Study Results Find No Difference in Chlorthalidone, Hydrochlorothiazide for Prevention of Cardiovascular Events in Patients with Hypertension


Chlorthalidone was associated with more individuals with potassium levels below 3.1 mmol/L, suggesting a greater risk of hypokalemia.

Results from a recent study presented at the American Heart Association 2022 Scientific Sessions found no difference in the prevention of major adverse cardiovascular events (MACE) among older veterans with hypertension who received either chlorthalidone or hydrochlorothiazide.

Presenter Areef Ishani, MD, MS, said the goal of the trial was to establish whether treatment with chlorthalidone reduced MACE compared to hydrochlorothiazide. Early studies have suggested better cardiovascular outcomes with chlorthalidone, including better 24-hour blood pressure control and pleiotropic effects. However, recent observational studies have found no cardiovascular disease benefit to chlorthalidone and a greater risk of adverse events (AEs) such as hypokalemia, acute kidney injury, and chronic kidney disease.

The investigators conducted a pragmatic study using a consent order distributed through electronic medical records because there were no study staff at any site. Ishani said he was pleasantly surprised that 68.5% of approached providers consented to participate.

Patients were randomized to either remain on their current dose of hydrochlorothiazide (25 mg or 50 mg) or to convert to an equipotent dose of chlorthalidone. Inclusion criteria required that participants be over 65 years of age, receiving either 25 mg or 50 mg of hydrochlorothiazide, and have a systolic blood pressure greater than or equal to 120 mm Hg in their most recent reading.

Approximately 16,500 patients were identified, and 13,523 were ultimately randomized 1:1. At baseline, approximately 95% were on the lowest dose of hydrochlorothiazide. The 2 groups were well compared, with an average age of approximately 72.5 years, 97% male, 15% African American, and 45% living in rural areas.

The primary outcome was time to the first occurrence of stroke, myocardial infarction, non-cancer death, hospitalization for acute heart failure, or urgent coronary revascularization. The investigators assumed a 3% per year event rate in the hydrochlorothiazide group and hypothesized a 17.5% reduction in the chlorthalidone group.

According to the results, the researchers found no difference in systolic blood pressure or mean potassium over time between the 2 groups. Both arms started with approximately 11% of patients on a potassium supplement, and this number increased slightly in the chlorthalidone group. There was no difference in time to the primary outcome in either group. Similarly, there was no difference in components of the primary outcome.

Ishani highlighted the AEs related to hypokalemia, noting that chlorthalidone was associated with more individuals with a potassium level below 3.1 mmol/L.

Based on these findings, the researchers concluded that chlorthalidone did not reduce the incidence of major cardiovascular outcomes or non-cancer deaths, compared to hydrochlorothiazide at doses commonly used in clinical practice. A subgroup analysis did suggest a difference in the primary outcome by the presence or absence of prior stroke or myocardial infarction, but Ishani said it is unclear how to interpret these results in the context of a negative study. This could be a chance finding and future studies should explore further.


Ishani A. Chlorthalidone Compared to Hydrochlorothiazide for Prevention of Cardiovascular Events in Patients With Hypertension. Presented at: American Heart Association 2022 Scientific Sessions. November 5, 2022.

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