Chlorthalidone versus hydrochlorothiazide for preventing cardiovascular disease in hypertension: Is the case closed?

The optimal diuretic choice [hydrochlorothiazide (HCTZ) or chlorthalidone (CTD)] for the management of hypertension has been an ongoing debate for several years. HCTZ is widely used in the form of single-pill combinations, whereas CTD is a more potent drug vs. HCTZ, especially in reducing nighttime blood pressure (BP), with some indirect evidence suggesting a superiority in terms of cardiovascular (CV) risk reduction. In addition, recent data showed that CTD was safe and effective in terms of BP lowering in predialysis patients with stage 4 chronic kidney disease. The Diuretic Comparison Project was the first head-to-head pragmatic, open-label trial that randomly assigned elderly patients with hypertension under HCTZ therapy to continue with HCTZ or to switch to CTD (equivalent doses). Office BP was similar for both groups throughout the study. The trial showed no difference in major CV events or non-cancer-related deaths during a median follow-up of 2.4 years; yet, CTD was associated with a benefit in participants with a previous myocardial infarction or stroke, which might be a chance finding but could also indicate that a high-risk population is more suitable for revealing the impact of slight differences in the 24-hour BP profile in a relatively short-term follow-up. Interestingly CTD vs. HCTZ was associated with higher hypokalemia rates apart from the latter group of patients where there was no difference. Overall, the available data do not confirm the superiority of CTD over HCTZ in general, but this could be questionable in selected patients.