Ranibizumab and risk of hospitalisation for ischaemic stroke and myocardial infarction in patients with age-related macular degeneration: a self-controlled case-series analysis

Abstract

BACKGROUND: Ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, is used in the treatment of age-related macular degeneration. Inhibition of VEGF has an anti-angiogenic action and is associated with thrombogenicity, thus, myocardial infarction and ischaemic stroke are potential side effects of VEGF inhibitors. OBJECTIVE: Our objective was to assess the association between use of ranibizumab and risk of hospitalisation for ischaemic stroke (IS) and myocardial infarction (MI). METHODS: The self-controlled case series design was used, including subjects exposed to ranibizumab (Anatomical Therapeutic Chemical [ATC] code S01LA04) who were hospitalized for IS (International Classification of Diseases, tenth edition [ICD-10] code I63) or the combined endpoint of stroke or transient ischaemic attack (TIA) (ICD-10 code G45) or MI (ICD-10 code I21) were identified between August 2007 and March 2013. Rate ratios in exposed periods compared with unexposed periods were calculated using conditional Poisson regression. RESULTS: A total of 323 subjects received ranibizumab and were hospitalized for IS, 490 for IS or TIA, and 391 for MI. Median period of exposure was 8-9 months with follow-up times of approximately 2.8 years. No elevated risk of IS was seen in the 1-30 days post initiation (incidence rate ratio [IRR] 1.36; 95% confidence interval [CI] 0.98-1.88); however, elevated risk was observed for those who received therapy for 31-60 days (IRR 1.91; 95% CI 1.13-3.24). Sensitivity analyses adjusting for time-varying confounders found elevated risk in both the 1-30 days and 31-60 days periods. Similar results to those for IS were observed for the combined endpoint of IS or TIA. No association was seen for MI in either time period (1-30 days IRR 0.90, 95% CI 0.65-1.23; 31-60 days IRR 0.98, 95% CI 0.54-1.79). CONCLUSION: This case-series analysis suggests an increased risk of hospitalisation for ischaemic stroke for patients receiving ranibizumab in the 31-60 days risk period. Studies with larger populations are required to confirm the risk in the 1-30 days risk period. No evidence of increased risk of hospitalisation for MI was observed.