Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis
Open Access
- 10 July 2022
- journal article
- research article
- Published by Wiley in British Journal of Clinical Pharmacology
- Vol. 88 (12), 5227-5237
- https://doi.org/10.1111/bcp.15436
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.This publication has 43 references indexed in Scilit:
- Assessing the extent and impact of the masking effect of disproportionality analyses on two spontaneous reporting systems databasesPharmacoepidemiology and Drug Safety, 2013
- Effect of Competition Bias in Safety Signal GenerationDrug Safety, 2012
- Endothelin‐1 as a Mediator and Potential Biomarker for Interferon Induced Pulmonary ToxicityPulmonary Circulation, 2012
- Novel Data-Mining Methodologies for Adverse Drug Event Discovery and AnalysisClinical Pharmacology & Therapeutics, 2012
- Treatment of pulmonary arterial hypertension with targeted therapiesNature Reviews Cardiology, 2011
- Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discoveryStatistical Methods in Medical Research, 2011
- Pulmonary Arterial HypertensionSocial psychiatry. Sozialpsychiatrie. Psychiatrie sociale, 2010
- Quantitative signal detection using spontaneous ADR reportingPharmacoepidemiology and Drug Safety, 2009
- Aminorex to Fen/PhenJournal of the American College of Cardiology, 1999
- Long term effects of the anorectic agent fenfluramine alone and in combination with aminorex on pulmonary and systemic circulation in the pigBasic Research in Cardiology, 1979