What are the treatment protocols for anti-VEGF (Vascular Endothelial Growth Factor) injections, including Ranibizumab (ranibizumab), Aflibercept (aflibercept), and Bevacizumab (bevacizumab), in patients with age-related macular degeneration, diabetic macular edema, and macular edema due to vascular occlusion?

Anti-VEGF Treatment Protocols for Retinal Vascular Diseases

For diabetic macular edema with vision loss (20/30 or worse), initiate intravitreal anti-VEGF therapy as first-line treatment; for retinal vein occlusion-related macular edema, anti-VEGF agents are the primary treatment; and for neovascular age-related macular degeneration, anti-VEGF therapy is the standard of care with specific dosing protocols for each agent. 1

Treatment Protocols by Condition and Agent

Condition	Ranibizumab	Aflibercept	Bevacizumab
Age-Related Macular Degeneration (AMD)	0.5 mg intravitreal injection; monthly dosing or treat-and-extend protocols [1]	2 mg intravitreal injection; monthly for first 3 months, then every 8 weeks [1]	1.25 mg intravitreal injection; monthly or PRN dosing (off-label) [1]
Diabetic Macular Edema (DME)	0.3 or 0.5 mg intravitreal injection; monthly initially, then PRN or treat-and-extend [1]	2 mg intravitreal injection; superior outcomes at 1 year for vision 20/50 or worse [1]	1.25 mg intravitreal injection; similar outcomes to other agents for mild impairment (20/32-20/40), less effective for retinal thickening [1]
Macular Edema due to Retinal Vein Occlusion (RVO)	FDA-approved; dosing per protocol for both BRVO and CRVO [1]	FDA-approved; dosing per protocol for both BRVO and CRVO [1]	1.25 mg intravitreal injection; off-label but commonly used [1]

Detailed Protocol Considerations by Condition

Age-Related Macular Degeneration

• Initial treatment phase: Monthly injections are typically required during the first year to achieve maximal visual benefit 1
• Maintenance strategies: After initial loading, treat-and-extend protocols reduce injection burden while maintaining visual gains; intervals are adjusted based on treatment response 1
• Alternative dosing: PRN (as-needed) dosing after initial loading phase is acceptable but may result in more frequent monitoring visits 1

Diabetic Macular Edema

Agent Selection Based on Baseline Vision

• Vision 20/40 or better: All three agents show no significant differences in visual outcomes 1
• Vision 20/50 or worse: Aflibercept provides superior visual outcomes at 1 year compared to ranibizumab and bevacizumab 1
• By 2 years: Ranibizumab achieves similar results to aflibercept; bevacizumab remains inferior only to aflibercept 1

Treatment Protocols

• Loading phase: Monthly injections for first 6 months, then transition to as-needed protocol based on stability 1
• Injection frequency: Most patients require near-monthly administration during first 12 months, with fewer injections in subsequent years 1
• Treat-and-extend approach: Comparable to monthly dosing at 2 years with fewer total injections; intervals doubled up to 4 months if consecutive visits show no need for treatment 1

Management of Persistent DME

• Definition: DME persisting through 24 weeks of treatment 2
• Incidence: More frequent with bevacizumab (65.6%) than aflibercept (31.6%) or ranibizumab (41.5%) 2
• Switching agents: Patients with incomplete response to ranibizumab/bevacizumab may show anatomic improvement when switched to aflibercept (79% response rate at 1 month) 3, 4
• Adjunctive therapy: Focal/grid laser photocoagulation may reduce injection burden for persistent edema despite anti-VEGF treatment 1

Retinal Vein Occlusion

Branch Retinal Vein Occlusion (BRVO)

• Primary treatment: Anti-VEGF agents for macular edema 1
• FDA-approved agents: Ranibizumab and aflibercept 1
• Off-label option: Bevacizumab commonly used 1
• Neovascularization management: Grid laser photocoagulation in area of nonperfusion reduces vitreous hemorrhage risk; anti-VEGF may be used adjunctively 1

Central Retinal Vein Occlusion (CRVO)

• Initial treatment: Similar to BRVO, using anti-VEGF agents as first-line 1
• Secondary treatments: Intravitreal corticosteroids for inadequate response 1
• Iris neovascularization: Extensive peripheral panretinal photocoagulation indicated; initial anti-VEGF may provide immediate benefit and improve laser delivery 1

Common Pitfalls and Caveats

Safety Considerations

• Endophthalmitis risk: 0.019% to 0.09% in clinical trials; use topical povidone iodine (mandatory), avoid routine antibiotic drops (not beneficial) 1
• Systemic thromboembolic events: Theoretical risk exists but remains inconclusive in clinical trials; moderate certainty evidence supports safety 1
• Bevacizumab-specific: Higher rate of serious systemic events (24% vs 19% with ranibizumab, p=0.04) including arteriothrombotic events and gastrointestinal disorders 1

Treatment Response Monitoring

• DME with good vision (20/25 or better): Close monitoring with initiation of anti-VEGF only if vision worsens provides similar 2-year outcomes to immediate treatment 1
• Persistent edema: Meaningful vision gains occur with little risk of vision loss regardless of agent or persistence through 2 years; exercise caution before switching therapies as improvements may reflect continued treatment rather than agent change 2

Adjunctive Treatments

• Corticosteroids: Reasonable first-line for patients not candidates for anti-VEGF (e.g., pregnancy); also option for persistent DME despite anti-VEGF 1
• Laser photocoagulation: For non-center-involving DME, focal/grid laser remains an option; for center-involving DME, laser may be added for persistent edema 1

Follow-up Schedules

• Center-involving DME: 1-3 month follow-up intervals during active treatment 1
• Stable DME: 3-6 month intervals 1
• RVO with macular edema: Monthly monitoring during intensive treatment phase 1