Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec;88(12):5227-5237.
doi: 10.1111/bcp.15436. Epub 2022 Jul 10.

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

Alex Hlavaty  1 , Matthieu Roustit  2   3 , David Montani  4   5   6 , Marie-Camille Chaumais  4   7   8 , Christophe Guignabert  4   5 , Marc Humbert  4   5   6 , Jean-Luc Cracowski  1   3 , Charles Khouri  1   2   3
Affiliations

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

Alex Hlavaty et al. Br J Clin Pharmacol. 2022 Dec.

Abstract

Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine-like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH.

Methods: We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories.

Results: We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin).

Conclusion: Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH.

Keywords: drug safety; pharmacovigilance; pulmonary arterial hypertension; respiratory medicine; vascular disease.

PubMed Disclaimer

Conflict of interest statement

Dr Roustit reports grants from United Therapeutic outside of the submitted work. Dr Montani reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, grants, personal fees and nonfinancial support from MSD, personal fees from Chiesi, personal fees from Boerhinger, nonfinancial support from Acceleron, and personal fees from Incyte Biosciences France, outside the submitted work. Dr Humbert reports personal fees from Acceleron, grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Merck, personal fees from Novartis, personal fees from AstraZeneca, and personal fees from Sanofi, outside the submitted work. Dr Chaumais reports personal fees from Bayer outside the submitted work. Dr Guignabert report grants from Acceleron, Janssen and Merck outside from the submitted work and personal fees Merck. Dr Khouri, Cracowski, Hlavaty have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Flow chart of the study
FIGURE 2
FIGURE 2
Circular bar plot presenting the results of disproportionality analyses. The bars are proportional to the magnitude of the disproportionality signals (information component values and lower 95% credibility intervals) and the colour indicates the plausibility of the signal. ¥ denotes disproportionality signals robust in sensitivity analyses
See this image and copyright information in PMC

References

    1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018 - DOI - PMC - PubMed
    1. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376‐387. doi:10.1378/chest.09-1140 - DOI - PubMed
    1. Greiser E. Epidemiologic studies on the relation between use of appetite depressants and primary vascular pulmonary hypertension. Internist. 1973;14(9):437‐442. - PubMed
    1. Correale M, Tricarico L, Grazioli D, et al. Drug‐Induced Pulmonary Arterial Hypertension: Mechanisms and Clinical Management. Cardiovasc Drugs Ther. 2019;33(6):725‐738. doi:10.1007/s10557-019-06920-x - DOI - PubMed
    1. McGee M, Whitehead N, Martin J, Collins N. Drug‐associated pulmonary arterial hypertension. Clin Toxicol. 2018;56(9):801‐809. doi:10.1080/15563650.2018.1447119 - DOI - PubMed

Publication types

MeSH terms