What are the thromboembolic risks associated with long-term use of Eylea (Aflibercept) in patients with a history of ocular disease and underlying conditions like diabetes, hypertension, or atherosclerosis?

Thromboembolic Risk with Long-Term Eylea (Aflibercept) Use

The FDA-approved label for Eylea explicitly warns of a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, with reported incidence rates of 3.3-6.4% over 96-100 weeks in clinical trials. 1

Documented Thromboembolic Event Rates

The FDA label provides specific incidence data across different conditions treated with standard-dose Eylea (2 mg):

Wet AMD Studies

• First year: 1.8% (32/1824 patients) with Eylea vs 1.5% (9/595) with ranibizumab 1
• Through 96 weeks: 3.3% (60/1824 patients) with Eylea vs 3.2% (19/595) with ranibizumab 1

Diabetic Macular Edema Studies

• Baseline to week 52: 3.3% (19/578 patients) with Eylea vs 2.8% (8/287) in control group 1
• Baseline to week 100: 6.4% (37/578 patients) with Eylea vs 4.2% (12/287) in control group 1

Retinal Vein Occlusion Studies

• First 6 months: No reported thromboembolic events in Eylea-treated patients 1

Critical Context: Eylea HD Data Gap

There is currently no published long-term thromboembolic safety data specifically for Eylea HD (8 mg formulation). The evidence provided pertains only to standard-dose Eylea (2 mg). Given that Eylea HD delivers a 4-fold higher dose, extrapolation of safety data requires caution until dedicated long-term studies are completed.

Definition of Arterial Thromboembolic Events

ATEs in these trials were defined as: 1

• Nonfatal stroke
• Nonfatal myocardial infarction
• Vascular death (including deaths of unknown cause)

Risk Stratification in High-Risk Populations

Patients with Diabetes, Hypertension, or Atherosclerosis

These underlying conditions independently increase baseline thromboembolic risk, which compounds with anti-VEGF therapy. 2, 3

The American Academy of Ophthalmology identifies critical modifiable cardiovascular risk factors in retinal vascular disease patients: 3

• Hypertension (present in 65-73% of retinal artery occlusion patients)
• Hyperlipidemia (49% of CRAO patients)
• Diabetes mellitus (14-25% of patients)
• Cigarette smoking
• Cardiac disease including atrial fibrillation

Stroke Risk Context

Patients with retinal vascular occlusions face 3-6% risk of ischemic stroke within 1-4 weeks of presentation, with 20-24% having concurrent stroke at time of ocular event. 2 This baseline elevated stroke risk must be considered when initiating anti-VEGF therapy in these populations.

Clinical Management Algorithm

Pre-Treatment Assessment

1. Document cardiovascular risk factors: hypertension, diabetes control (HbA1c), hyperlipidemia, smoking status, history of stroke/MI, atrial fibrillation 2, 3
2. Optimize systemic risk factors before initiating therapy: blood pressure control, glycemic control (target HbA1c <7.0%), lipid management 2
3. Consider cardiology consultation for patients with multiple risk factors or prior cardiovascular events 2

During Long-Term Treatment

1. Monitor for ATE symptoms at each visit: new neurological deficits, chest pain, sudden vision changes in fellow eye 1
2. Reassess cardiovascular risk factors every 3-6 months 2
3. Maintain communication with primary care physician or cardiologist regarding ongoing anti-VEGF therapy 2

High-Risk Patient Considerations

For patients with prior stroke or MI (secondary prevention), the decision requires weighing vision-threatening disease severity against elevated thromboembolic risk. 2 The American Diabetes Association recommends aspirin 75-162 mg/day for secondary prevention in diabetic patients with atherosclerotic cardiovascular disease, which may provide some protection but increases bleeding risk. 2

For elderly patients (>70 years), thromboembolic risk increases substantially with age, as age is the dominant risk factor for both retinal vascular occlusions and stroke. 2, 3 The incidence of retinal artery occlusions peaks near age 80 years. 3

Common Pitfalls to Avoid

• Do not assume Eylea HD has identical safety profile to standard Eylea - the 4-fold higher dose may alter systemic exposure and thromboembolic risk 1
• Do not overlook baseline cardiovascular optimization - uncontrolled hypertension, diabetes, and hyperlipidemia independently drive thromboembolic events 2, 3
• Do not dismiss subtle neurological symptoms - patients may not recognize transient ischemic attacks or minor strokes 2
• Do not continue therapy without reassessing risk-benefit if cardiovascular events occur during treatment 1