By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration (FDA) has approved a first-in-class endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled with other antihypertensives. Aprocitentan inhibits the binding of endothelin-1 (ET-1) to ETA and ETB receptors.1 It has the same chemical structure as the metabolite of macitentan, which is approved for treating pulmonary arterial hypertension.2 Endothelin receptor antagonists currently are approved for pulmonary arterial hypertension (bosentan, ambrisentan, and macitentan) and primary immunoglobulin A nephropathy (sparsentan). Aprocitentan was given an orphan designation and is distributed by Idorsia Pharmaceutical U.S. Inc as Tryvio.
Indications
Aprocitentan is indicated for the treatment of hypertension in combination with other antihypertensive drugs to lower blood pressure in adults who are not adequately controlled on other drugs.1
Dosage
The recommended dose is 12.5 mg orally once daily.1 It may be taken with or without food. It is available as 12.5-mg tablets through the TRYVIO REMS restrictive distribution program.
Potential Advantages
Aprocitentan provides an option with a different mechanism of action for reducing blood pressure — by inhibiting the binding of ET-1 to ETA and ETB receptors. ET-1 mediates a variety of deleterious effects, such as vasoconstriction, fibrosis, cell proliferation, and inflammation and is implicated in the pathogenesis of hypertension. Aprocitentan has been shown to reduce blood pressure when added to regimen of amlodipine/valsartan/diuretic ± a beta blocker.1,2 Its blood pressure-lowering effect appeared consistent among subgroups defined by age, sex, race, body mass index, baseline estimated glomerular filtration rate, baseline urine albumin-to-creatinine ratio, and history of diabetes.2
Potential Disadvantages
Aprocitentan is embryo-fetal toxic.1 It is contraindicated for use in patients who are pregnant. An acceptable contraceptive method should be initiated prior to treatment, during treatment, and for one month after discontinuation (final dose). Aprocitentan should be discontinued if pregnancy is detected. To reduce the risk of hepatotoxicity, serum aminotransferase levels and total bilirubin should be assessed prior to treatment initiation and repeated periodically and as clinically indicated.1 Most common adverse reactions reported (vs. placebo) are edema/fluid retention (9.1% vs. 2.1%) and anemia (decrease in hemoglobin and hematocrit) (3.7% vs. 0%). The most common adverse reactions were mild-to-moderate edema or fluid retention (9% vs. 2% for placebo).3 Similar to other agents in the class, aprocitentan may have an adverse effect on spermatogenesis.1
Comments
The efficacy of aprocitentan was evaluated in a phase 3, blinded, randomized, parallel group study in subjects with resistant hypertension (RH) (PRECISION).1,3 RH was defined as sitting systolic blood pressure of ≥ 140 mmHg on standardized background therapy of three antihypertensive drugs, including a diuretic. In
phase 1, all subjects were switched to standard background antihypertensive therapy consisting of amlodipine, valsartan, and hydrochlorothiazide. Patients on beta blockers continued their treatment throughout the study.
Following a placebo-run period, subjects were allocated to aprocitentan 12.5 mg (n = 243), 25 mg (n = 243), or placebo (n = 244), for four weeks. All subjects
(n = 704) then received aprocitentan 25 mg for 32 weeks after which they were re-randomization to remain on aprocitentan 25 mg (n = 307) or placebo (n = 307) for 12 weeks.
The primary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline (week 36) to week 40. A secondary endpoint was 24-hour ambulatory blood pressure change. Mean difference (vs. placebo) changes in systolic blood pressure at four weeks were -3.8 mmHg (97.5% confidence interval [CI], -6.8, -0.8; P = 0.0043) for the 12.5-mg dose and -3.7 mm Hg (CI -6.6, -0.7; P = 0.0054) for the 25-mg dose. The respective difference in 24-hour ambulatory systolic blood pressure were -4.2 mmHg and -5.9 mmHg. After four weeks of withdrawal, patients randomized to placebo showed a 5.8-mmHg increase (95% CI, 3.7, 7,9; P < 0.0001) in systolic blood pressure compared to aprocitentan 25 mg. The frequencies of mild-to-moderate edema/fluid retention were 9%, 18%, and 2%, respectively. The FDA only approved the 12.5-mg dose because the 25-mg dose adds little additional efficacy but a higher frequency of adverse reactions (e.g., edema/fluid retention).
Clinical Implications
Approximately 9% of adults in the United States with hypertension met the criteria for resistant hypertension.4 This represents 12.8% of the antihypertensive drug-treated population. Patients with difficult-to-control blood pressure often need several drugs (e.g., ≥ 3) from different pharmacological classes to achieve blood pressure goals.2 A scientific statement from the American Heart Association recommends the following steps for pharmacologic management of RH:5
- optimized 3-drug regimen (renin-angiotensin system blocker, calcium channel blocker, diuretic);
- substitute optimally dosed thiazide diuretic (chlorthalidone or indapamide) for prior diuretic;
- add beta blocker (if heart rate not < 70 beats per minute);
- add hydralazine; and
- substitute minoxidil for hydralazine
Because of aprocitentan’s safety profile, it is not a first-line agent, but it offers a novel mechanism of action and may fill a therapeutic gap for patients with RH. The cost for aprocitentan is $775 for a 30-day supply.
References
- Tryvio Prescribing Information. Idorsia Pharmaceuticals US Inc. March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217686s000lbl.pdf
- Center for Drug Evaluation and Research. Application number: 217686Orig1s000 integrated review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217686Orig1s000IntegratedR.pdf
- Schlaich MP, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 2022;400:1927-1937.
- Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension 2011;57:1076-1080.
- Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: Detection, evaluation, and management: A scientific statement from the American Heart Association. Hypertension 2018;72:e53-e90.
The U.S. Food and Drug Administration (FDA) has approved a first-in-class endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled with other antihypertensives.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content