New Therapy for Resistant Hypertension
By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: Aprocitentan demonstrated efficacy for additional therapy beyond standard multidrug treatment in resistant hypertension.
SOURCE: Schlaich M, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomized, parallel-group, phase 3 trial. Lancet 2022;400:1927-1937.
The failure to control high blood pressure (BP) with currently available drugs suggests there are other pathophysiologic pathways for raising blood pressure that are going unaddressed. The endothelin pathway has been implicated in hypertension, but has not been targeted therapeutically. Aprocitentan is an endothelin A and B receptor antagonist with a 44-hour half-life and low drug interaction potential. The authors of PRECISION studied the short-term effect of aprocitentan in patients with resistant hypertension.
PRECISION was a multicenter, blinded, randomized, parallel-group, Phase III study of adding aprocitentan to three other antihypertension drugs from different classes to determine if this technique would lower BP vs. placebo after four weeks of double-blind therapy. The authors also wanted to learn whether any positive effect could be maintained during and after 36 weeks on single-blind therapy.
Investigators measured BP via a standardized, unattended, automated device, then reported the mean of three measurements after a five-minute rest. Before study entry, patients switched from their medications to amlodipine, valsartan, and hydrochlorothiazide at maximally tolerated, fixed doses. If they were taking beta-blockers, those patients could continue taking those drugs. Patients were randomized to adding aprocitentan 12.5 mg/day or 25 mg/day or placebo in a 1:1:1 ratio. The primary outcome was the change in office and ambulatory 24-hour BP at week 4 of therapy. Secondary outcomes included the response to single-blind therapy with 25 mg/day of aprocitentan and from withdrawal of aprocitentan at week 36 until week 40.
Between 2018 and 2022, the authors enrolled 730 patients, 704 of whom completed the four-week, double-blind period; 613 completed the single-blind period, and 577 completed the withdrawal period. The change in office systolic BP (SBP) at four weeks was -15.3 mmHg for 12.5 mg/day, -15.2 mmHg for 25 mg/day of aprocitentan, and -11.5 mmHg for placebo.
The mean difference vs. placebo for 12.5 mg/day was -3.8 mmHg (97.5% CI, -6.8 to -0.8; P < 0.0001) and -3.7 mmHg for 25 mg/day (-6.7 to -0.8; P = 0.0046). The difference in 24-hour ambulatory SBP readings was -4.2 mmHg (95% CI, -6.2 to -2.1) and -5.9 mmHg (-7.9 to -3.8). After withdrawal of aprocitentan, office SBP levels were significantly higher for placebo subjects vs. those taking aprocitentan (5.8 mmHg; 94% CI, 3.7 to 7.9; P < 0.0001). Diastolic BP followed a similar pattern.
The most common adverse event was fluid retention/edema, which occurred in 9% at 12.5 mg/day, 18% at 25 mg/day, and 2% on placebo. Seven patients withdrew from the study. During the study, 11 patients died of causes unrelated to their treatment. The authors concluded that in patients with resistant hypertension, aprocitentan was well tolerated and effective compared to placebo for lowering BP, and had a sustained effect after drug cessation.
After decades of the same drugs for hypertension, it is exciting to see a potential new class of agents, especially for resistant hypertension. The 5 mmHg decrease in SBP levels observed with aprocitentan correlated with a 10% decrease in cardiovascular (CV) events. Also, aprocitentan profoundly affected nocturnal BP levels, which are known to predict adverse CV events.
The withdrawal phase of PRECISION demonstrated a prolonged effect vs. placebo, which is important in the treatment of hypertension because patients often miss doses of their medications. That is especially true if patients must take pills multiple times a day. Another benefit of aprocitentan it that it sustains action for a long duration. The major adverse effect of aprocitentan treatment was fluid retention, which was dose-related. Since the 12.5 mg per day dose was as effective as 25 mg per day, it would seem the lower dose would be preferred to prevent edema. In addition, aprocitentan produced beneficial effects on renal function, especially in patients with poor kidney function. Researchers found albuminuria in 37% of patients in PRECISION at baseline. The urinary albumin creatinine ratio decreased by 28% and 31% in the low dose and high dose groups taking aprocitentan, respectively, but increased 5% for placebo.
There were several strengths to PRECISION. The authors used pill counts to ensure adherence to drug regimens. Researchers included racial and ethnic minorities, who struggle with resistant hypertension. For example, 12% of the study population was Black, which approximates the prevalence in the U.S. population at large. Also, investigators included patients with obesity, sleep apnea, diabetes, coronary disease, and heart failure. In addition, ambulatory BP measurements were conducted and correlated well with office BP measurements. Mineralocorticoid receptor antagonists, such as spironolactone, can be used as a fourth-line therapy in resistant hypertension, but those drugs carry a risk of causing hyperkalemia, which these authors did not see with aprocitentan.
There were weaknesses to the PRECISION study. Researchers did not use maximum doses of standard therapy. Further, they did not employ more potent diuretics, such as chlorthalidone. The bulk of the study time was single-blinded, which could have induced biases. However, this is an encouraging Phase III study that raises the hope that a new class of drugs for resistant hypertension may be just around the corner.
Aprocitentan demonstrated efficacy for additional therapy beyond standard multidrug treatment in resistant hypertension.
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