Comparative Safety of Drugs Targeting the Nitric Oxide Pathway in Pulmonary Hypertension: A Mixed Approach Combining a Meta-Analysis of Clinical Trials and a Disproportionality Analysis From the World Health Organization Pharmacovigilance Database.

Abstract

BACKGROUND:

Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension.

METHODS:

We combined two approaches. First, we performed a meta-analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization's global database of individual case safety reports, to compare the safety profiles with real-life data.

RESULTS:

In the meta-analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat (P < .01 for interaction). In the disproportionality analysis, the use of riociguat was associated with fewer reports of visual disorders but increased reporting of gastrointestinal, hemorrhagic, and musculoskeletal disorders compared with sildenafil and tadalafil. Pharmacovigilance signals of hearing/vestibular disorders were heterogeneous: vestibular disorders (dizziness) were reported more frequently for riociguat, whereas hearing disorders (deafness) were reported less frequently compared with PDE5is.

CONCLUSIONS:

The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects.

TRIAL REGISTRY:

PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/.

• Authors: Charles Khouri, Marion Lepelley, Matthieu Roustit, François Montastruc, Marc Humbert, Jean-Luc Cracowski
• Journal: Chest (Chest) Vol. 154 Issue 1 Pg. 136-147 (07 2018) ISSN: 1931-3543 [Electronic] United States
• PMID: 29275134 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chemical References

• Phosphodiesterase 5 Inhibitors
• Tadalafil
• Sildenafil Citrate

Topics

• Adverse Drug Reaction Reporting Systems (statistics & numerical data)
• Clinical Trials as Topic
• Humans
• Hypertension, Pulmonary (drug therapy, physiopathology)
• Pharmacovigilance
• Phosphodiesterase 5 Inhibitors (therapeutic use)
• Pulmonary Wedge Pressure (drug effects, physiology)
• Sildenafil Citrate (therapeutic use)
• Tadalafil (therapeutic use)
• World Health Organization