Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan

Abstract

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel-group Phase 3 study and its three-part design assesses the short-term and sustained long-term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single-tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo run-in period. The 4-week placebo run-in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4-week double-blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32-week single-blind part with aprocitentan 25 mg; and (3) a 12-week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

Keywords: aprocitentan; blood pressure; endothelin receptor antagonist; pseudoresistant hypertension.

Conflict of interest statement

Parisa Danaietash, Pierre Verweij, and Marc Bellet are employees of Idorsia Pharmaceuticals Ltd. Ji‐Guang Wang has received lecture and consulting fees from Novartis, Omron and Viatris. George Dresser has received lecture fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Medtronic, Pfizer, and Servier. Ilkka Kantola has received lecture, travel, and consulting fees from Amicus, Chiesi, Bayer, Boehringer‐Ingelheim, Sanofi‐Genzyme and Takeda‐Shire. Mary Katherine Lawrence has received funding to perform clinical trials for Idorsia. Krzysztof Narkiewicz has received lecture and consulting fees from Berlin‐Chemie/Menarini, Egis, Gedeon Richter, Krka, Medtronic, Merck, Polpharma, Recordati, Sandoz and Servier. Markus Schlaich has received lecture fees and consulting fees from Medtronic, Abbot, Merck, Boehringer Ingelheim, Servier, ReCor and has been supported by an NHMRC Senior Research Fellowship.

© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.

Figures

FIGURE 1

PRECISION study design

FIGURE 2

Patient disposition. *From different pharmacological classes for at least 4 weeks before screening. †Laboratory values out of accepted ranges included: alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal, hemoglobin <100 g/L, estimated glomerular filtration rate <15 mL/min/1.73 m2, N‐terminal pro‐brain natiuretic peptide ≥500 pg/ml. ‡Causes for exclusion/non‐inclusion reported under 'other' relate to the inclusion/exclusion criteria provided in Tables S1–S3 in the Data Supplement. More than one cause of inclusion failure may apply per patient. BP indicates blood pressure

FIGURE 3

Main individual antihypertensive therapies of randomized participants at screening. ACEIs indicates angiotensin‐converting enzyme inhibitors; ARBs: angiotensin receptor blockers; RD renal denervation; MRAs: mineralocorticoid receptor antagonists

FIGURE 4

Illustration of the blood pressure lowering effect associated with study design (n: patients with assessments). SBT indicates standard background therapy; SiSBP: sitting systolic blood pressure