Darusentan: An effective endothelin_A receptor antagonist for treatment of hypertension

Background: The antihypertensive efficacy and safety of darusentan, a new selective endothelin_A antagonist was investigated. Methods: In a multicenter randomized, double-blind, parallel-group, dose-response study, a 2-week placebo run-in period was followed by a 6-week treatment period and then a 2-week placebo withdrawal period. At baseline before darusentan therapy, the average blood pressure (BP) of the patient population studied was diastolic 103.49 (SD 3.55) and systolic 168.27 (SD 16.63) mm Hg. In total, 392 patients were randomized (darusentan 10 mg: 94 patients, 30 mg: 103 patients, 100 mg: 96 patients, placebo: 99 patients). Results: Darusentan significantly reduced diastolic (mean difference to placebo: 10 mg: -3.7 mm Hg, 95% confidence interval (CI): -6.6, -0.9, P =. 009; 30 mg: -4.9 mm Hg, 95% CI: -7.7, -2.2, P =. 0005; 100 mg: -8.3 mm Hg, 95% CI: -11.1, -5.5, P =. 0001) and systolic BP (mean difference to placebo: 10 mg: -6.0 mm Hg, 95% CI: -11.0, -0.9, P =. 02; 30 mg: -7.3 mm Hg, 95% CI: -12.3, -2.4, P =. 004; 100 mg: -11.3 mm Hg, 95% CI: -16.3, -6.2, P =. 0001). Pulse rate remained unchanged in all groups. There was a trend toward more adverse events in the active treatment groups (placebo: 30.3%, 10 mg: 44.7%, 30 mg: 40.8%, 100 mg: 49.0%). Héadache was the most commonly reported adverse event, with no relevant difference among treatments. Flushing and peripheral edema were seen in a dose-dependent fashion in the active treatment groups only. Conclusion: These data, the first, suggest the therapeutic benefit of selective endothelin_A receptor antagonism in human hypertension.