (MI) and stroke. The study will use a new, efficient and less expensive study design termed 'point of care', in which study operations will be conducted centrally and patient data will be collected passively through the electronic medical record.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Hydrochlorothiazide (HCTZ); Drug: Chlorthalidone	Phase 3

Detailed Description:

Over 1 million Veterans are prescribed a thiazide-type diuretic each year; over 95% receive hydrochlorothiazide, and fewer than 2.5% receive chlorthalidone. Both medications are thiazide-type diuretics that have been used for more than 50 years and are considered first-line treatment for hypertension. Indirect evidence has been accumulating, however, that chlorthalidone may be more effective than hydrochlorothiazide at preventing cardiovascular events. This will be the first randomized head-to-head comparison of the effectiveness of these two drugs. The study plans to enroll 13,500 Veterans over 3 years and follow them on average for 3 years, resulting in a total study duration of 4.5 years. Patients currently prescribed hydrochlorothiazide will be randomized to either continue taking hydrochlorothiazide or to receive an equivalent dose of chlorthalidone. The unique 'point of care' or 'clinically integrated' study design will identify, enroll and follow subjects using the electronic medical record system and national VA and non-VA databases. The primary outcome is an event composite consisting of: stroke, myocardial infarction, non-cancer death, urgent revascularization, and hospitalization for acute congestive heart failure. All patient care, including the study drug, will continue to be managed by the primary care provider.

Primary Care Providers will also be included as participants in this research study. Adding providers as subjects will allow us to study the implementation of the point of care protocol design in addition to the original research question. The study team will collect data on diuretic management within the study and may contact providers by phone or email to learn reasons for declining a particular patient or discontinuing a new chlorthalidone order or an ongoing diuretic prescription.

If cardiovascular events are reduced by even a small amount by chlorthalidone, the public health effect will be considerable because of the large number of patients who take diuretics. A randomized trial, now feasible due to the investigators' efficient and inexpensive design, will provide evidence needed to better inform practice throughout the VA.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 13500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CSP #597 - Diuretic Comparison Project
• Actual Study Start Date: June 15, 2016
• Estimated Primary Completion Date: October 15, 2022
• Estimated Study Completion Date: April 15, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Hydrochlorothiazide; Hydrochlorothiazide daily dose of 50 mg or 25 mg for duration of study	Drug: Hydrochlorothiazide (HCTZ); Thiazide-type diuretic. Daily dose of 50 or 25 mg for duration of the study.; Other Name: HCTZ
Active Comparator: Chlorthalidone; Chlorthalidone daily dose of 25 mg or 12.5 mg for duration of study	Drug: Chlorthalidone; Thiazide-type diuretic. Daily dose of 25 or 12.5 mg for duration of the study.

Outcome Measures

Primary Outcome Measures :

1. Time to major cardiovascular event [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   The Primary outcome measure will be time to a major cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, hospitalization for acute congestive heart failure, non-cancer death.

Secondary Outcome Measures :

1. Time to event for each component of the composite primary outcome and additional cardiovascular events [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   The Secondary outcomes will include time to event for (1) each of the 5 components of the composite primary outcome, (2) all deaths, (3) the composite outcome substituting all deaths for non-cancer deaths, (4) "possibly vascular deaths," (5) the composite outcome substituting "possibly vascular deaths" for non-cancer deaths, (6) any revascularization of any artery.
2. All Deaths [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   All Deaths
3. Urgent revascularization because of unstable angina [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   Urgent revascularization because of unstable angina
4. Hospitalization for acute congestive heart failure [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   Hospitalization for acute congestive heart failure
5. Non-cancer death [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   Non-cancer death
6. The primary composite outcome substituting 'all deaths' for 'non-cancer deaths' [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   This secondary outcome measure will be time to a major cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, hospitalization for acute congestive heart failure, all deaths.
7. Possibly Vascular Deaths [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   Defined as all deaths caused by vascular diseases, diabetes, external causes, and unknown causes.
8. The primary composite outcome substituting 'possibly vascular deaths' for 'non-cancer deaths' [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   This secondary outcome measure will be time to a major cardiovascular event, defined as a composite outcome comprised of the first occurrence after randomization of any of the following: stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, hospitalization for acute congestive heart failure, possibly vascular deaths. 'Possibly vascular deaths' are defined as all deaths caused by vascular diseases, diabetes, external causes, and unknown causes.
9. Any revascularization of any artery [ Time Frame: Randomization to time to event; average follow-up 3 years ]
   Any revascularization of any artery
10. Erectile dysfunction (ED) [ Time Frame: Randomization to time to event; average follow-up 3 years ]
    Defined as first prescription for phosphodiesterase Type 5 (PDE5) inhibitor or referral for ED

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Veterans who:

• Are over age 65 years
• Are receiving hydrochlorothiazide from the VA pharmacy at a daily dose of 25 or 50 mg
• Have a most recent systolic blood pressure (SBP) in CPRS greater than or equal to 120 mm Hg, with no SBP less than 120 mm Hg recorded in CPRS in the previous 90 days

Primary Care Providers will also be included as participants in this research study.

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 EMR 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)
• K<3.1 meq/L (or K<3.5 meq/L if on digoxin) in the past 90 days
• Na<130 meq/L in the past 90 days
• Known to be enrolled in Medicare Part C (assessed on consent phone call). This exclusion will only be employed if the investigators determine that sufficient information from Part C data cannot obtained.

Contacts and Locations

Contacts

Contact: Jade Fiotto; (617) 232-9500; Jade.Fiotto@va.gov

Contact: Alison L Majkut; (857) 364-4885; Alison.Majkut@va.gov

  Show 47 Study Locations

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Study Chair: Areef Ishani, MD MS; Minneapolis VA Health Care System, Minneapolis, MN
• Study Chair: William C Cushman, MD; Memphis VA Medical Center, Memphis, TN

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02185417 History of Changes
• Other Study ID Numbers: 597
• First Posted: July 9, 2014
• Last Update Posted: August 13, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:

Hypertension; Diuretic; Comparative Effectiveness Research; Point of Care Research

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Hydrochlorothiazide; Chlorthalidone; Diuretics; Antihypertensive Agents; Natriuretic Agents; Physiological Effects of Drugs; Sodium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action