Abstract
IntroductionSince vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, particularly in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases. Two recent case reports have found a potential link between intravitreal anti-VEGF use and Parkinson’s disease (PD) and dementia.AimTo evaluate disproportionality in a large spontaneous reporting database concerning intravitreal anti-VEGF drugs and PD or dementia, and related conditions.MethodsUsing VigiBase, individual case safety reports (ICSRs) attributed to intravitreal ranibizumab, aflibercept, pegaptanib, and bevacizumab were identified from 2010 to 2016. Within Standardised Narrow Medical Dictionary for Regulatory Activities (MedDRA®) Queries (SMQs) for “Parkinson-like events” and “Dementia,” suspected events were identified using preferred terms (PTs). The Proportional Reporting Ratio (PRR) was estimated with the lower 95% confidence intervals (CIs) for all drug-event pairs with ≥3 suspected events. The vigiGrade completeness score was reported for the ICSRs. The analyses were repeated, including only persons aged 65 and over.ResultsOut of 18.9 million ICSRs, 7,945 (0.004%) concerned intravitreal anti-VEGF drugs. Of these, 27 (0.34%) were identified concerning the SMQs “Dementia” (N = 17, 62.96%) and “Parkinson-like events” (N = 10, 37.94%) in persons of all ages. Among persons age 65 and over, 4,758 (59.88% of relevant ICSRs) ICSRs were identified for anti-VEGF drugs. When restricting disproportionality analysis to persons aged 65 and over, no disproportionality was seen for any of the drug-event pairs at the level of SMQ. However, on analysing disproportionality by PT, a potential signal emerged for intravitreal ranibizumab and Parkinson’s disease [N = 6 ICSRs; PRR: 3.05 (95% CI: 1.36-6.81)]. In general, the vigiGrade completeness score was low for all the ICSRs of interest, as no ICSR had a score >0.8.ConclusionPresent findings suggest a potential signal for Parkinson’s disease related to intravitreal ranibizumab. This is supported by several biologically plausible mechanisms but requires confirmation through pharmacoepidemiological studies, especially because of the low number of cases.
Highlights
Since vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases
Findings by Thulliez et al were in line with findings of a previous meta-analysis of randomized clinical trials (RCTs), suggesting that long-term intravitreal ranibizumab users were at risk of systemic vascular adverse events (Ueta et al, 2014)
This study found that VEGF improved neuron survival in a dose-dependent manner; this correlated with a reduction in apoptosis-inducing proteins, an increase in apoptosis-preventing proteins and neurotrophic factors such as pigment epithelial-derived factor and a reduction in amyloid beta, which is the neurotoxic protein involved in Alzheimer’s disease (Sanchez et al, 2010)
Summary
Since vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases. Findings by Thulliez et al were in line with findings of a previous meta-analysis of RCTs, suggesting that long-term intravitreal ranibizumab users were at risk of systemic vascular adverse events (Ueta et al, 2014) Both meta-analyses suggested that the systemic ADRs investigated in clinical trials were more likely to occur in patients with AMD. An Italian nationwide pharmacovigilance study confirmed the plausibility of intravitreal anti-VEGF drugs being associated with systemic ADRs, including arterial thromboembolic events, such as stroke and myocardial infarction (Cutroneo et al, 2017). In addition to these ADRs, it has recently come to light that anti-VEGF drugs could be a risk factor for neurodegenerative processes
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