What are the ocular and systemic side effects of intravitreal anti‑vascular endothelial growth factor (anti‑VEGF) injections for macular degeneration?

Side Effects of Eye Injections for Macular Degeneration

Anti-VEGF intravitreal injections for macular degeneration are generally safe and effective, with serious ocular complications occurring in less than 1% of cases, though patients must be counseled about both rare vision-threatening ocular events and theoretical systemic risks 1.

Ocular (Eye-Related) Side Effects

Most Serious Complications (Rare but Vision-Threatening)

Endophthalmitis (eye infection) is the most feared complication:

• Occurs in ≤1.0% of patients over 1-2 years with ranibizumab and aflibercept 1
• 0.16% per injection with bevacizumab 1
• 1.3% with pegaptanib 1
• Requires immediate recognition and treatment to prevent permanent vision loss

Retinal detachment and tears:

• Rhegmatogenous retinal detachment: 0.02% with bevacizumab 1
• Tractional retinal detachment: 0.16% with bevacizumab 1
• Retinal tears can occur, particularly in eyes with vitreous traction 1
• Less than 0.1% with ranibizumab during first year 1

Other serious ocular complications:

• Noninfectious inflammation (sterile uveitis): 0.09% with bevacizumab 1
• Vitreous hemorrhage: 0.16% with bevacizumab 1
• Traumatic lens injury: 0.6% with pegaptanib, <0.1% with ranibizumab 1
• Severe vision loss (≥15 letters) within 1 week: occurs in 1-4% of patients and may be permanent 1

Common but Less Serious Ocular Effects

Increased intraocular pressure (IOP):

• Can occur as transient spike immediately after injection or sustained elevation with repeated treatments 2
• All anti-VEGF agents carry theoretical risk, though clinical trial results remain inconclusive 1

Retinal pigment epithelium (RPE) tears:

• May occur with or without treatment
• Not a contraindication to continued anti-VEGF therapy 1

Systemic (Body-Wide) Side Effects

Cardiovascular and Thromboembolic Events

The evidence on systemic risks is mixed but suggests caution in high-risk patients:

Bevacizumab shows slightly higher systemic event rates:

• CATT study found 24% vs 19% serious systemic events (bevacizumab vs ranibizumab, P=0.04) 1
• Events included arteriothrombotic events, venous thrombosis, and gastrointestinal hemorrhage
• This difference persisted at 2-year follow-up 1
• However, IVAN trial showed no statistically significant difference in serious systemic adverse events despite greater serum VEGF suppression with bevacizumab 1

Overall systemic safety profile:

• Recent real-world data from Taiwan (2024) showed all three agents (bevacizumab, ranibizumab, aflibercept) had low and comparable rates of major adverse cardiac events, heart failure, thromboembolic events, major bleeding, and death 3
• No differences in long-term changes in blood pressure, kidney function, or liver enzymes 3
• Theoretical risks for arterial thromboembolic events exist but clinical trial results remain inconclusive 1

Other Systemic Considerations

Blood pressure and renal effects:

• Potential cardiovascular events and blood pressure alterations reported, particularly in patients with preexisting vascular risk factors 2
• Proteinuria has been reported 4

Pregnancy and lactation:

• Risks in pregnant or lactating women have not been studied 1
• Should be avoided in these populations

Clinical Implications and Risk Stratification

Patients at higher risk for systemic complications:

• Those with preexisting cardiovascular disease
• History of stroke or transient ischemic attacks
• Active thromboembolic disease
• Uncontrolled hypertension

Key counseling points:

• Overall, anti-VEGF therapy is safe and effective for neovascular AMD 1
• Serious ocular complications are rare (mostly <1%)
• Systemic events appear uncommon but may be slightly higher with bevacizumab in certain populations
• Benefits of vision preservation typically outweigh risks for most patients
• Immediate reporting of symptoms (pain, vision loss, floaters, flashes) is critical

Common Pitfalls to Avoid

1. Failing to distinguish sterile inflammation from infectious endophthalmitis - these require completely different management and have vastly different prognoses 2

2. Dismissing patient concerns about systemic risks - while rare, cardiovascular events can occur, particularly in high-risk patients; individualized risk assessment is warranted

3. Not monitoring IOP - both acute and chronic IOP elevation can occur and requires monitoring, especially with repeated injections

4. Stopping treatment due to RPE tears - these are not a contraindication to continued therapy 1