Diuretic Comparison Project

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.

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.