1. Compared to placebo, participants on aprocitentan had a greater reduction in office systolic blood pressure at four weeks and this was sustained for a total of 40 weeks.
2. The most common adverse effect of aprocitentan was fluid retention and edema.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Hypertension is a common medical condition that increases the risk of cardiovascular disease. While there exist numerous classes of antihypertensive drugs, there are cases of resistant hypertension in which blood pressure remains suboptimally controlled on three or more antihypertensives. This study, PRECISION, was a phase 3 randomized control trial that evaluated the safety and efficacy of a dual endothelin antagonist, aprocitentan, for the treatment of resistant hypertension. This study was broken down into three parts. In part one, patients were randomized to either a low dose or a higher dose of aprocitentan or to a placebo. The second part of the study treated all participants with the higher dose of aprocitentan for 32 weeks. The third part of the study was a double-blind withdrawal, where half of the participants received a placebo and half remained on aprocitentan for 12 weeks. Study results showed that aprocitentan was more effective at lowering blood pressure at four weeks compared to placebo. In the withdrawal study, blood pressure significantly increased in the placebo group compared to those that remained on aprocitentan. The most common adverse effect was mild-to-moderate fluid retention, which occurred in approximately one-fifth of those on the highest dose of aprocitentan. Limitations of this study include the inability to evaluate the use of other medications, such as thiazide diuretics, to manage fluid retention as an adverse effect. Nonetheless, this study provides strong evidence to support the use of an endothelin antagonist for the treatment of resistant hypertension.
Click to read the study in the Lancet
Relevant Reading: Randomized dose-response study of the new dual endothelin receptor antagonist aprocitentan in hypertension.
In-Depth [randomized controlled trial]: PRECISION was a randomized phase 3 study which enrolled participants with a history of uncontrolled office blood pressure (systolic BP of 140 mm Hg or higher) despite taking at least three anti-hypertensive medications, with at least one diuretic. All patients were switched to the same background therapy of a triple-combination pill with amlodipine, valsartan, and hydrochlorothiazide at the maximally tolerated standardized background therapy dose. A total of 730 participants were randomized 1:1:1 to either aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo for 4 weeks in the first part of the study. A total of 704 individuals that completed the previous treatment (96%) went onto part 2 and received aprocitentan 25 mg for 32 weeks. In the double-blind withdrawal, a total of 613 individuals from the previous treatment (87%) were re-randomized to either placebo or aprocitentan 25 mg for 12 weeks.
The primary outcome was a change in office systolic blood pressure from baseline. The change in office systolic blood pressure at four weeks following part 1 of treatment was -15.3 mm Hg for aprocitentan 12.5 mg, -15.2 for aprocitentan 25 mg, and -11.5 mm Hg for placebo (p=0.0042 for aprocitentan 12.5 vs. placebo and p=0.0046 for aprocitentan 25 mg vs placebo). After part 3 (withdrawal), the change in office blood pressure significantly increased with placebo a total of +5.8 mm Hg (p<0.0001) versus aprocitentan 25 mg. The most frequent adverse event was edema or fluid retention, which was present in 9% of the 12.5 mg group, 18% of the 25 mg group, and 2% of the placebo group.
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