Chlorthalidone associated with electrolyte abnormalities in older hypertensive patients

Chlorthalidone does not lead to fewer cardiovascular events and deaths than hydrochlorothiazide but may be more likely to cause electrolyte imbalances, especially hypokalemia, according to a new study.

Researchers in Canada performed a propensity score-matched observational cohort study to compare the safety and effectiveness of chlorthalidone and hydrochlorothiazide in older adults with hypertension. Patients who were at least 66 years of age, began treatment with either drug between Jan. 1, 1993, and March 31, 2010, and had not been hospitalized for heart failure, stroke or myocardial infarction in the previous year were included. Each patient taking chlorthalidone was matched with at least two patients taking hydrochlorothiazide by age, sex, year in which treatment began, and propensity score (a statistical indicator that accounts for other differences between the matched patients that might bias the results of the comparison).

The study's primary outcome measure was death or hospitalization for heart failure, stroke or myocardial infarction. Hospitalization with hypokalemia or hyponatremia was included as a safety outcome. Results appeared in the March 19 Annals of Internal Medicine.

Overall, 29,873 patients were included in the study, 10,384 receiving chlorthalidone and 19,489 receiving hydrochlorothiazide. Over five years of follow-up, the primary outcome occurred at a rate of 3.2 events per 100 person-years of follow-up in the chlorthalidone group and 3.4 events per 100 person-years of follow-up in the hydrochlorothiazide group (adjusted hazard ratio, 0.93 [95% CI, 0.81 to 1.06]). Hospitalization with hypokalemia and hyponatremia was more common in the chlorthalidone group (adjusted hazard ratios, 3.06 [95% CI, 2.04 to 4.58] and 1.68 [95% CI, 1.24 to 2.28], respectively). The authors performed nine post hoc analyses to compare patients taking 12.5, 25 or 50 mg of each of the drugs per day and found that the chlorthalidone group had a higher risk for hospitalization in all six of the comparisons that yielded a statistically significant difference.

The authors noted that sample size or differences in patients' characteristics or physicians' treatment approaches may have affected the study's ability to detect small differences in the two drugs' effectiveness. However, they concluded that with typical use, chlorthalidone in older patients yielded similar adverse cardiovascular events and deaths compared with hydrochlorothiazide, but was associated with higher rates of electrolyte abnormalities, notably hypokalemia.

In the absence of a larger randomized trial, they wrote, “it may be reasonable to conclude that hydrochlorothiazide is safer than chlorthalidone in elderly patients at typically prescribed doses.”