Aprocitentan in resistant hypertension
Since the 1960s, modern studies of hypertension and the availability of antihypertensive drugs have significantly improved blood pressure control. However, it has reached a plateau in high-income countries in the past decade. Many patients who have uncontrolled BP despite three antihypertensive treatments at optimal dose and from different classes including a diuretic, so-called resistant hypertension (RHT), have an increased risk of cardiovascular mortality and morbidity.
The PRECISION Study
This study was designed to investigate the BP-lowering effects of the endothelin receptor antagonist, aprocitentan, and its sustained effect in a prospective, blinded, randomized, parallel-group Phase 3 clinical trial in patients with “true” RHT, excluding those with apparent/pseudo-RHT, as per recent American Heart Association Scientific Statement. It 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.
The PRECISION study investigates the effect of adding aprocitentan, an endothelin receptor antagonist, on top of guideline-recommended antihypertensive medications, thereby exploring the utility of dual endothelin antagonism as a complementary therapeutic approach for the treatment of RHT. The study was designed to overcome frequent methodological limitations that may result in the inclusion of patients who do not have “true” RHT. An analysis of the study inclusion failures shows that 44.4% of the screened patients considered as candidates for a supplementary treatment for RHT have pseudo-RHT.
The main strength of the study design is the use of a long screening/run-in period (at least 8 weeks) before randomization to select patients with “true” RHT. This period includes 4 weeks of SBT provided as a single-tablet triple antihypertensive treatment combination, which should reduce medical inertia while improving adherence, and 16 and 4 weeks of placebo run-in to exclude placebo responders. To the best of our knowledge, this is the most rigorous study design yet employed to ensure the inclusion of patients with “true” RHT within a clinical trial. Another strength of the design is a long treatment period extending over 48 weeks with 16 planned visits.
Methods
Patients with uncontrolled 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 and the persistence of this effect.
Study Design
The study comprises four consecutive periods.
- (Period 1) The screening period (4–12 weeks) is used to select patients with RHT and confirm the diagnosis of “true” RHT; patients fulfilling the screening criteria SiSBP ≥ 140 mm Hg are switched to SBT for 4 weeks to improve treatment adherence.
- (Period 2) The single-blind (SB) run-in period (4 weeks), where a placebo is added to SBT, is used to exclude placebo responders.
- (Period 3) This treatment period (48 weeks) consists of three sequential parts: (Part 1) a 4-week double-blind (DB), randomized, parallel-group, and placebo-controlled part, where patients receive aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; (Part 2) a 32-week SB and single-arm part, where patients receive aprocitentan 25 mg; and (Part 3) a 12-week DB, randomized, parallel-group and placebo-controlled withdrawal (DB-WD) part, where patients are rerandomized to aprocitentan 25 mg or placebo in a 1:1 ratio.
- (Period 4) The safety follow-up period covers the 30 days after the last dose of study treatment.
Results
Of the 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 the failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.
The initial 4 weeks DB part is designed to confirm the BP treatment effect compared with placebo and the tolerability of the two-dose strengths of aprocitentan (12.5 and 25 mg) selected from the previous Phase 2 dose-finding study, thereby demonstrating the short-term effects and fast onset of BP-lowering efficacy. In the dose-finding study, at least 80% of the expected BP reduction was already observed within the first 2 weeks of treatment.
To demonstrate the long-term BP-lowering effect of aprocitentan, a randomized DB-WD part was added following a long-term SB active treatment part. This design has become standard at least in children to avoid long-term placebo exposure. Thus, the PRECISION design addresses both the BP-lowering effect of aprocitentan and the persistence of this effect for up to 48 weeks in a single study.
Conclusion
Resistant hypertension is often linked with significantly increased cardiovascular risk. Identification of “true” RHT requires a specific emphasis on appropriate BP measurement techniques, confirmation of uncontrolled BP by out-of-office BP measurement, attention to potential secondary causes, and assessment/confirmation of patient adherence with prescribed medication, which should be optimal.
The current study applies a rigorous workup to confirm “true” RHT and a design that includes a placebo-controlled phase with two doses of aprocitentan to demonstrate the short-term BP-lowering efficacy in “true” RHT. Importantly, the study design also allows the assessment of long-term sustainability of BP lowering up to 48 weeks to confirm the durability of the effect.
The baseline data from the PRECISION study presented here readily demonstrates the high rate of pseudo-RHT in a patient population referred for RHT and the importance of thorough clinical workup as summarized above. Most importantly, findings from this study will inform on the utility of aprocitentan as add-on therapy to established guideline-recommended background medication to reduce BP in patients with “true” RHT and its capacity to achieve BP control. More broadly, the study will establish the usefulness of dual endothelin antagonism as a therapeutic principle in the treatment of RHT.
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