Hydrochlorothiazide as Effective as Chlorthalidone for Preventing CVD, Death in Hypertension

Areef Ishani, MD

There were no significant differences in cardiovascular outcomes, including death, between use of hydrochlorothiazide or chlorthalidone among older adults with hypertension, according to new research presented at the American Heart Association’s (AHA) Scientific Sessions 2022.

Presented by Areef Ishani, MD, results of The Diuretic Comparison Project, which enrolled more than 13,000 participants with hypertension, suggest there were no difference in cardiovascular outcomes or noncancer deaths with use of chlorthalidone over hydrochlorothiazide, but investigators pointed out subgroup analyses suggested chlorthalidone could provide benefit in those with a history of cardiovascular disease or stroke.

“We were surprised by these results,” said Ishani, the director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and the director of the VA Midwest Health Care Network in Minneapolis, in a statement. “We expected chlorthalidone to be more effective overall, however, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

A paradox exists in the management of hypertension in the US. Although recent guidelines recommend chlorthalidone over other diuretics for treatment of hypertension, real-world data suggests hydrochlorothiazide remains the preferred choice for most clinicians prescribing diuretics for management of hypertension. Launched in 2016, the Diuretic Comparison Project was created with the intent of enrolling 13,500 Veterans with hypertension identified using national Veterans Affairs (VA) and non-VA databases with a follow-up of 3 years to better understand how diuretic choice might influence clinical outcomes.

An open-label study, patients were randomized to remain on current dose of hydrochlorothiazide or converted to an equipotent dose of chlorthalidone. For inclusion in the study, patients needed to be at least 65, be receiving hydrochlorothiazide from the VA, and have a most recent systolic blood pressure reading at or exceeding 120 mmHg. The primary outcome of interest for the study was a composite of major adverse cardiovascular events that included stroke, myocardial infarction, hospitalization for heart failure, urgent coronary revascularization, and non cancer death.

Overall, 16,595 individuals from 500 medical centers across the US underwent screening for participation. Of these, 13,523 underwent randomization, with 6756 randomized to chlorthalidone and 6767 randomized to hydrochlorothiazide. The overall study population had a mean baseline systolic blood pressure of 139 mmHg, was 97% men, 77% White, 93% non-Hispanic, and 55% reported living in urban areas. The median length of follow-up for the study was 2.4 years.

Upon analysis, results indicated a primary outcome event occurred among 10.4% of those receiving chlorthalidone and 10.0% of those receiving hydrochlorothiazide (HR, 1.04 [95% CI, 0.94-1.16]; P=.04). Further analysis indicated the rate of cardiovascular disease or death was 9.4% with chlorthalidone and 9.3% with hydrochlorothiazide. Investigators pointed out there were no significant differences observed for incidence of myocardial infarction, stroke, heart failure, or other cardiovascular outcomes observed in their analyses.

However, investigators pointed out differences of note were observed in subgroups analyses. Specifically, those with a history of myocardial infraction or stroke receiving chlorthalidone experienced a 27% relative risk reduction for all-cause mortality and cardiovascular disease compared with hydrochlorothiazide, but chlorthalidone did appear to worsen these same outcomes in those without a history of myocardial infarction or stroke. Additional analyses revealed there were increased rates of hospitalization with hypokalemia among those randomized to chlorthalidone (1.5%) compared to those randomized to hydrochlorothiazide (1.1%).

“We were surprised by these results,” Ishani said. “We expected chlorthalidone to be more effective overall, however, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.

This study, “Chlorthalidone compared with Hydrochlorothiazide for the prevention of cardiovascular events in patients with hypertension: The Diuretic Comparison Project (DCP),” was presented at AHA 22.