Comparative Effectiveness of Chlorthalidone Versus Hydrochlorothiazide and Dose–Response of Amiloride on Blood Pressure and Biochemical Parameters

Background Diuretics are widely used alone or in combination with other medications to lower blood pressure (BP). The dosing ratio between hydrochlorothiazide and chlorthalidone for lowering BP, as well as the effects of different amiloride doses on BP and their ability to counteract thiazide's adverse metabolic effects, remain unclear. Methods In a factorial superiority randomized clinical trial with blinded participants and investigators, we compared the effects of chlorthalidone 25 mg with hydrochlorothiazide 50 mg and amiloride 5 mg with 10 mg on BP measured by office and ambulatory BP monitoring and laboratory parameters. Patients were followed for 12 weeks. Results The treatments showed no statistically significant interaction; comparisons were evaluated separately. Hydrochlorothiazide and chlorthalidone had similar effects on systolic and diastolic BP measured at the office and by ambulatory BP monitoring. The between‐group δs (hydrochlorothiazide minus chlorthalidone) for systolic 24‐hour and nighttime BP were −1.1 (95% CI, −8.0 to 5.9; P =0.8), and −2.3 (95% CI, −10.3 to 5.7; P =0.6), respectively. The effects of amiloride 5 mg and 10 mg on BP were similar. Laboratory parameters did not differ between hydrochlorothiazide and chlorthalidone. Comparing amiloride doses, serum sodium decreased more with 10 mg, while the remaining parameters were similar between doses. Conclusions Chlorthalidone and hydrochlorothiazide, administered at a 1:2 dosing ratio, show similar effects on BP and laboratory parameters. Amiloride 5 and 10 mg show similar effects on BP and most metabolic parameters, with no clear dose–response relationship, suggesting that any independent BP‐lowering effect of amiloride is, at best, weak. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT03928145.