A multicentre, randomized, double-blind, active and placebo-controlled study of pecavaptan, a dual V1a/V2 vasopressin receptor antagonist, in patients with acute heart failure: The AVANTI trial

Abstract

Aims: Balanced dual V1a/ V2 vasopressin receptor antagonism may offer potential advantages as an adjunctive and/or a replacement therapy to loop diuretic therapy.

Methods and results: AVANTI was a double-blind, randomized trial in patients hospitalized with heart failure and residual congestion. In Part A, patients received pecavaptan or placebo as adjunctive therapy to standard of care for 30 days. In Part B, patients were randomized to continuation of furosemide or replacement by pecavaptan, as single diuretic therapies for 30 days. Co-primary endpoints were for Part A changes in weight and serum creatinine and for Part B, changes in weight and blood urea nitrogen/creatinine ratio. Among 483 patients randomized into Part A, there was no difference in weight reduction between pecavaptan and placebo (between-group difference: -0.27 kg, upper one-sided 95% confidence interval [CI] -0.29, p = 0.21) and no effect on serum creatinine (between-group difference: 0.05 mg/dl, upper one-sided 95% CI 0.12, p = 0.87). Subsequently, 286 patients were randomized into Part B. The difference in weight change between the pecavaptan and furosemide monotherapy groups over 30 days was 0.69 kg (upper one-sided 80% CI 0.95, p = 0.16), satisfying non-inferiority criteria of 1 kg. The between-group difference in log-transformed change in blood urea nitrogen/creatinine ratio was -0.22 (upper one-sided 80% CI -0.19, p < 0.0001) favouring pecavaptan. Adverse events and serious adverse events related to congestion including heart failure hospitalizations were numerically higher in the pecavaptan groups in both parts of the trial.

Conclusions: Adjunctive pecavaptan for 30 days in patients with residual congestion had no impact on weight loss nor on renal function. Post-discharge pecavaptan monotherapy was non-inferior to furosemide monotherapy for weight change over 30 days, but was associated with improved renal function. The increase in congestion events suggests that future trials will need optimized background diuretic dosing.

Clinical trial registration: ClinicalTrials.gov NCT03901729.

Keywords: Decongestion; Diuretic; Heart failure; Vasopressin.