COMPARATIVE CARDIOVASCULAR OUTCOMES OF CHLORTHALIDONE VERSUS HYDROCHLOROTHIAZIDE IN HYPERTENSIVE PATIENTS: A MULTICENTER RETROSPECTIVE COHORT STUDY WITH SUBGROUP ANALYSIS

Objective: To evaluate cardiovascular outcomes between chlorthalidone and hydrochlorothiazide in hypertensive patients, with particular focus on differential effects across various patient subgroups. Design and method: This multicenter retrospective cohort study analyzed data from 14,257 hypertensive patients (1,920 chlorthalidone users and 12,337 hydrochlorothiazide users) using electronic health records from three tertiary hospitals in South Korea. After 1:1 propensity score matching, 1,606 pairs were analyzed for cardiovascular outcomes and safety profiles. Comprehensive subgroup analyses were performed based on age, sex, socioeconomic status, lifestyle factors, and comorbidities. Results: The average age was 61.8 ± 14.6 years in the chlorthalidone group, with 59.3% being male. The 3-year major adverse cardiovascular events occurred in 1.2% of the chlorthalidone group versus 1.4% of the hydrochlorothiazide group (hazard ratio 0.91, p = 0.77). Cardiovascular mortality was 0.2% in both groups (p = 0.92), and myocardial infarction occurred in 0.3% of chlorthalidone users versus 0.4% of hydrochlorothiazide users (p = 0.65). Subgroup analyses revealed varying effects: patients older than 65 years showed a trend toward benefit with chlorthalidone (HR 0.72, 95% CI 0.35-1.49), while those with prior heart failure demonstrated the most pronounced effect (HR 0.32, 95% CI 0.07-1.60). Hyperkalemia was significantly less frequent in the chlorthalidone group (12.4%) compared to the hydrochlorothiazide group (17.7%, p < 0.001), while hypokalemia rates were comparable (19.2% vs 16.7%, p = 0.07). Conclusions: While chlorthalidone and hydrochlorothiazide demonstrated comparable overall cardiovascular outcomes in the general hypertensive population, specific subgroups showed differential responses. The safety profiles were comparable, with distinct effects on potassium homeostasis requiring monitoring in both treatment groups. These findings suggest the importance of individualized thiazide diuretic selection based on patient characteristics and risk factors.