Hydrochlorothiazide or Chlorthalidone for Hypertension?

Nearly half of adults in the U.S. have hypertension, and prevalence continues to rise. Chlorthalidone, a thiazide diuretic, was a popular antihypertensive in the 1970s when it was first developed. However, usage dropped sharply during the next 20 years for unclear reasons, and then rose again after some studies suggested that the cardiovascular risk reduction profile for chlorthalidone was better than for hydrochlorothiazide. Despite changes in the guidelines that recommend chlorthalidone, prescribing patterns from Medicare data in 2020 showed that hydrochlorothiazide was still prescribed far more often than chlorthalidone.

The Diuretic Comparison Project investigators surmised that the discrepancy between guideline recommendations and real-world use was related to the belief that chlorthalidone was associated with a greater risk of adverse events (e.g., hypokalemia) than hydrochlorothiazide. To try and resolve this uncertainty, they compared the efficacy and safety of the two drugs in a large pragmatic study using the Veterans Affairs health system database. Patients aged 65 and older with a systolic blood pressure of at least 120 mm Hg and active prescriptions for hydrochlorothiazide (25 or 50 mg per day) were randomized to continue hydrochlorothiazide or switch to chlorthalidone (12.5 or 25 mg per day). Patients with comorbidities such as diabetes, heart failure, MI and stroke were included, reflecting the real-world nature of this study. Most patients were taking antihypertensives. Patients taking hydrochlorothiazide in combination with other medications were excluded.

After a median of 2.4 years, the primary composite outcome (stroke, myocardial infarction, hospitalization due to heart failure, unstable angina requiring urgent revascularization, non-cancer related death) and safety outcomes were similar in the two groups. Pre- and post-trial blood pressures also remained similar in the two groups. Patients in the chlorthalidone group had more laboratory studies for potassium levels, prescriptions for potassium, and slightly more hospitalizations for hypokalemia.

Does this trial settle the question of which thiazide diuretic is better for treating patients with hypertension when it comes to cardiovascular outcomes? Perhaps not. The authors note that the dosing of both diuretics was lower than in previous studies. Therefore, they can only conclude that chlorthalidone at a dose of 12.5 mg/day did not lead to a lower incidence of major cardiovascular outcomes or non-cancer related deaths as compared to hydrochlorothiazide at a dose of to 25 mg/day.

Read the following NEJM Journal Watch summary for more details of this study.

Allan S. Brett, MD, reviewing Ishani A et al. N Engl J Med 2022 Dec 29

Which diuretic is better for treating patients with hypertension: chlorthalidone or hydrochlorothiazide (HCTZ)? Researchers in the U.S. Veterans Affairs healthcare system addressed this question in a large head-to-head trial.

Nearly 14,000 patients with hypertension (age, ≥65) who were already taking HCTZ (25–50 mg daily) were randomized either to continue HCTZ or to switch to chlorthalidone (12.5–25 mg daily). At baseline, most patients were taking the 25-mg HCTZ dose plus one or two additional antihypertensive drugs, and about 15% had prior myocardial infarction (MI), stroke, or heart failure.

During median follow-up of 2.4 years, the primary composite outcome (i.e., MI, stroke, heart failure hospitalization, urgent coronary revascularization, or noncancer-related death) was 10% in each group. Individual components of this endpoint occurred with virtually identical frequency in the two groups. Chlorthalidone recipients were more likely than HCTZ recipients to develop hypokalemia, but the difference was modest (6.0% vs. 4.4%). Blood pressure remained similar in the two groups.

Comment: HCTZ and chlorthalidone performed similarly in this trial. However, the trial included only patients who were 65 or older, so the results don't necessarily apply to younger people. Additionally, 23% of patients had glomerular filtration rate (GFR) <60 mL/minute/1.73 m2 at baseline, but the paper doesn't tell us whether patients with severely impaired renal function were included; that information is important because thiazide diuretics traditionally have been thought to lose effectiveness when GFR is markedly reduced. Notably, a recent 12-week, placebo-controlled study showed that chlorthalidone did lower blood pressure in patients with GFRs between 15 and 30 mL/minute (NEJM JW Gen Med Dec 15 2021 and N Engl J Med 2021; 385:2507), but I'm not aware of similar data for HCTZ.

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Mridula Nadamuni, MD, is a 2022–2023 NEJM Editorial Fellow. She completed her internal medicine/pediatrics residency and chief residency at UT Southwestern Medical Center.