LEGEND Study: An Effectiveness and Safety Comparison of Chlorthalidone and Hydrochlorothiazide

LEGEND Study: An Effectiveness and Safety Comparison of Chlorthalidone and Hydrochlorothiazide
Kylea Larsen, Pharm.D., Coborn’s Pharmacy | Little Falls Family Medical Center

Background: Chlorthalidone and hydrochlorothiazide are classified as thiazide/thiazide-type diuretics. These medications work by inhibiting the reabsorption of sodium in the kidneys and are first-line treatment options for hypertension according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines. While hydrochlorothiazide is the most commonly prescribed thiazide/thiazide-type diuretic, the 2017 ACC/AHA hypertension guidelines include a statement that chlorthalidone is preferred. This statement is based on the fact that chlorthalidone has a longer half-life and has shown a reduction of cardiovascular disease in previous meta-analyses. Prior to this study from Hripcsak et al., there were no large randomized clinical trials available that directly compared chlorthalidone and hydrochlorothiazide. 

Objective: The objective of this study was to evaluate and compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide for use as first-line treatment options for hypertension in treatment-naïve patients.

Study Design: This study is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) retrospective, observational, comparative, controlled cohort study. Data from three Observational Health Data Sciences and Informatics (OHDSI) databases in the United States was collected from January 2001 to December 2018. Individuals starting chlorthalidone or hydrochlorothiazide at any dose for first-line treatment of hypertension were included in the study. Patients were included if they had a diagnosis of hypertension on or before the index time, which was defined as the first exposure to either treatment medication. Patients were excluded if they had previous exposure to any hypertension treatments prior to the index time. A total of 36,918 patients received chlorthalidone and 693,337 patients received hydrochlorothiazide. Baseline covariates between the two treatment groups were adjusted for with propensity score stratification. The primary efficacy outcomes included acute myocardial infarction (MI), hospitalization for heart failure, stroke, and a composite cardiovascular disease outcome that included the first three primary outcomes plus sudden cardiac death. This study evaluated 51 secondary safety outcomes, including electrolyte imbalances and renal abnormalities.

Results: There were no statistically significant differences found between chlorthalidone and hydrochlorothiazide at any of the primary endpoints using an on-treatment analysis. The hazard ratios for all endpoints were reported as calibrated hazard ratios. The composite primary endpoint occurred in 149 out of 36,628 patients receiving chlorthalidone and 3,089 out of 687,106 patients receiving hydrochlorothiazide (HR 1.00 [95% CI 0.85-1.17]). The hazard ratios for occurrence of acute MI, hospitalization for heart failure, and stroke were 0.92 [95% CI 0.64-1.31], 1.05 [95% CI 0.82-1.34], and 1.10 [95% CI 0.86-1.41] respectively. While no significant differences were found in the primary outcomes, there were some statistically significant differences in the secondary safety outcomes. Chlorthalidone was found to have an increased risk of hypokalemia (HR 2.72 [95% CI 2.38-3.12]), increased risk of hyponatremia (HR 1.31 [95% CI 1.16-1.47]), increased risk of acute renal failure (HR 1.37 [95% CI 1.15-1.63]), increased risk of chronic kidney disease (HR 1.24 [95% CI 1.09-1.42]), increased risk of type 2 diabetes mellitus (HR 1.21 [95% CI 1.12-1.30]), and decreased risk of abnormal weight gain (HR 0.73 [95% CI 0.61-0.86]).

Conclusion: The results of this study do not support the use of chlorthalidone over hydrochlorothiazide for first-line use in treatment-naïve patients with hypertension. Chlorthalidone did not show statistically significant cardiovascular benefits when compared to hydrochlorothiazide, but it was associated with significantly greater risk of electrolyte and renal abnormalities than hydrochlorothiazide.

Key Point: The use of chlorthalidone as a first-line treatment for hypertension in patients who are treatment-naïve may not be preferred over hydrochlorothiazide based on the results of this study. This contradicts the 2017 ACC/AHA hypertension guidelines, which state that chlorthalidone is preferred.


  1. Hripcsak G, Suchard MA, Shea S, et al. Comparison Of Cardiovascular And Safety Outcomes Of Chlorthalidone Vs Hydrochlorothiazide To Treat Hypertension. JAMA Intern Med. 2020;180(4):542-551.