Published: 5 March 2015

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Risk of Stroke with Ranibizumab (Lucentis), Bevacizumab (Avastin) and Aflibercept (Eylea), Administered by Intravitreal Injection

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Prescriber Update 36(1): 9
March 2015

The Centre for Adverse Reactions Monitoring (CARM) has received two reports of systemic arterial thromboembolic events (ATE) after intravitreal injection of bevacizumab. In the first case a transient ischaemic attack was reported by a female patient. In the second case, a male patient over 70 years old experienced a stroke four days after treatment.

Bevacizumab is a recombinant humanised monoclonal antibody that binds to and inactivates vascular endothelial growth factor (VEGF-A). Ranibizumab is a fragment derived from the same antibody. Aflibercept is a fusion protein with acts as a VEGF-A decoy receptor. Only ranibizumab and aflibercept are approved for the treatment of age-related macular degeneration (AMD). However, bevacizumab has been used off-label for this indication.¹

VEGF-A inhibitors can be detected in the plasma after intravitreal administration and can result in systemic effects. The risk of arterial thrombotic effects such as stroke, transient ischaemic attack and myocardial infarction are of particular concern. There is some evidence that ranibizumab is associated with ATE, but this association requires further research. ^2,3

Bevacizumab may be associated with a higher risk of ATE than ranibizumab since it remains in the systemic circulation for longer. Meta-analysis of trials comparing bevacizumab with ranibizumab did not show a statistically significant difference in ATE, although there was an imbalance in the number of events (higher in the bevacizumab treated patients). ⁴ A recent observational study found a significantly higher number of ATE in patients treated with bevacizumab compared to ranibizumab.⁵

Patients who require treatment for AMD should be assessed for their risk of stroke and treatment should only be initiated if the benefits are considered to outweigh the risk of harm. Patients should be monitored after each intravitreal administration and instructed to seek immediate medical attention if they develop any symptoms associated with stroke.

References

1. Tridente G. 2014. Adverse events with Biomedicines Milan: Springer.
2. Bressler NM, Boyer DS, Williams DF et al 2012 'Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials' Retina. 32: 1821-1828.
3. Pratt NL, Ramsay EN, Kemp A et al. 2014 'Ranibizumab and risk of hospitalisatino for ischaemic stroke and myocardial infarction in patients with age-related macular degeneration: a self-controlled case-series analysis' Drug Safety. 37: 1021-1027.
4. Wang W, Zhang X. 2014 'Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age-related macular degeneration: a meta-analysis' PLoS ONE 9(10) e 109744.
5. Carneiro AM, Barthelmes D, Falcao MS. et al 2011. 'Arterial thromboembolic events in patients with exudative age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab' Ophthalmologica. 225: 211-221.