Do VEGF (Vascular Endothelial Growth Factor) eye injections, such as ranibizumab (generic name) or bevacizumab (generic name), increase the risk of cerebrovascular accident (CVA) in patients with macular degeneration?

Risk of Cerebrovascular Accidents with VEGF Eye Injections for Macular Degeneration

Anti-VEGF eye injections for macular degeneration carry a theoretical risk for systemic arterial thromboembolic events including CVA, but clinical trials have shown this risk to be low and inconclusive. 1

Evidence on CVA Risk with Anti-VEGF Therapy

General Safety Profile

• According to the American Academy of Ophthalmology's Preferred Practice Pattern (2020), all anti-VEGF treatments may theoretically increase the risk of systemic arterial thromboembolic events, though clinical trial results remain inconclusive 1
• A recent literature review concluded that anti-VEGF therapy is generally safe and effective for neovascular AMD 1

Comparative Safety Between Anti-VEGF Agents

• At 1 year of treatment, there were no statistically significant differences in rates of arteriothrombotic events between ranibizumab and aflibercept 1
• The CATT study showed no statistically significant differences in rates of arteriothrombotic events between bevacizumab and ranibizumab at 1 year 1
• However, the CATT study did report a higher rate of serious systemic events (including arteriothrombotic events and venous thrombosis) with bevacizumab compared to ranibizumab (24% vs. 19%, P=0.04), which persisted at 2 years of follow-up 1

Recent Research on Stroke Risk

• A 2021 large retrospective cohort study of 87,844 patients found no differences in the risk of acute cerebrovascular disease within 180 days when comparing bevacizumab, ranibizumab, and aflibercept 2
• However, smaller studies have identified potential concerns:
  • A 2018 study found increased mortality in patients who received bevacizumab within 3 months after a stroke/TIA compared to patients not exposed to bevacizumab (OR = 6.92,95% CI 1.88-25.43, p < 0.01) 3
  • Similarly, increased mortality was observed in patients who received bevacizumab shortly after myocardial infarction 4

Risk Stratification

Higher Risk Patients

• Patients with recent cerebrovascular events (within 3-6 months) appear to have significantly higher mortality risk when receiving bevacizumab 3
• Patients with recent myocardial infarction (within 3-24 months) also show increased mortality risk with bevacizumab treatment 4

Medication-Specific Considerations

• The IVAN trial showed greater serum VEGF suppression with bevacizumab compared to ranibizumab, though this did not translate to statistically significant differences in serious systemic adverse events 1
• Ranibizumab may have a slightly better systemic safety profile than bevacizumab based on the CATT study, though most major clinical trials have not shown significant differences in arteriothrombotic events 1, 5

Clinical Recommendations

1. For patients with no history of recent CVA or cardiovascular disease:

   • Standard anti-VEGF therapy can be administered with routine monitoring
   • Discuss the theoretical but low risk of thromboembolic events with patients

2. For patients with recent CVA (within past 6 months):

   • Consider delaying anti-VEGF therapy if possible
   • If treatment is necessary, ranibizumab may be preferable to bevacizumab based on available evidence
   • More intensive monitoring for neurological symptoms is warranted

3. For patients with history of CVA >6 months ago:

   • Anti-VEGF therapy can be administered with appropriate caution
   • Monitor for neurological symptoms after injections

4. For all patients receiving anti-VEGF therapy:

   • Educate about warning signs of stroke that require immediate medical attention
   • Consider less frequent dosing schedules when clinically appropriate

Important Caveats

• The systemic absorption of anti-VEGF agents after intravitreal injection is relatively small but measurable
• Many studies have limited statistical power to detect small differences in rare events like CVA
• Most clinical trials exclude patients with recent thromboembolic events, limiting data on highest-risk populations
• The risk-benefit ratio strongly favors treatment for most patients with neovascular AMD, as untreated disease leads to significant vision loss

When treating patients with macular degeneration who have cardiovascular risk factors or history of stroke, careful consideration of the timing of anti-VEGF therapy and selection of specific agents may help minimize the risk of adverse cerebrovascular outcomes.