In the Journals

Chlorthalidone as effective as hydrochlorothiazide with worse safety profile

Photo of George Hripcsak
George Hripcsak

Despite guidelines recommending chlorthalidone over hydrochlorothiazide for hypertension, the drugs have similar effectiveness and chlorthalidone was associated with a significantly worse safety profile, according to research published in JAMA Internal Medicine.

George Hripcsak, MD, MS, the Vivian Beaumont Allen Professor of Biomedical Informatics and chair of the department of biomedical informatics at Columbia University, told Healio Primary Care that although hydrochlorothiazide is more commonly used, the most recent hypertension guidelines prefer chlorthalidone because it “is known to be longer acting and therefore perhaps more effective.”

Results from other non-randomized studies have been inconsistent with some suggesting that chlorthalidone is more effective, and others showing that it may be associated with more adverse events, Hripcsak explained.

Hripcsak and colleagues conducted an observational comparative cohort study that used data from two administrative claims databases and a collection of electronic health records with information from January 2001 through December 2018. They used large-scale propensity score stratification as well as negative-control and synthetic positive-control calibration to assess the risk for adverse events among participants with hypertension who took chlorthalidone compared with those who took hydrochlorothiazide.

Source: Hripcsak G, et al. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2019.7454.

Among 730,227 people included in the study, 36,918 patients received chlorthalidone and 693,337 received hydrochlorothiazide.

Researchers found no significant difference in the associated risks for myocardial infarction, hospitalization for heart failure or stroke.

However, chlorthalidone was associated with significantly higher risks for hyperkalemia (HR = 2.72; 95% CI, 2.38-3.12), hyponatremia (HR = 1.31; 95% CI, 1.16-1.47) and acute renal failure (HR = 1.37; 95% CI, 1.15-1.63) compared with hydrochlorothiazide, according to Hripcsak and colleagues. Chlorthalidone was also linked to significantly higher risks for chronic kidney disease (HR = 1.24; 95% CI, 1.09-1.42) and type 2 diabetes (HR = 1.21; 95%CI, 1.12-1.3).

Compared with hydrochlorothiazide, researchers identified a significantly lower risk for abnormal weight gain associated with chlorthalidone (HR = 0.73; 95% CI, 0.61-0.86).

“We carried out the largest and, we believe, most sophisticated non-randomized study comparing the two drugs, and we found little difference in effectiveness — preventing heart attacks, strokes, and heart failure — but that chlorthalidone produces more side effects, especially low potassium — almost three times as much — and other electrolyte disorders and kidney problems,” Hripcsak told Healio Primary Care.

“Therefore, we believe that if you are taking hydrochlorothiazide, our study shows no reason to switch to chlorthalidone at this time,” he said. “And if you are taking chlorthalidone, your physician should be monitoring your electrolytes and kidney function carefully.”

He noted that there is currently a randomized clinical trial underway that will provide more information on the risks associated with each drug, but that the current study is “reflective of what happens in real world practice.” – by Erin Michael

Disclosures: The study was funded in part by the NIH and the National Science Foundation. Hripcsak reports receiving grant funding from Janssen Research through his university to support methods research not directly related to this study. Janssen did not have input in the design, execution, interpretation of results or decision to publish.

Photo of George Hripcsak
George Hripcsak

Despite guidelines recommending chlorthalidone over hydrochlorothiazide for hypertension, the drugs have similar effectiveness and chlorthalidone was associated with a significantly worse safety profile, according to research published in JAMA Internal Medicine.

George Hripcsak, MD, MS, the Vivian Beaumont Allen Professor of Biomedical Informatics and chair of the department of biomedical informatics at Columbia University, told Healio Primary Care that although hydrochlorothiazide is more commonly used, the most recent hypertension guidelines prefer chlorthalidone because it “is known to be longer acting and therefore perhaps more effective.”

Results from other non-randomized studies have been inconsistent with some suggesting that chlorthalidone is more effective, and others showing that it may be associated with more adverse events, Hripcsak explained.

Hripcsak and colleagues conducted an observational comparative cohort study that used data from two administrative claims databases and a collection of electronic health records with information from January 2001 through December 2018. They used large-scale propensity score stratification as well as negative-control and synthetic positive-control calibration to assess the risk for adverse events among participants with hypertension who took chlorthalidone compared with those who took hydrochlorothiazide.

Source: Hripcsak G, et al. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2019.7454.

Among 730,227 people included in the study, 36,918 patients received chlorthalidone and 693,337 received hydrochlorothiazide.

Researchers found no significant difference in the associated risks for myocardial infarction, hospitalization for heart failure or stroke.

However, chlorthalidone was associated with significantly higher risks for hyperkalemia (HR = 2.72; 95% CI, 2.38-3.12), hyponatremia (HR = 1.31; 95% CI, 1.16-1.47) and acute renal failure (HR = 1.37; 95% CI, 1.15-1.63) compared with hydrochlorothiazide, according to Hripcsak and colleagues. Chlorthalidone was also linked to significantly higher risks for chronic kidney disease (HR = 1.24; 95% CI, 1.09-1.42) and type 2 diabetes (HR = 1.21; 95%CI, 1.12-1.3).

Compared with hydrochlorothiazide, researchers identified a significantly lower risk for abnormal weight gain associated with chlorthalidone (HR = 0.73; 95% CI, 0.61-0.86).

“We carried out the largest and, we believe, most sophisticated non-randomized study comparing the two drugs, and we found little difference in effectiveness — preventing heart attacks, strokes, and heart failure — but that chlorthalidone produces more side effects, especially low potassium — almost three times as much — and other electrolyte disorders and kidney problems,” Hripcsak told Healio Primary Care.

“Therefore, we believe that if you are taking hydrochlorothiazide, our study shows no reason to switch to chlorthalidone at this time,” he said. “And if you are taking chlorthalidone, your physician should be monitoring your electrolytes and kidney function carefully.”

He noted that there is currently a randomized clinical trial underway that will provide more information on the risks associated with each drug, but that the current study is “reflective of what happens in real world practice.” – by Erin Michael

Disclosures: The study was funded in part by the NIH and the National Science Foundation. Hripcsak reports receiving grant funding from Janssen Research through his university to support methods research not directly related to this study. Janssen did not have input in the design, execution, interpretation of results or decision to publish.