- Despite the many drug classes available to treat hypertension, the prevalence of resistant hypertension (hypertension requiring at least 3 blood pressure medications of different classes) points to significant pathways not yet explored or addressed by current therapeutics
- Dual endothelin receptor antagonist (ERA), aprocitentan, offers a new pathway to the treatment of hypertension, pertinent to those prone to developing resistant hypertension including Black patients, patients with obesity or obstructive sleep apnea
- Aprocitentan lowered both office and 24-hour ambulatory blood pressures compared to placebo after 4 weeks of treatment, maintaining its effect over 48 weeks. It was, however, associated with fluid retention/edema which was clinically manageable with diuretic therapy.
Resistant hypertension, defined as hypertension requiring at least 3 blood pressure medications of different classes, carries with it significant cardiovascular risk and poses a challenge to providers and patients alike. Aprocitentan is a new dual endothelin receptor antagonist targeting both endothelin A and B receptors implicated in the pathogenesis of resistant hypertension. No therapeutic currently exists that can block this pathway and thus aprocitentan opens a new window for the treatment of particular subgroups prone to developing resistant hypertension including Black patients, patients with obesity or obstructive sleep apnea. In a breaking presentation today at the 2022 AHA Conference, Dr. Markus Schlaich (University of Western Australia, Perth, Australia) and his team presented their study: “Sustained Blood Pressure Lowering Effect with the Dual Endothelin Receptor Antagonist Aprocitentan in Resistant Hypertension: Results from a Randomized, Controlled Study Including a Withdrawal Phase”, or the PRECISION trial.
The PRECISION study was a randomized, multicenter phase 3 trial with a withdrawal phase which evaluated the blood pressure lowering effect and safety of aprocitentan in those high blood pressure despite being on a stable regimen of antihypertensive medications. For patients to be included in the study, they had to have a sitting SBP≥140 mmHg and be on at least 3 antihypertensive agents of different classes for at least 4 weeks before being switched to a standardized regimen of antihypertensives for 1 week. Important exclusion criteria included severe hypertension (sitting systolic BP≥180/110 mm Hg measured at two points), pregnancy, apparent/pseudo resistant HTN (white coat effect, medical inertia, poor adherence, secondary causes of HTN except OSA), major cardiovascular, renal, cerebrovascular medical complications in the past 6 months or NYHA stage III-IV heart failure, or severe renal insufficiency. Once in the study, patients were randomized to one of three initial trial arms for 4 weeks which included either placebo or one of two aprocitentan dosage arms (12.5 mg or 25 mg); each arm was then treated with the study medication for 32 weeks at 25 mg before being randomized again to either a withdrawal period or aprocitentan continuation to shed light on withdrawal effects. A follow up safety period of 30 days followed. A total of 730 patients were enrolled into the study, with equal proportions in each of the three study arms. Patient demographics were evenly distributed across groups with an average age of 61 years, about 40% female, 11-12% Black patients, and also had similar levels of comorbidities including eGFR of 19-23% with similar levels of micro/macroalbuminuria, more than half having diabetes, and greater than 20% with a diagnosis of heart failure.
The primary outcome investigated was the change from baseline to week 4 in mean trough sitting systolic blood pressure measured by ambulatory office blood pressure monitor. The study found a significant difference in blood pressures in the groups taking aprocitentan at 4 weeks as assessed by least square mean change in both the 12.5 mg group (-15.3 mm Hg (SE 0.9)), and the 25 mg group (–15.2 (0.9) mm Hg) for a difference versus placebo of –3.8 (1.3) mm Hg (97.5% CI –6.8 to –0.8, p=0·0042) and –3.7 (1.3) mm Hg (–6.7 to –0.8; p=0.0046), respectively. Similarly, the respective difference for 24-hour ambulatory systolic blood pressure was –4.2 mm Hg (95% CI –6.2 to –2.1) and –5.9 mm Hg (–7.9 to –3.8). Importantly, there was a significant increase in blood pressures of the withdrawal group, those patients who were randomized to placebo, compared to those who stayed on aprocitentan (5.8 mm Hg, 95% CI 3.7 to 7.9, p<0·0001). Investigators noted fluid retention as the most frequent adverse event and added that this could be addressed with uptitration or addition of a diuretic; it is worthwhile to note that this event led to stopping the drug in seven patients.
Primary investigator Dr. Markus Schlaich concluded the presentation highlighting that aprocitentan “successfully met both primary and secondary outcomes”, significantly lowering both office and 24-hour ambulatory blood pressures compared to placebo, adding that this effect was maintained over 48 weeks. In a remarkable series of trials presented in the last day of AHA 2022, the future of aprocitentan and other dual ET antagonists in the battle against resistant hypertension remains bright for provider and patient alike.