Abstract P438: Is aprocitentan also sympatholytic in patients with resistant hypertension?

Abstract

Background: Aprocitentan is an endothelin ET A /ET B receptor antagonist (ERA) approved for the treatment of hypertension not adequately controlled on other drugs. Resistant hypertension is associated with sympathetic activation. The insufficient blood pressure (BP) lowering of many patients at night (non-dipping) and an often-increased heart rate are signs of sympathetic activation. Because ET A and ET B receptors participate in adrenaline and noradrenaline release and dual ERAs have been shown to decrease catecholamines, we hypothesized that aprocitentan might, among the various effects of dual blockade, behave as a sympathetic inhibitor. To assess this hypothesis, we investigated the effect of aprocitentan on nighttime BP and heart rate, both influenced by the sympathetic system. Methods: In the PRECISION study, where enrolled subjects were still hypertensive despite being on a standard fixed-dose background combination therapy composed of amlodipine, valsartan and hydrochlorothiazide, 730 patients were randomized to receive aprocitentan 12.5 mg, 25 mg or placebo for the first 4 weeks (double-blind placebo-controlled phase). 24-hour ambulatory BP monitoring (ABPM) was recorded in all randomized patients at baseline and Week 4. Results: At baseline, 60% of patients were non-dippers at night . Among those, 25%, 39% and 37% were reverted to dippers in the placebo, aprocitentan 12.5 and 25 mg groups, respectively, at Week 4. Accordingly, aprocitentan 12.5 mg and 25 mg decreased nighttime BP by -8.1 and -11 mmHg, respectively, vs -2.6 mmHg on placebo at Week 4. This reduction in nighttime BP by aprocitentan was larger than the reduction in daytime BP (-6.2 and -7.8 mmHg decrease at 12.5 and 25 mg, respectively, vs -2.3 mmHg on placebo). At baseline, mean heart rate, measured by office BP measurement at trough, was 74 beats/min. At Week 4, aprocitentan 12.5 mg and 25 mg, despite the respective 15.3 and 15.5 mmHg reduction of office BP from baseline, did not increase heart rate (-3.3 and -2.6 beats/min at 12.5 and 25 mg, respectively, versus -2.7 beats/min on placebo). Conclusion: We conclude that, by blocking ET A and ET B receptors, aprocitentan may have downstream sympatholytic effects, which may help its efficacy on nighttime BP – a prognostic factor for CV events in hypertension – and allow marked BP lowering without any reactive tachycardia.