Chlorthalidone vs. Hydrochlorothiazide to Treat Hypertension

Study Questions:

Is hydrochlorothiazide (HCTZ) as effective and safe compared to chlorthalidone as a first-line therapy for hypertension?


Data from the LEGEND (Large-Scale Evidence Generation and Evaluation in a Network of Databases) observational comparative cohort study were used for the present analysis. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on two administrative claims databases and one collection of electronic health records were analyzed. The exposures of interest were use of chlorthalidone and HCTZ. The primary outcomes were acute myocardial infarction (AMI), hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first three outcomes and sudden cardiac death. Secondary outcomes included 51 safety outcomes. Propensity scoring was used to estimate treatment exposure probability; Cox proportional models were used to compare the two thiazide diuretics accounting for time on therapy and censoring.


A total of 730,225 adults (mean age 51.5 years, 450,100 women [61.6%]) were included in the present analysis, of which 36,918 were dispensed or prescribed chlorthalidone and 693,337 were dispensed or prescribed HCTZ. Among the chlorthalidone group, 149 composite events were identified. Among those in the HCTZ group, 3,089 composite events were identified. No significant difference was found in the associated risk for AMI, hospitalized heart failure, or stroke. The composite outcome of AMI, hospitalization for heart failure, ischemic or hemorrhagic stroke, and sudden cardiac death was also not significant (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.85-1.17). Chlorthalidone was associated with a significantly higher 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), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86). When time at risk was shifted to starting at 91 days after first drug exposure, the results were similar. When baseline blood pressure was included in the models, the resuits were also similar.


The investigators concluded that chlorthalidone use was not associated with significant cardiovascular benefits when compared with HCTZ, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone versus HCTZ for hypertension treatment in first-time users.


Although not a randomized controlled design, these real-world data suggest that preferences for chlorthalidone for a thiazide diuretic may be in question. Particularly given that higher adverse effects observed in this study were associated with chlorthalidone as compared to HCTZ, such a randomized clinical trial is warranted.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, SCD/Ventricular Arrhythmias, Statins, Acute Heart Failure, Hypertension

Keywords: Acute Coronary Syndrome, Acute Kidney Injury, Antihypertensive Agents, Blood Pressure, Chlorthalidone, Death, Sudden, Cardiac, Diabetes Mellitus, Type 2, Diuretics, Electrolytes, Electronic Health Records, Heart Failure, Hydrochlorothiazide, Hypertension, Hypokalemia, Hyponatremia, Myocardial Infarction, Primary Prevention, Renal Insufficiency, Chronic, Sodium Chloride Symporter Inhibitors, Stroke, Weight Gain

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