What are the risks of stroke associated with intravitreal anti-Vascular Endothelial Growth Factor (VEGF) therapy, including medications such as Bevacizumab (bevacizumab), Ranibizumab (ranibizumab), and Aflibercept (aflibercept)?

Stroke Risk with Intravitreal Anti-VEGF Therapy

While intravitreal anti-VEGF agents carry a theoretical risk of arterial thromboembolic events including stroke, the absolute risk remains low and clinical trial data show inconclusive evidence of increased stroke risk, though patients with diabetic macular edema and prior cardiovascular disease warrant heightened caution. 1

Overall Stroke Risk Profile

The American Academy of Ophthalmology states that all anti-VEGF treatments may carry theoretical risks for systemic arterial thromboembolic events, although results of clinical trials studying these risks remain inconclusive. 1

Risk by Indication and Agent

Age-Related Macular Degeneration:

• In pooled 2-year AMD studies, the stroke rate (ischemic and hemorrhagic) was 2.7% with ranibizumab 0.5 mg versus 1.1% in controls [odds ratio 2.2,95% CI 0.8-7.1]. 2
• At 1 year, no statistically significant differences in arteriothrombotic events or stroke rates were found between ranibizumab and aflibercept. 1
• The arterial thromboembolic event rate in the first year was 1.9% with ranibizumab (0.3 or 0.5 mg) compared to 1.1% in controls. 2

Retinal Vein Occlusion:

• The stroke rate in controlled RVO studies was 0.2% with ranibizumab versus 0.4% in controls during the first 6 months. 2
• Arterial thromboembolic event rates were 0.8% in both ranibizumab and control arms. 2

Diabetic Macular Edema and Diabetic Retinopathy (Highest Risk Population):

• At 2 years, stroke rates were 3.2% with ranibizumab 0.5 mg, 1.2% with 0.3 mg, and 1.6% with control. 2
• At 3 years, stroke rates increased to 4.8% with ranibizumab 0.5 mg and 2.0% with 0.3 mg. 2
• The arterial thromboembolic event rate at 2 years was 7.2% with 0.5 mg ranibizumab, 5.6% with 0.3 mg, and 5.2% with control. 2
• Patients with diabetic macular edema at high risk of arteriothrombotic events who receive high exposure to monthly anti-VEGF therapy demonstrate increased risk of all-cause mortality compared with controls. 3

Agent-Specific Considerations

Bevacizumab versus Ranibizumab:

• The CATT study showed no statistically significant differences in stroke rates between bevacizumab and ranibizumab at 1 year. 1
• However, bevacizumab was associated with a higher rate of serious systemic events (24% vs 19%, P=0.04), including arteriothrombotic events, which persisted at 2 years. 1
• A large population-based nested case-control study (91,378 patients) found no increased risk of ischemic stroke with either bevacizumab (adjusted OR 0.95% CI 0.68-1.34) or ranibizumab (adjusted OR 0.87,95% CI 0.68-1.10). 4

Aflibercept:

• At 1 year, no statistically significant differences in arteriothrombotic events or stroke rates between aflibercept and ranibizumab. 1
• One case report documented ischemic stroke following aflibercept administration in a patient on vitamin K antagonist therapy, suggesting potential drug interaction or direct prothrombotic effect. 5

Mechanism of Stroke Risk

Anti-VEGF agents suppress systemic VEGF levels, leading to:

• Decreased nitric oxide and prostaglandin-I2 production. 3
• Vascular endothelial cell dysfunction and death. 3
• The pharmacokinetics show sustained reduction in free plasma VEGF levels after intravitreal aflibercept and bevacizumab injection, consistent with potential systemic effects. 3

High-Risk Patient Identification

Patients at elevated stroke risk include:

• Those with history of stroke or arterial thromboembolic events may be at higher risk for future stroke with anti-VEGF therapy. 6
• Patients with diabetic macular edema receiving monthly injections (highest exposure). 3
• Those with cardiovascular disease history should receive treatment with caution. 6
• Patients on anticoagulation therapy (potential drug interactions). 5

Clinical Management Algorithm

Pre-Treatment Assessment:

• Document cardiovascular history, particularly prior stroke or myocardial infarction. 6, 3
• Review current anticoagulation or antiplatelet therapy. 5
• Obtain informed consent discussing theoretical thromboembolic risks. 1

Treatment Selection:

• For patients with recent stroke or multiple strokes, consider special measures to minimize systemic complications. 3
• In diabetic macular edema, consider less frequent dosing regimens when clinically appropriate to reduce cumulative exposure. 3
• No definitive evidence supports choosing one anti-VEGF agent over another solely for stroke risk reduction. 1, 4

Post-Treatment Monitoring:

• Instruct patients to report symptoms of stroke (sudden weakness, speech difficulty, vision changes) immediately. 1
• The FDA label for ranibizumab specifically warns about potential arterial thromboembolic events and requires monitoring. 2

Critical Caveats

• Study limitations include inadequate statistical power to definitively identify differences in low-frequency events like stroke. 1, 7
• Most trials used strict enrollment criteria that excluded high-risk patients, limiting generalizability. 3
• The level of evidence is "low" or "very low" for most stroke risk assessments due to sparse data and imprecision. 7
• A 2018 Cochrane review reported "moderate certainty evidence" of safety, with no studies showing definite increased risk as of 2019. 1