Anti-VEGF Therapy: Data on MI, Stroke, and Mortality Risk

Matthew R. Starr, MD; Sophie J. Bakri, MD


October 23, 2015

Incidence of Myocardial Infarction, Stroke, and Death in Patients With Age-Related Macular Degeneration Treated With Intravitreal Anti-Vascular Endothelial Growth Factor Therapy

Study Summary

The study is a population-linkage study that examined the incidence of heart attacks, strokes, and deaths in patients with age-related macular degeneration who were treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents from January 1, 2008, to December 31, 2011, at the Singapore National Eye Center.

These patients were matched to the National Registry of Diseases Office of Singapore. This database housed all of the health records needed to calculate the incidence of heart attacks, strokes, and deaths. The data were generated through patients' electronic medical records and inpatient notes; diagnosis was verified by nurses. Patients who suffered heart attacks were identified through clinical diagnosis or autopsy. Strokes were identified using the ICD-9 codes 430-433 and 436-437. The codes 432.0 (extradural hemorrhage), 432.1 (subdural hemorrhage), and 435 (transient ischemic attacks) were excluded.

The study identified 1182 patients who received at least 1 intravitreal anti-VEGF injection. Thirty-four patients were excluded for having a prior history of heart attack or stroke, resulting in 1148 patients being analyzed. During the 4-year period, there were a total of 78 adverse events for 68 patients, including 19 heart attacks, 16 strokes, and 43 deaths. The calculated age-adjusted incidence was 350.2 per 100,000 person-years for heart attacks, 299.3 per 100,000 person-years for stroke, and the mortality rate was 778.9 per 100,000 person-years. The average time between the first event and the first injection was just under 1.5 years. The study also noted that those patients who suffered any one of the three events had fewer injections overall as compared with patients who did not have an adverse event. This difference was not significant and may be due to the healthier patients living longer and thus being capable of receiving more injections.

The study found no significant differences between the age-adjusted incidence rates of heart attack, stroke, and mortality in the anti-VEGF-treated patients compared with the age-standardized weighted incidence rates of the Singapore population.

Limitations of the study included: short period for which patients were followed, given that the reported average time to the first adverse event was almost 1.5 years; exclusion of transient ischemic attacks, which were included in a study that examined the safety of the systemic use of bevacizumab; and exclusion of patients who had previously had a stroke or heart attack, as those patients could have provided more insight into the use of intravitreal agents in patients with known previous arterial thromboembolic events.


It is widely accepted that the systemic use of anti-VEGF agents results in an increased risk for arterial thromboembolic events. Ever since bevacizumab was initially used in the eye, there has been concern that the systemic risk for thromboembolic adverse events would be associated with the intravitreal administration of anti-VEGF agents. Given the systemic absorption (although very small), there is concern for an increased stroke risk with intravitreal administration.

This study concludes that the incidence for heart attacks, strokes, and mortality rate in patients receiving intravitreal anti-VEGF therapy was no different than in the general population. However, due to the aforementioned limitations, more studies are warranted to further delineate the risk for intravitreal anti-VEGF therapy.


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