Thiazides attenuate the diuretic response to pecavaptan, a dual vasopressin receptor antagonist, in hospitalized heart failure patients
D C H Ceelen, G H D Voordes, L Cosic, S R Goldsmith, D Burkhoff, F Gustafsson, R Frost, K Duarte, L Monzo, N Girerd, F Zannad, J E Udelson, R Gansevoort, J M Ter Maaten, A A VoorsAbstract
Background
In patients with acute heart failure (AHF), pecavaptan had a modest effect on weight loss at 7 days, which was no longer present by day 30. Previous reports suggested that thiazides may attenuate the diuretic effect of vasopressin antagonists.
Purpose
We aim to explore the potential impact of concomitant use of thiazides on the effect of pecavaptan on weight change.
Methods
AVANTI was a double-blind, randomised, placebo-controlled trial in patients with AHF and incomplete decongestion. In Part A, patients received 30 mg pecavaptan or placebo as adjunctive therapy for 30 days. We used mixed-effects models to assess the effect of pecavaptan on weight trajectories and tested its interaction with thiazide use, adjusting for baseline confounders. Finally, we used linear regression, adjusting for baseline weight, to compare weight change between treatment groups by thiazide use. We validated our findings using multivariable linear regression in a previous randomized controlled trial with tolvaptan (EVEREST).
Results
We included 482 patients with a mean age of 70 years, of whom 24.5% were women and 80 patients (16.6%) used a thiazide. Pecavaptan did not affect weight change in thiazide users at day 7 (0.22kg gain versus placebo, p=0.808) or day 30 (1.14kg gain, p=0.341). In contrast, patients who did not use thiazides showed a modest albeit significant weight reduction at day 7 (-0.68 kg, p=0.002) and day 30 (-0.77 kg, p=0.029) when taking pecavaptan (adjusted-p for interaction <0.001). In the EVEREST trial, concomitant thiazide use also significantly attenuated the effect of tolvaptan on weight loss, with a reduction in body weight at discharge of –0.95 kg in patients not receiving thiazides (p<0.001) compared with a negligible change in those on thiazides (–0.06 kg, p=0.907; adjusted-p for interaction=0.046).
Conclusion
Our findings suggest that thiazide use may attenuate pecavaptan-induced weight loss. This may partly account for the modest effect of pecavaptan on weight loss in the AVANTI trial.Efficacy stratified by thiazide-useFor image description, please refer to the figure legend and surrounding text.Validation in the EVEREST trialFor image description, please refer to the figure legend and surrounding text.