Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study

Objective To assess the risk of systemic adverse events associated with intravitreal injections of vascular endothelial growth factor inhibiting drugs. Design Population based nested case-control study. Setting Ontario, Canada. Participants 91 378 older adults with a history of physician diagnosed retinal disease identified between 1 April 2006 and 31 March 2011. Cases were 1477 patients admitted to hospital for ischaemic stroke, 2229 admitted for an acute myocardial infarction, 1059 admitted or assessed in an emergency department for venous thromboembolism, and 2623 admitted for congestive heart failure. Event-free controls (at a ratio of 5:1) were matched to cases on the basis of year of birth, sex, history of the outcome in the previous 5 years, and diabetes. Main exposure measure Exposure to vascular endothelial growth factor inhibiting drugs identified within 180 days before the index date. Results After adjustment for potential confounders, participants who had ischaemic stroke, acute myocardial infarction, congestive heart failure, or venous thromboembolism were not more likely than control participants to have been exposed to either bevacizumab (adjusted odds ratios of 0.95 (95% confidence interval 0.68 to 1.34) for ischaemic stroke, 1.04 (0.77 to 1.39) for acute myocardial infarction, 0.81 (0.49 to 1.34) for venous thromboembolism, and 1.21 (0.91 to 1.62) for congestive heart failure) or ranibizumab (adjusted odds ratios 0.87 (0.68 to 1.10) for ischaemic stroke, 0.90 (0.72 to 1.11) for acute myocardial infarction, 0.88 (0.67 to 1.16) for venous thromboembolism, and 0.87 (0.70 to 1.07) for congestive heart failure). Similarly, a secondary analysis of exclusive users of bevacizumab or ranibizumab showed no differences in risk between the two drugs (adjusted odds ratios for bevacizumab relative to ranibizumab of 1.03 (0.67 to 1.60) for ischaemic stroke, 1.23 (0.85 to 1.77) for acute myocardial infarction, 0.92 (0.51 to 1.69) for venous thromboembolism, and 1.35 (0.93 to 1.95) for congestive heart failure). These findings were consistent for all but one outcome in subgroup analyses. Conclusions Intravitreal injections of bevacizumab and ranibizumab were not associated with significant risks of ischaemic stroke, acute myocardial infarction, congestive heart failure, or venous thromboembolism.