Chlorthalidone vs Hydrochlorothiazide for Hypertension-Related Cardiovascular Events
The New England Journal of Medicine: Published on December, 2022
Hypertension increases the risk of complications and death
from cardiovascular disease. Thiazide diuretics are first-line
antihypertensive agents that lower blood pressure and prevent adverse
cardiovascular outcomes.
Early studies suggested that chlorthalidone was superior to
hydrochlorothiazide in patients with hypertension; however, more recent
observational studies have shown that the two drugs reduced cardiovascular
events at a similar rate. Chlorthalidone may be associated with an
increased risk of adverse events, including hypokalemia.
Authors 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.
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In this trial involving 13,523 patients with hypertension
receiving hydrochlorothiazide (HCTZ) at baseline, switching to chlorthalidone
instead of continuing HCTZ therapy did not reduce the risk of the primary
composite outcome (nonfatal myocardial infarction, stroke, heart failure
resulting in hospitalization, urgent coronary revascularization for unstable
angina, and non–cancer-related death) after a median follow-up period of 2.4
years.
Results from the present trial suggest no difference between
the drugs with regard to cardiovascular outcomes, with potential disparate
results in the primary outcome caused by the presence or absence of a history
of stroke or myocardial infarction at baseline.
Those assigned to the chlorthalidone group were more likely
to switch to the other trial drug than those assigned to the
hydrochlorothiazide group.
Patients assigned to receive chlorthalidone had a greater
incidence of hypokalemia than those assigned to receive hydrochlorothiazide. The
incidence of hypokalemia was greater in the chlorthalidone group than in the
HCTZ group (6.0% vs 4.4%).
These findings show that chlorthalidone is not superior to HCTZ for reducing the rate of major adverse cardiovascular events or non–cancer-related deaths.
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Background: Whether chlorthalidone is superior to hydrochlorothiazide for
preventing major adverse cardiovascular events in patients with hypertension is
unclear.
Methods: In a pragmatic trial, we randomly assigned adults 65 years of
age or older who were patients in the Department of Veterans Affairs health
system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50
mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone
at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of
nonfatal myocardial infarction, stroke, heart failure resulting in
hospitalization, urgent coronary revascularization for unstable angina, and
non-cancer-related death. Safety was also assessed.
Results: A total of 13,523 patients underwent randomization. The mean
age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day
had been prescribed in 12,781 patients (94.5%). The mean baseline systolic
blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years,
there was little difference in the occurrence of primary-outcome events between
the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide
group (675 patients [10.0%]). There were no between-group differences in the
occurrence of any of the components of the primary outcome. The incidence of
hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide
group (6.0% vs. 4.4%).
Conclusions: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide.
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