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

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.

An interesting case of pulmonary hypertension in nephrotic syndrome due to amphetamine use for attention-deficit hyperactivity disorder

“…Recently a study conducted by Hlavaty A and colleagues, identified 15 new drugs likely to be related to PAH. These drugs were protein kinase inhibitors (lapatinib, lorlatinib, ponatinib, and ruxolitinib), antimetabolites (fludarabine, cytarabine, fluorouacil, and gemcitabine), immunosuppressants (thalidomide, ciclosporin, leflunomide), chemotherapeutics (trastuzumab and etoposide), and angiogenesis inhibitors (bevacizumab) 10 . While the exact pathomechanism by which drugs cause PAH is unclear, it could be explained by increased levels of serotonin in the blood due to interaction between these drugs and serotonin receptors 11 .…”

Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies

“…As of December 31, 2017, the World Health Organization Pharmacovigilance Database (Vigibase ® ) included >440 cases of PAH associated with protein kinase inhibitors ( 8 ). In registry data, the overall incidence of dasatinib-related PH was <1%( 113 ). In the DASISION trial ( 11 ), PH was suspected in 5% of patients based on echocardiography; nevertheless, only one patient underwent right-heart catheterization, which did not confirm the presence of PH.…”

Angiogenesis Redux: An Overall Protective Role of VEGF/KDR Signaling in the Microvasculature in Pulmonary Arterial Hypertension

“…Bevacizumab-a humanized monoclonal anti-VEGF-A antibody approved for oncology applications with an extensive record of human safety data 20 has been associated with rare reports of PAH, which may be transient and resolve after discontinuation. 21,22 Alternatively, ramucirumab-a VEGFR2 blocking antibody…”

“…Bevacizumab—a humanized monoclonal anti–VEGF-A antibody approved for oncology applications with an extensive record of human safety data 20 —has been associated with rare reports of PAH, which may be transient and resolve after discontinuation. 21,22 Alternatively, ramucirumab—a VEGFR2 blocking antibody also approved for oncology applications—has not been associated with PAH, and individuals with known PAH have tolerated bevacizumab without clinical worsening. 23 VEGFR1/2 antagonist SU5416 is routinely combined with hypoxia to induce severe obliterative PH in adult rats, 24 suggesting an important role of VEGFR1/2 in rodent PH, but its impact appears to require Ahr (aryl hydrocarbon receptor) signaling, as the potent VEGFR2 inhibitors Ki8751 and TAK-593 that do not activate Ahr do not potentiate PH.…”