Program

OR25-5

VEriciguat NItroglycerin Clinical IntEraction (VENICE): A phase 1, multicenter, randomized, placebo-controlled, double-blind group-comparison study in patients with stable coronary artery disease to evaluate tolerability and blood pressure effects of nitroglycerin after pre-treatment with multiple oral doses of vericiguat

[Speaker] Gerd Mikus:1
[Co-author] Michael F Boettcher:2, Hans-Dirk Duengen:3, Frank Donath:4, Nikos Werner:5, Petra A Thuermann:6, Mahir Karakas:7, Boris Weimann:8, Tanja Koch:2, Corina Becker:2
1:University of Heidelberg, Heidelberg, Germany, 2:Bayer AG, Germany, 3:Charite Universitaetsmedizin Berlin, Berlin, Germany, 4:Socra Tec R&D GmbH, Erfurt, Germany, 5:University Hospital Bonn, Bonn, Germany, 6:HELIOS Klinikum Wuppertal GmbH, Wuppertal, Germany, 7:University Heart Center Hamburg, Hamburg, Germany, 8:Chrestos Concept GmbH & Co. KG, Essen, Germany

Introduction
Vericiguat is under investigation in the VICTORIA phase 3 study (NCT02861534) in patients with HFrEF. Current guidelines recommend nitroglycerin (NTG) for acute angina in patients with CAD, a common comorbidity in HF. Combination of PDE-5 or riociguat and organic nitrates is contra-indicated. The study tested if co-administration of vericiguat and NTG can be allowed.

Hypothesis
Co-administration of NTG and vericiguat will be well tolerated in patients with stable CAD, without significant adverse effects beyond those known for NTG.

Methods
Patients were randomized to placebo+NTG or vericiguat+NTG in this multicenter, placebo-controlled, double-blind, parallel group study (NCT02617550). Two weekly step-wise up-titration of placebo/vericiguat from 2.5 mg to 5 mg to 10 mg was performed, with co-administration of 0.4 mg NTG spray 2.5 hours before vericiguat (trough concentrations) or 4 hours after vericiguat (peak concentrations) at steady state. The primary objective was to assess safety and tolerability; the secondary objective was to evaluate pharmacodynamic interactions (assessed by BP and heart rate [HR]). Safety was assessed by AEs and clinically relevant findings.

Results
In total, 36 patients (33 male) were randomized (12 to placebo+NTG and 24 to vericiguat+NTG) and 31 patients completed treatment (placebo 10/12; vericiguat 21/24). Baseline characteristics were similar between arms, with the exception of SBP (placebo: 120 +/- 16.6 mmHg; vericiguat: 127 +/- 17.6 mmHg).
There was no increase in TEAEs when NTG was given with vericiguat compared with placebo; 3 patients discontinued due to an AE (vericiguat [n=1] - sinoatrial block of moderate intensity; placebo [n=2] - orthostatic dysregulation, postural dizziness).
Decreases in BP were independent of vericiguat exposure, and occurred to a similar extent at trough and peak concentrations with all vericiguat doses and with placebo.
During up-titration of vericiguat to 10 mg, a decrease from baseline in SBP of ~10 mmHg over 42 days was observed, without changes in DBP and HR (limitation: large variability, baseline SBP difference between arms).

Conclusions
Co-administration of multiple doses of vericiguat and NTG was well tolerated. Concomitant use of short-term NTG for acute angina in the VICTORIA study is unlikely to cause adverse effects beyond those known for NTG.
Advanced Search