Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Oct 26, 2020; 12(10): 501-512
Published online Oct 26, 2020. doi: 10.4330/wjc.v12.i10.501
Safety and efficacy of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis
Waqas Ullah, Maryam Mukhtar, Aws Al-Mukhtar, Rehan Saeed, Margot Boigon, Donald Haas, Eduardo Rame
Waqas Ullah, Rehan Saeed, Margot Boigon, Donald Haas, Department of Internal Medicine, Abington Jefferson Health, Abington, PA 19001, United States
Maryam Mukhtar, Department of Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi 44000, Punjab, Pakistan
Aws Al-Mukhtar, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, United Kingdom
Eduardo Rame, Department of Cardiology, Thomas Jefferson University, Philadelphia, PA 19001, United States
Author contributions: Ullah W contributed to the conceptualization, writing, data analysis; Al-Mukhtar A contributed to the data curation; Mukhtar M contributed to the investigation; Al-Mukhtar A and Mukhtar M wrote the original draft; Saeed R and Ullah W contributed to the review and editing; Ullah W and Boigon M contributed to the project administration; Haas D and Rame E contributed to the supervision and validation.
Conflict-of-interest statement: The authors deny any conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Waqas Ullah, MD, Doctor, Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA 19001, United States.
Received: May 7, 2020
Peer-review started: May 7, 2020
First decision: May 24, 2020
Revised: May 31, 2020
Accepted: September 11, 2020
Article in press: September 11, 2020
Published online: October 26, 2020

The utility of novel oral soluble guanylate cyclase (sGC) stimulators (vericiguat and riociguat), in patients with reduced or preserved ejection fraction heart failure (HFrEF/HFpEF) is currently unclear.


To determine the efficacy and safety of sGC stimulators in HF patients.


Multiple databases were searched to identify relevant randomized controlled trials (RCTs). Data on the safety and efficacy of sGC stimulators were compared using relative risk ratio (RR) on a random effect model.


Six RCTs, comprising 5604 patients (2801 in sGC stimulator group and 2803 placebo group) were included. The primary endpoint (a composite of cardiovascular mortality and first HF-related hospitalization) was significantly reduced in patients receiving sGC stimulators compared to placebo [RR 0.92, 95% confidence interval (CI): 0.85-0.99, P = 0.02]. The incidence of total HF-related hospitalizations were also lower in sGC group (RR 0.91, 95%CI: 0.86-0.96, P = 0.0009), however, sGC stimulators had no impact on all-cause mortality (RR 0.96, 95%CI: 0.86-1.07, P = 0.45) or cardiovascular mortality (RR 0.94, 95%CI: 0.83-1.06, P = 0.29). The overall safety endpoint (a composite of hypotension and syncope) was also similar between the two groups (RR 1.50, 95%CI: 0.93-2.42, P = 0.10). By contrast, a stratified subgroup analysis adjusted by type of sGC stimulator and HF (vericiguat vs riociguat and HFrEF vs HFpEF) showed near identical rates for all safety and efficacy endpoints between the two groups at a mean follow-up of 19 wk. For the primary composite endpoint, the number needed to treat was 35, the number needed to harm was 44.


The use of vericiguat and riociguat in conjunction with standard HF therapy, shows no benefit in terms of decreasing HF-related hospitalizations or mortality.

Keywords: Vericiguat, Riociguat, Soluble guanylate cyclase, Heart failure, Guanylate cyclase stimulator

Core Tip: Recently soluble guanylate cyclase (sGC) stimulators (vericiguat and riociguat) have emerged as a novel treatment for heart failure with reduced or preserved ejection fraction. Data published in literature revealed no additional benefits to guideline-based medical therapy in reducing incidence of heart failure hospitalization and mortality with sGC stimulator use. Large scale studies are required to determine the efficacy of sGC stimulators in patients with heart failure.