New Kid on the Block: Aprocitentan for the Treatment of Difficult-to-Treat Hypertension

Lilian White, MD
Posted on August 26, 2024

Approximately 30% to 40% of adults in the United States are diagnosed with hypertension. Hypertension is among the key modifiable risk factors for cardiovascular disease, making it not only a common but also valuable condition to treat. A recent AFP review article, Hypertension in Adults, outlines current methods for the diagnosis and management of hypertension. The AAFP guideline on the treatment of hypertension strongly recommends a goal blood pressure of < 140/90 in adults to reduce the risk of all-cause and cardiovascular mortality. A treatment goal of < 135/85 to reduce the risk of myocardial infarction may also be considered based on patient preferences and values.

In March 2024, the U.S. Food and Drug Administration approved aprocitentan (Tryvio) as an adjunctive treatment for patients who continue to have an overall blood pressure above goal despite combination therapy with at least three antihypertensive medications. This approval is significant because aprocitentan uses a unique mechanism of action, making it the first novel medication mechanism for the treatment of hypertension in almost 40 years. Aprocitentan is an endothelin receptor antagonist. Endothelin mediates vasoconstriction, inflammation, and fibrosis, among other mechanisms.

Aprocitentan is available in 12.5 mg tablets and has been approved for use only at the 12.5 mg dose. Aprocitentan has a half-life of approximately 41 hours and reaches a steady state by 8 days, which is similar to amlodipine. Aprocitentan is contraindicated during pregnancy because of the risk of teratogenicity. Risk of hepatotoxicity and liver failure is possible with aprocitentan, and it is recommended to monitor liver enzymes before and periodically during treatment. Aprocitentan is also contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Aprocitentan appears to be safe in patients with mild to moderate renal failure but is not recommended in patients on dialysis or with an eGFR < 15 mL per minute. Other adverse effects include fluid retention, reduced spermatogenesis, and reduced hemoglobin/hematocrit. It is not currently recommended for use in children.

Aprocitentan appears to be a promising new addition to the medication management of hypertension; however, the narrow indication for using aprocitentan for patients who are not at goal with three antihypertensive medications makes its application limited. Although a clinical trial demonstrated that aprocitentan may be useful as monotherapy, the medication was specifically developed and studied to treat resistant hypertension. Additionally, the medication was found to be statistically significant in lowering blood pressure (reducing systolic blood pressure by about 15 mmHg). The clinical significance of this change is questionable when the placebo in the study reduced blood pressure by approximately 11 mmHg. Aprocitentan is available for use only through a restricted distribution program because of its teratogenicity, further limiting its use.