What are the available intravitreal injections for age-related macular degeneration and how to choose between them?

Intravitreal Anti-VEGF Injections for Age-Related Macular Degeneration

For neovascular (wet) AMD, initiate treatment immediately with aflibercept, ranibizumab, bevacizumab, or brolucizumab—all are effective, but aflibercept offers the advantage of every-8-week dosing after loading, while brolucizumab provides superior fluid reduction and may allow 8-12 week intervals. 1, 2

Available Intravitreal Anti-VEGF Agents

FDA-Approved Options

• Aflibercept (Eylea): Approved for neovascular AMD, dosed at 2 mg per injection 3, 4
• Ranibizumab (Lucentis): Approved for neovascular AMD, dosed at 0.5 mg per injection 5, 6
• Brolucizumab (Beovu): FDA-approved October 2019 for neovascular AMD, dosed at 6 mg per injection 1, 2

Off-Label Option

• Bevacizumab (Avastin): Used off-label for economic reasons, though it may be slightly less effective than other anti-VEGF regimens and carries higher rates of serious systemic adverse events (24% vs 19% with ranibizumab) 1

Treatment Algorithm: How to Choose Between Agents

Step 1: Initial Loading Phase (All Agents)

• Aflibercept, ranibizumab, bevacizumab: Administer three loading doses at exactly 4-week intervals 1
• Brolucizumab: Administer three loading doses at 4-week intervals (approximately every 25-31 days) 2

Step 2: Maintenance Regimen Selection

Aflibercept is the preferred first-line agent because it allows bimonthly (every 8 weeks) dosing after loading, which is noninferior to monthly ranibizumab while reducing injection burden and risk 1, 3, 4

• Aflibercept maintenance: Every 8 weeks after loading doses—this regimen achieved 95.1-95.6% of patients maintaining vision (losing <15 letters), equivalent to monthly ranibizumab 3
• Brolucizumab maintenance: Every 8-12 weeks after loading—achieved noninferiority to aflibercept with superior central subfield thickness reduction and greater fluid resolution 1, 2
• Ranibizumab maintenance: Monthly, treat-and-extend, or PRN (as-needed) 1, 6
• Bevacizumab maintenance: Monthly or PRN, but use caution with PRN dosing as it may be slightly less effective 1

Step 3: Alternative Dosing Strategies

Treat-and-extend regimens are frequently used in clinical practice and show similar efficacy to monthly injections while reducing treatment burden 1

• After loading doses, extend intervals based on treatment response (presence/absence of fluid on OCT) 1
• LUCAS study demonstrated similar efficacy between monthly and treat-and-extend for bevacizumab and ranibizumab 1

PRN (as-needed) regimens are acceptable but slightly less effective long-term 1

• PRN ranibizumab has comparable efficacy to monthly over 1 year but does not maintain initial visual gains with longer follow-up 1
• Monthly regimens provide approximately 1.7 letters better visual acuity than PRN 7

Specific Clinical Scenarios

Treatment-Naive Patients

Start with aflibercept due to the every-8-week maintenance advantage after loading 1, 3, 4

• Achieves mean visual acuity gains within 0.5 letters of monthly ranibizumab 3
• Reduces injection frequency by 50% compared to monthly regimens 3

Patients with Persistent Fluid After Loading

Consider switching to brolucizumab if persistent subretinal, intraretinal, or sub-RPE fluid remains after initial anti-VEGF therapy 1, 2

• Brolucizumab achieved superior reductions in central subfield thickness compared to aflibercept 1
• Fewer patients treated with brolucizumab had residual fluid of any type 1

Non-Responders to Other Anti-VEGF Agents

Switch to aflibercept for patients with inadequate response to ranibizumab or bevacizumab 4, 8

• Switching study showed mean CST decrease of 38.6 µm (p<0.001) and mean BCVA increase of +5.9 letters (p<0.001) at 6 months 8
• 84.6% of switched patients gained visual acuity, with 15% experiencing >15-letter improvement 8

Cost-Constrained Settings

Bevacizumab is acceptable when cost is prohibitive, but patients must be informed of off-label status and potentially higher systemic adverse event rates 1, 6

• CATT trial showed bevacizumab monthly was equivalent to ranibizumab monthly for visual outcomes 1, 6
• However, bevacizumab had higher rates of serious systemic events (24% vs 19%, p=0.04) 1

Safety Considerations

Ocular Complications (All Agents)

• Endophthalmitis risk: ≤1.0% cumulative over 1-2 years for aflibercept and ranibizumab; 0.16% per injection for bevacizumab 1, 7
• Retinal detachment, retinal tear, vitreous hemorrhage: Rare but possible with all agents 1
• RPE tears: May occur but are not a contraindication to continued therapy 1

Systemic Adverse Events

• All anti-VEGF agents carry theoretical risks for arterial thromboembolic events, though clinical trial results remain inconclusive 1
• Bevacizumab has higher systemic SAE rates (24% vs 19% for ranibizumab, persistent at 2 years) 1
• No statistically significant differences in death, arteriothrombotic events, or venous thrombotic events between ranibizumab and aflibercept at 1 year 1

Special Brolucizumab Considerations

• Monitor specifically for inflammatory complications, particularly retinal (occlusive) vasculitis 9
• Safety profile is generally excellent and comparable to other anti-VEGF treatments 9

Monitoring Protocol

• OCT at every visit to assess for subretinal or intraretinal fluid 1, 7
• Biomicroscopic fundus examination at each follow-up 1
• Fluorescein angiography and fundus photography when clinically indicated 1
• Patients must report symptoms of endophthalmitis, retinal detachment, or decreased vision immediately 1, 7

Critical Pitfalls to Avoid

• Do not use PRN bevacizumab as first-line: It may be slightly less effective than other monthly anti-VEGF regimens and other PRN anti-VEGF regimens 1
• Do not delay treatment: Early treatment within 2 years of diagnosis significantly reduces legal blindness and visual impairment 10, 7
• Do not abandon monthly monitoring with PRN regimens: Vision gains are not maintained long-term without appropriate monitoring 1
• Obtain informed consent for bevacizumab: Discuss off-label status and higher systemic adverse event rates 7

Long-Term Outcomes

• At 5-year follow-up in CATT, 50% of patients maintained visual acuity of 20/40 despite initial vision gains not being fully maintained 1, 7
• Fellow eyes remain at exceptionally high risk (up to 36% over 10 years) and should be monitored every 6-12 months even without symptoms 1, 10