Study Contradicts ACC/AHA Recommendation of Chlorthalidone for Hypertension

George Hripcsak, MD

New research from the Columbia University Irving Medical Center is raising questions about whether the guideline-recommended chlorthalidone may not be the safest choice of diuretic for lowering blood pressure.

Results of the comparative study indicated chlorthalidone use did not provide significant cardiovascular benefits but was associated with an increase in serious side effects—including chronic kidney disease (CKD) and electrolyte abnormalities—when compared to hydrochlorothiazide.

"Doctors prescribing chlorthalidone should monitor for certain side effects in their patients," said lead investigator George Hripcsak, MD, MS, chair and professor of Biomedical Informatics at Columbia University Vagelos College of Physicians and Surgeons, in a statement. “The difference in the occurrence of side effects was striking. Hypokalemia, hyponatremia, chronic and acute kidney problems, along with other electrolyte imbalances, are all potentially dangerous side effects."

While the 2017 American College of Cardiology/American Heart Association hypertension guideline-recommended chlorthalidone as a first-line treatment, previous studies have associated the diuretic with increased side effects and no large-scale randomized trials had ever compared it with hydrochlorothiazide—the most commonly prescribed treatment in the thiazide class. With this in mind, Hripcsak and a team of colleagues conducted a study with the intent of comparing the safety and effectiveness of the therapies in real-world practice.

The Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) study was designed as a retrospective, observational, comparative cohort study. Using data from an Observational Health Data Sciences and Informatics (OHDSI) initiative, which included data from the MarketScan Commercial Claims and Encounters database, the Clinformatics Data Mart Database, and the Medicare claims database, investigators obtained 17 years of information on a cohort of 730,255 individuals for their analyses.

In regard to effectiveness, the primary outcomes of the trial were hospitalization for acute myocardial infarction (MI), heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease (CVD) outcome, which included the first 3 outcomes and sudden cardiac death. A total of 51 prespecified safety outcomes were selected by investigators, including hepatic failure, hypotension, hyperkalemia, anaphylactoid reactions, gout, CKD, acute renal failure and type 2 diabetes mellitus.

Of the 730,255 included in the study, 36,918 were dispensed or prescribed chlorthalidone and 693,337 were dispensed or prescribed hydrochlorothiazide. Of note, 149 composite outcome events occurred in the chlorthalidone group compared to 3089 in the hydrochlorothiazide group (HR 1.00; 95% CI, 0.85-1.17).

When examining safety outcomes, results indicated chlorthalidone was associated with an increases risk of hypokalemia (HR, 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), CKD (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Conversely, chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain compared to hydrochlorothiazide (HR, 0.73; 95% CI, 0.61-0.86).

Using the results of their study and previous observational studies as their basis, investigators wrote they do not support the use of chlorthalidone over hydrochlorothiazide. Furthermore, Hripcsak added the results have spurred the creation of an ongoing randomized, clinical trial comparing conducted by the Veterans Affairs Office of Research and Development to shed further light on the topic.

"Until we have more studies directly comparing the two diuretics, we don't really know whether the risk of the side effects seen in observational studies outweighs the potential cardiovascular benefits," Hripcsak said.

Investigators noted limitations within their study, including the possibility of residual confounding by indication, differences in physician characteristics, concomitant use of other drugs after index date, differences in blood pressure measurement error, and formative censoring. However, investigators noted the use of newer methods to account for bias and detect residual bias.

This study, “Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension,” is published in JAMA Internal Medicine.