Chlorthalidone vs. Hydrochlorothiazide: Which Is Superior for Treating Hypertension?
By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: Randomly switching half of patients with hypertension on hydrochlorothiazide to chlorthalidone did not produce any difference in major cardiovascular outcomes.
SOURCE: Ishani A, Cushman WC, Leatherman SM, et al. Chlorthalidone vs. hydrochlorothiazide for hypertension-cardiovascular events. N Engl J Med 2022;387:2401-2410.
Ishani et al sought to determine if chlorthalidone (CTD) is superior to hydrochlorothiazide (HCT) for controlling hypertension and preventing cardiovascular (CV) events at the expense of more adverse events, such as hypokalemia. They also considered if both drugs prevent CV events equally. In the Diuretic Comparison Project of the Veterans Affairs (VA) Healthcare System’s Cooperative Studies Program, researchers compared two thiazide diuretics for reducing the risk of major nonfatal CV events and non-cancer-related deaths in older patients.
This was a pragmatic, open-label, multicenter trial conducted in VA medical centers. Eligible patients were age 65 years or older, recorded a systolic blood pressure of 120 mmHg or higher, and were actively taking HCT at 25 mg/day or 50 mg/day. Patients were assigned randomly to continuing HCT at their current dose of 25 mg/day or 50 mg/day or switching to CTD at the dose equivalents of 12.5 mg/day or 25 mg/day. All other medications or treatments were considered usual care and not dictated by the study.
The outcome of non-fatal CV events included myocardial infarction (MI), stroke, heart failure hospitalization, or urgent coronary revascularization for unstable angina. Safety outcomes included electrolyte abnormalities and acute kidney injury.
Baseline data and outcomes were assessed using electronic health records (EHR) and administrative databases (pharmacy, deaths). From 2016 to 2021, the authors randomized 13,523 patients at 72 VA centers (mean age was 72 years; 97% men; 15% Black, and 11% with a history of MI or stroke). The mean systolic blood pressure at baseline was 139 mmHg in both groups and did not change significantly during follow-up. The mean number of antihypertensive agents patients were receiving was 2.6.
At a median follow-up of 2.4 years, the primary composite endpoint was 10.4% in patients in the CTD group and 10% in patients in the HCT group (HR, 1.04; 95% CI, 0.94-1.16; P = 0.45). Also, there were no differences in any of the components of the primary outcome. A subgroup analysis of the primary outcome revealed an interaction between treatments in those with a prior MI or stroke in favor of CTD. None of the other subgroups showed an interaction.
Hospitalizations for hypokalemia were slightly more common in the CTD group (1.5% vs. 1.1%; HR, 1.35; 95% CI, 1.00-1.82). A follow-up potassium level of less than 3.1 mmol/L was more common in the CTD group (5% vs. 3.6%; P < 0.001). Adherence to the study drug was 80% in the CTD group and 79% in the HCT group. The authors concluded that a pragmatic comparison of CTD to HCT treatment in patients with hypertension failed to show a difference in major CV outcomes over a 2.4-year median follow-up. However, the authors reported more episodes of hypokalemia in the CTD group.
COMMENTARY
One of the interesting features of this trial was the pragmatic design, which relied on EHR and pharmacy systems for follow-up data rather than prescribed clinic visits or case report forms. This approach greatly lowered the cost of the study and allowed for a large study population. Also, it allowed smaller VAs to participate, resulting in 45% representation of rural patients, who usually are not enrolled in trials. In addition, adherence to therapy was about 80% in both groups, which is similar if not better than real-world experience.
In the Ishani et al study, blood pressure control was the same in both groups. However, patients were taking an average of 2.6 medications for hypertension. Manipulation of the doses of the other medications was not prohibited nor assessed.
Also, most of the VA patients in this trial were on 12.5 mg/day or on 25 mg/day of HCT, with only 5% receiving 50 mg/day of HCT at baseline. Thus, the primary comparison in the Ishani et al study was between 25 mg/day of HCT and 12.5 mg/day of CTD. Extrapolation to other doses of these diuretics may not be warranted.
The increased incidence of hypokalemia with CTD compared to HCT should be interpreted with caution, as those randomized to CTD were starting a new drug and probably were checked for low potassium more frequently (at least initially). Also, the prior MI or stroke subgroup finding of better outcomes with CTD could be attributed to chance, as the overall trial did not show any difference between the two diuretics. One could conclude that at these commonly used doses, the lack of CV outcome benefit observed with switching from HCT to CTD, along with the evidence of more hypokalemia episodes for those taking CTD, supports the usual practice of preferentially prescribing HCT for hypertension.
Randomly switching half of patients with hypertension on hydrochlorothiazide to chlorthalidone did not produce any difference in major cardiovascular outcomes.
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