Chlorthalidone versus hydrochlorothiazide: major cardiovascular events, blood pressure, left ventricular mass, and adverse effects

Background: There is continuous debate whether chlorthalidone (CTD) and hydrochlorothiazide (HCTZ) differ in reducing major cardiovascular events (MACE). HCTZ is prescribed 10 times more commonly than CTD. Method: A systematic literature search yielded 14 references, including two network meta-analyses of randomized trials with MACE and left ventricular mass as outcomes. Results: The network meta-analysis of randomized trials showed CTD reducing MACE more than HCTZ, hazard ratio = 0.79 (0.72-0.88), P < 0.0001, and an observational cohort study gave an identical point estimate: hazard ratio = 0.79 (0.68-0.92), P = 0.002. In contrast, two observational cohort studies reported no differences between CTD and HCTZ. However, in the studies showing the superiority of CTD median follow-up was 4.3 and 7.0 years, respectively, whereas in the latter studies showing no difference between the two drugs follow-up was only 0.95 and 0.25 years. As differences in outcomes for MACE in hypertension trials with various interventions only emerge after prolonged (>1 year) therapy, differences in follow-up explain these discrepant results. CTD also more effectively reduced left ventricular mass in observational data and network analysis of trials. These advantages of CTD over HCTZ are consistent with greater reductions in night-time blood pressure, greater reductions in oxidative stress and platelet aggregation, and greater improvements in endothelial function. Conclusion: Over the short-term there were no differences in the net clinical benefit between HCTZ and CTD. However, long-term available data document CTD to be significantly more effective in reducing MACE than HCTZ. The Veterans Administration's trial in progress may provide definitive answer to these questions.