Hripcsak G, Suchard MA, Shea S, et al. - This study was intended to correlate the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in the real-world practice. Researchers conducted a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning between January 2001 and December 2018. The study population consisted of 730,225 individuals (mean [SD] age, 51.5 [13.3] years; 450,100 women [61.6%]), 36,918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693,337 were dispensed or prescribed hydrochlorothiazide and had 3,089 composite outcome events. Compared with hydrochlorothiazide, chlorthalidone use was not correlated with significant cardiovascular advantages, while its use was correlated with a greater risk of renal and electrolyte abnormalities.