Risk of Systemic Adverse Events Associated with Intravitreal Anti–VEGF Therapy for Diabetic Macular Edema in Routine Clinical Practice

Purpose: Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy has become standard of care for the management of diabetic macular edema (DME). The systemic safety profile of this treatment in routine clinical practice remains incompletely understood. We used a large claims database to investigate the risk of systemic serious adverse events (SAEs) in patients receiving anti-VEGF for DME compared with controls treated with macular laser photocoagulation or intravitreal corticosteroid. Design: Retrospective cohort study. Participants: By using a large U.S. insurance database, we identified privately insured and Medicare Advantage patients aged ≥18 years treated with anti-VEGF for DME between January 1, 2006, and December 31, 2015, along with control patients receiving macular laser or corticosteroid. We included patients with 1 year of medical coverage before initial DME treatment. Methods: We assessed associations between treatment modalities and predefined systemic outcomes using Cox proportional hazards regression. We performed 2 separate comparisons, one between anti-VEGF and macular laser and one between anti-VEGF and corticosteroid. We used inverse propensity score weighting for the first comparison to account for treatment selection bias. For the second, we used 2:1 propensity score matching on demographics, year, and baseline comorbidities because of the smaller number of corticosteroid-treated patients. Main Outcome Measures: Risk of cerebrovascular disease, myocardial infarction, major bleeding, and all-cause hospitalization occurring within 6 months of initial DME treatment as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 23 348 patients receiving treatment for DME met inclusion criteria; 13 365 received macular laser, 9219 received intravitreal anti-VEGF, and 764 received intravitreal corticosteroid as initial treatment. Anti-VEGF pharmacotherapy was not associated with an increased hazard of cerebrovascular disease (HR, 0.96; 95% CI, 0.65–1.41; P = 0.83), major bleeding (HR, 1.23; 95% CI, 0.76–1.99; P = 0.41), or myocardial infarction (HR, 1.03; 95% CI, 0.73–1.44; P = 0.88) when compared with macular laser for DME; however, there was an increased hazard of post-treatment all-cause hospital admission (HR, 1.17; 95% CI, 1.05–1.30; P = 0.01). The rates of all primary systemic SAE outcomes were similar after treatment with anti-VEGF versus corticosteroid (P > 0.05 for all). Conclusions: We identified no increased risk of cerebrovascular disease, myocardial infarction, or major bleeding within 6 months after intravitreal anti-VEGF pharmacotherapy for the treatment of DME in routine clinical practice. A potential difference in all-cause hospitalization may merit further investigation.