Drug Watch: Aprocitentan for Resistant Hypertension

Educational Objectives

Summary

Drug Watch: Aprocitentan, a Newly Approved Drug for Resistant Hypertension

On March 19, 2024, the U.S. Food and Drug Administration (FDA) approved aprocitentan (Trade name: Tryvio), a new drug for treating patients with resistant hypertension (https://www.hcplive.com/view/fda-approves-aprocitentan-tryvio-for-treatment-resistant-hypertension). As an endothelin-receptor antagonist, the drug blocks the activity of endothelin-1, a vasoconstrictor that is secreted by endothelial cells. According to the manufacturer, aprocitentan is the first oral drug with a novel mechanism of action to be approved to manage systemic hypertension in decades. (Note: Several drugs in this class previously have been approved for managing pulmonary hypertension).

In 2022, NEJM Journal Watch covered the pivotal trial that resulted in aprocitentan’s FDA approval (https://www.jwatch.org/na55640 and Lancet 2022; 400:1927). The study involved 730 patients with office systolic blood pressure (BP) greater than 140 mm Hg despite treatment with at least 3 antihypertensive drugs. At baseline (on background drug therapy), mean office BP was 153/88 mm Hg, and mean 24-hour ambulatory BP was 138/83 mm Hg. Patients were randomized to receive daily oral aprocitentan or placebo, plus a fixed-dose combination of amlodipine, valsartan, and hydrochlorothiazide.

After 4 weeks, mean change in office systolic BP was 15 mm Hg with aprocitentan and 11 mm Hg with placebo; this 4 mm difference was statistically significant. Similar differences between aprocitentan and placebo were found on 24-hour ambulatory monitoring. Fluid retention with edema, the most common side effect, occurred in ≈10% of patients who took the FDA-approved dose of 12.5 mg. During a 32-week extension phase that wasn’t placebo-controlled, the small reduction in mean BP with aprocitentan was maintained; however, that phase exclusively involved a 25-mg dose that ultimately wasn’t approved by the FDA.

According to the official FDA prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217686s000lbl.pdf), aprocitentan is indicated “for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs.” The prescribing information includes a black-box warning regarding embryo–fetal toxicity (based on birth defects in animal studies), and the drug is contraindicated in pregnancy. For this reason, aprocitentan will be available only through a restricted program called REMS (Risk Evaluation and Mitigation Strategy), and physicians will have to be certified to prescribe it.

Having a new antihypertensive medication with a novel mechanism of action is a welcome development, but several issues come to mind:

• Although the average lowering of systolic BP by 4 mm Hg might be clinically important at a population level, its importance at the individual level is less clear. In the large pivotal trial, the large placebo response was striking and demonstrated the importance of placebo-controlled studies.

• Patients in the clinical trial were considered to have resistant hypertension although mean 24-hour ambulatory BP was only 138/83 mm Hg. How would aprocitentan fare in people with more-severe resistant hypertension?

• How would add-on therapy with this drug have compared to add-on therapy with older inexpensive agents such as spironolactone?

• Longer-term data on BP reduction and adverse effects with the approved 12.5-mg dose are needed.

Finally, as of this writing, the company has not yet published the drug’s list price. It surely will be expensive, which will raise questions about incremental cost-effectiveness compared with less-expensive alternatives.

Allan S. Brett, MD

Readings

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Acknowledgements

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