Chlorthalidone vs. Hydrochlorothiazide for Hypertension

By Michael H. Crawford, MD, Editor

SYNOPSIS: A subgroup analysis of those with prior myocardial infarction or ischemic stroke in the Diuretic Comparison Project for the treatment of hypertension has found that this higher-risk group experiences fewer major adverse cardiovascular events while taking chlorthalidone compared to hydrochlorothiazide, but at the expense of more hypokalemia.

SOURCE: Ishani A, Hau C, Cushman WC, et al. Chlorthalidone vs hydrochlorothiazide for hypertension treatment after myocardial infarction of stroke: A secondary analysis of a randomized clinical trial. JAMA Netw Open 2024;7:e2411081.

The Diuretic Comparison Project (DCP) was a pragmatic, randomized clinical trial (RCT) comparing chlorthalidone (CTD) to hydrochlorothiazide (HCT) for the treatment of hypertension in U.S. veterans; it did not show a difference in major adverse clinical events (MACE) between the two therapies.¹ However, there was a proposed prespecified subgroup analysis to evaluate whether this outcome would be different in patients with a prior myocardial infarction (MI) or stroke. The report by Ishani et al explores this hypothesis.

DCP was a multicenter, open-label, RCT conducted in 72 Veterans Affairs (VA) hospitals from 2016-2021. Eligible patients were ≥ 65 years of age with hypertension, had a last systolic blood pressure (BP) of ≥ 120 mmHg, and were taking HCT 25 mg/day or 50 mg/day. They were randomized to continue HCT or change to CTD at equivalent pharmacologic doses (HCT 25 mg = CTD 12.5 mg). They were followed during otherwise usual care with no specific BP targets and no limitation to the use of other antihypertensive agents or potassium chloride. The primary outcome was MACE (MI, stroke, urgent revascularization for unstable angina, heart failure hospitalization [HFH], and non-cancer mortality). Each component of MACE was a secondary endpoint. The safety endpoints were potassium (K+) < 3.1 mEq/L or acute kidney injury.

The 13,523 randomized patients had a median age of 72 years, 97% were men, and 15% were Black. Of these, 1,455 (11%) had a history of prior MI or stroke. There were no significant differences in baseline characteristics between the two groups except for more sodium glucose cotransporter-2 (SGLT2) use in the prior MI/stroke group. During a mean follow-up of 2.4 years, there was no difference in systolic BP or K+ between groups.

The prior MI/stroke group participants randomized to CTD had a lower risk of MACE compared to those receiving HCT (14% vs. 19%; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.57-0.94; P = 0.01). The absolute risk reduction was 5%, driven largely by a lower risk of HFH (4.6% vs. 7.2%; HR, 0.64; 95% CI, 0.41-0.98), but all-cause mortality also was lower in those taking CTD (8.9% vs. 12.2%; P = 0.04).

In those without a prior MI/stroke, MACE was slightly higher in the CTD arm vs. the HCT arm (9.9% vs. 8.9%; HR, 1.12; 95% CI, 1.00-1.26; P = 0.054). Also, the overall adverse event rate was higher in those taking CTD (20% vs. 18%; P < 0.001), as was K+ < 3.1 (4.9% vs. 3.4%; P < 0.001) in those without a prior MI/stroke. The authors concluded that, in hypertensive patients with a history of prior MI/Stroke, CTD may reduce MACE and noncancer mortality compared to HCT.

COMMENTARY

Thiazide diuretics are part of first-line therapy for hypertension and have been shown to reduce MACE. Many believe that CTD has advantages over HCT because of a longer pharmacologic half-life, better 24-hour BP control, and pleiomorphic effects such as reduced platelet aggregation and vascular permeability as the result of carbonic anhydrase inhibition. However, because of a greater incidence of reduced hypokalemia with CDT, most clinicians in the United States use HCT.

The long-anticipated head-to-head DCP trial between CDT and HCT at pharmacologically equivalent doses showed no differences in BP or MACE, but a possible qualitative interaction was observed in those with prior MI/stroke. A qualitative interaction is when a treatment benefits one subgroup but harms another. Thus, Ishani et al pursued this prespecified subgroup analysis in the current report. It confirmed the significant qualitative interaction between treatment assignment and baseline history of MI/stroke (P = 0.002).

The latter subgroup exhibited a significant reduction in MACE, noncancer deaths, and all-cause mortality with CTD compared to HCT, but also a higher incidence of hypokalemia and more prescriptions for potassium chloride (although there was no difference in prescriptions for renin, angiotensin, and mineralocorticoid inhibitors between those on CDT compared to HCT). Concern that the doses of CTD were not pharmacologically equivalent is tempered by the almost identical BPs in patients taking HCT and patients taking CTD. Other studies have shown that hypokalemia is associated with a higher risk of MACE, but that was not observed in the DCP study, perhaps because of a higher use of potassium chloride supplementation in those taking CTD.

There are limitations to this DCP trial subgroup analysis. There were fewer participants in the prior MI/stroke group and fewer events. Also, the mechanism of the benefit of CTD compared to HCT in the prior MI/stroke group is not clear. It could be because of differences in baseline risk, treatment of hypokalemia, or other factors not explored in the DCP. Of course, it could just be the result of chance. Regardless, this subgroup analysis of DCP suggests that there may be an advantage to CTD over HCT in higher-risk patients with hypertension, as long as potassium levels are regulated.

REFERENCE

1. Hripcsak G, Suchard MA, Shea S, et al. Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension. JAMA Intern Med 2020;180:542-551.