Clinical Inquiries

How do hydrochlorothiazide and chlorthalidone compare for treating hypertension?

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Both medications reduce theincidence of cardiovascular events in patients with hypertension, but chlorthalidone may confer additional cardiovascular risk reduction (strength of recommendation [SOR]: B, conflicting network meta-analysis and cohort studies). (No head-to-head studies of hydrochlorothiazide [HCTZ] and chlorthalidone have been done.)

Serious hypokalemia and hyponatremia can occur with either medication; it is unclear if the rates of these adverse effects are the same at equivalent doses. Patients taking chlorthalidone are less likely to need a second antihypertensive medication but more likely to be nonadherent than patients taking HCTZ (SOR: B, cohort studies).


A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.1 Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.2 Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.


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