Uncovering Knowledge Gaps in the Safety Profile of Antiangiogenic Drugs in Cancer Patients: Insights from Spontaneous Reporting Systems Studies

Abstract

Global repositories of postmarketing safety reports improve understanding of real-life drug toxicities, often not observed in clinical trials. The aim of this scoping review was to map the evidence from spontaneous reporting systems studies (SRSs) of antiangiogenic drugs (AADs) in cancer patients and highlight if the found disproportionality signals of adverse events (AEs) were validated and thus mentioned in the respective Summary of product Characteristics (SmPC). This scoping review was conducted according to PRISMA guidelines for scoping reviews. A knowledge gap on the safety of AADs was found: firstly, several cardiovascular AEs were not mentioned in the SmPCs and no pharmacovigilance studies were conducted despite the well-known safety concerns about these drugs on the cardiovascular system. Second, a disproportionality signal (not validated through causality assessment) of pericardial disease was found in the literature for axitinib with no mention in SmPC of the drug. Despite the exclusion of pharmacoepidemiological studies, we believe that this scoping review, which focuses on an entire class of drugs, could be considered as a novel approach to highlight possible safety concerns of drugs and as a guide for the conduction of a target postmarketing surveillance on AADs.

Keywords: VEGF; adverse drug reaction; angiogenesis; disproportionality analysis; postmarketing surveillance; spontaneous reporting systems.

Figure 1

Flow chart of SRS studies.

Figure 2

Overview of the frequency of adverse cardiovascular reactions coming from SmPCs and disproportionality signals coming from pharmacovigilance SRS studies of AADs grouped by class. ^a The frequency of the event is classified as not known in Section 4.8 “undesirable effects” of the SmPC or it is reported but it is not clear (e.g., (1) if the SmPCs reported haemorrhage without specifying the type, frequency of cerebral haemorrhage was considered as not known, (2) acute myocardial infarction was included in the list of other thromboembolic events). ^b Not mentioned in Section 4.8 “undesirable effects” of the SmPCs. * As for cardiac arrhythmia, the following adverse events were the most frequent: tachycardia, atrial fibrillation and bradycardia. As for embolic and thrombotic events, the following adverse events were the most frequent: venous thromboembolism, arterial thromboembolism and thrombosis. As for pericardial/myocardial disease, the following adverse events were the most frequent: pericarditis, myocarditis, pericardial effusion, cardiomyopathy.