Boettcher Michael, Mikus Gerd, Trenk Dietmar, Düngen Hans-Dirk, Donath Frank, Werner Nikos, Karakas Mahir, Besche Nina, Schulz-Burck Dominik, Gerrits Mireille, Hung James, Becker Corina
Clinical Pharmacology, Bayer AG, Wuppertal, Germany.
Graduate Physicist and Physician and Lecturer at the University of Applied Science at the RFH-Cologne, Cologne, Germany.
Clin Transl Sci. 2022 May;15(5):1204-1214. doi: 10.1111/cts.13238. Epub 2022 Mar 17.
Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long-acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co-administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double-blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co-administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty-five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline- and placebo-adjusted vital signs showed reductions of 1.4-5.1 mmHg (systolic blood pressure) and 0.4-2.9 mmHg (diastolic blood pressure) and increases of 0.0-1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose-dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well-tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.
维立西呱是用于治疗近期失代偿事件后病情稳定的射血分数降低的成年患者的症状性慢性心力衰竭（HF）。指南推荐使用长效硝酸盐类药物，如单硝酸异山梨酯，用于慢性冠状动脉综合征（CCS，HF常见的合并症）的心绞痛预防。本研究评估了联合使用维立西呱和单硝酸异山梨酯在CCS患者中的安全性、耐受性及药效学（PD）相互作用。在这项Ib期、双盲、多中心研究中，患者按2:1随机分组，分别接受维立西呱加单硝酸异山梨酯（n = 28）或安慰剂加单硝酸异山梨酯（n = 13）。单硝酸异山梨酯剂量逐渐增加至每日一次60 mg的稳定剂量，随后与维立西呱（每2周从2.5 mg滴定至5 mg和10 mg）或安慰剂联合使用。35例患者完成治疗（维立西呱组，n = 23；安慰剂组，n = 12）。维立西呱加单硝酸异山梨酯组的平均基线及安慰剂校正生命体征显示收缩压降低1.4 - 5.1 mmHg，舒张压降低0.4 - 2.9 mmHg，心率增加0.0 - 1.8次/分钟。未观察到维立西呱剂量依赖性的一致PD效应。维立西呱组和安慰剂组不良事件（AE）的发生率分别为92.3%和66.7%，大多数AE强度为轻度。维立西呱加单硝酸异山梨酯观察到的血压和心率变化不被认为具有临床相关性。这种联合用药总体耐受性良好。维立西呱与单硝酸异山梨酯联合使用不太可能引起超出单硝酸异山梨酯已知AE的显著AE。
