Aprocitentan in Resistant Hypertension: Mechanistic Insights, Clinical Evidence, and Future Directions

Resistant Hypertension is a significant clinical problem. It is found in the most of individuals who, even with the greatest multi-drug therapy, are not able to manage their blood pressure. A new dual endothelin receptor antagonist (ERA) called aprocitentan (Aprocitirom) inhibits both ETA and ETB receptors. It has emerged as a potentially useful treatment for such patients. This review article considers Aprocitentan's pharmacological profile, preclinical development, clinical efficacy, and potential. Preclinical experiments revealed that Aprocitentan possesses vasodilatory, anti-inflammatory, & anti-fibrotic activities. It is also well absorbed from the gastrointestinal tract and safe in various species. The Phase I trials reinforced that it is well tolerated and can be administered once daily. In Phase II trials, Aprocitentan induced dose-proportional reductions in systolic and diastolic blood pressure in patients with resistant hypertension. The critical Phase III PRECISION trial also validated its efficacy. It showed impressive and sustained decreases in blood pressure, with a favorable safety profile and low hepatotoxicity, and minimal fluid retention. An important step forward in the treatment of ERA has come with the FDA and EMA approval of aprocetentan in resistant hypertension. Its metabolism, which is not dependent on CYP enzymes, adds to its therapeutic applications and minimizes the likelihood of drug interactions. Subgroup analysis and further real-world studies indicate further benefits in patients with metabolic disorders and chronic kidney disease. Aprocitentan could potentially prove useful in the future for vascular disease, heart failure, and diabetic nephropathy. Clarifying its potential role in the future to treat hypertension and cardiorenal disease will only be discernible through longer-term trials on cardiovascular endpoints and cost-effectiveness.