Diuretic Duels for Patients With Hypertension

Volume 22, Issue 3

Hypertension remains extremely prevalent worldwide and still accounts for significant morbidity and mortality despite contemporary drug therapy. This can be explained by the fact that many patients with hypertension require multiple medications to control their blood pressure, and medication adherence is known to steadily decline over time. Therefore, the most effective medications for hypertension are the ones that are the safest and easiest to take.

Owing to their once daily administration and favorable safety profile, thiazide diuretics have been first-line agents to treat hypertension for several decades. The original ALLHAT trial demonstrated chlorthalidone effectively controlled blood pressure and reduced rates of major adverse cardiac events. Despite this, hydrochlorthiazide (HCTZ) has become the most widely prescribed thiazide diuretic for hypertension. There are several key differences between these agents, as chlorthalidone is more potent and longer-lasting than HCTZ. Several retrospective trials have signaled that chlorthalidone may be the superior agent for controlling hypertension.

In a previous issue of Talking Therapeutics, I mentioned a trial that was presented at AHA Scientific Sessions 2022 which compared these two diuretics with respect to cardiovascular outcomes. In this week’s issue, we’re going to discuss this trial in more detail now that the full version has been published in The New England Journal of Medicine this week.

Point 1: No Difference Between Diuretics

In the study, a total of 13,523 patients were randomized to continue HCTZ or switch to chlorthalidone. At baseline, 94.5% of patients had been prescribed HCTZ at a dose of 25 mg daily. The mean baseline systolic blood pressure in each group was 139 mm Hg.

Patients were evaluated for the occurrence of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non–cancer-related death. At a median follow-up of 2.4 years, components of the primary outcome occurred at a similar rate across groups, at 10.4% in those receiving chlorthalidone and 10.0% in the HCTZ group (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = .45). Interestingly, in the chlorthalidone group, the primary outcome occurred more often in patients who had a history of myocardial infarction or stroke compared to those who did not.

With respect to safety, hypokalemia incidence was higher in the chlorthalidone group than in the HCTZ group (6.0% vs 4.4%, P < .001).

Point 2: Randomized Trials Are Still Key

These findings are pivotal, given the high prevalence of hypertension and the widespread use of thiazide diuretics for this indication.

This trial also underscores an important notion in clinical medicine. Oftentimes, a signal for benefit or harm is noted in smaller, non-randomized analyses, only to be disproven when a more robust clinical trial is completed. When evaluating a new finding for a medication, it’s important to remember to not jump the gun if this finding wasn’t tested in a randomized fashion.