Cardiovascular events similar, adverse effects worse with chlorthalidone compared to hydrochlorothiazide

Chlorthalidone was associated with a significantly higher risk of hypokalemia, hyponatremia, acute renal failure, chronic kidney disease, type 2 diabetes, and abnormal weight gain.

Chlorthalidone was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide for hypertension in real-world practice, but it was associated with a greater risk of renal and electrolyte abnormalities, according to a study of three large databases.

Researchers analyzed first-time users of antihypertensive monotherapy in outpatient or inpatient care using data gathered from two administrative claims databases and one collection of electronic health records from January 2001 through December 2018. The study's primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite outcome that added sudden cardiac death to the other three. Fifty-one safety outcomes were measured. Results were published Feb. 17 by JAMA Internal Medicine.

Of 730,255 individuals, 36,918 received chlorthalidone and had 149 composite outcome events. The other 693,337 received hydrochlorothiazide and had 3,089 composite outcome events. Calibrated and uncalibrated hazard ratios for the studied outcomes were very close. There was little evidence of residual confounding from false-positive or skewed results in the controls. No significant difference was seen between the drugs in risk of myocardial infarction, hospitalized heart failure, or stroke. The calibrated hazard ratio (HR) for the composite outcome was 1.00 (95% CI, 0.85 to 1.17) for chlorthalidone compared with hydrochlorothiazide.

Chlorthalidone was associated with a significantly higher risk of hypokalemia (HR, 2.72; 95% CI, 2.38 to 3.12), hyponatremia (HR, 1.31; 95% CI, 1.16 to 1.47), acute renal failure (HR, 1.37; 95% CI, 1.15 to 1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09 to 1.42), and type 2 diabetes (HR, 1.21; 95% CI, 1.12 to 1.30) than hydrochlorothiazide. It was also associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61 to 0.86).

The results suggest that recommendations to prefer chlorthalidone to hydrochlorothiazide are not supported by real-world evidence, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted, the authors wrote.

“Based on the electrolyte findings, chlorthalidone's association with an increase in rate of type II diabetes may be associated with potassium depletion or to dehydration,” the authors wrote. “Chlorthalidone's lower rate of abnormal weight gain may be associated with more effective diuresis.”