Anti-VEGF Agents in Ophthalmology: Comprehensive Review

Currently Available Anti-VEGF Agents

Four anti-VEGF agents are routinely used in ophthalmology: bevacizumab (off-label), ranibizumab (FDA-approved), aflibercept (FDA-approved), and pegaptanib (FDA-approved but rarely used). 1, 2 Additionally, brolucizumab received FDA approval in October 2019 for neovascular AMD. 1

Bevacizumab (Avastin)

Dosage: 1.25 mg intravitreal injection 1
FDA Status: Off-label use for all ophthalmic indications 3
Cost Profile: Significantly less expensive than FDA-approved alternatives, making it the most commonly used anti-VEGF agent (64.6% of all injections from 2006-2015) 3

Ranibizumab (Lucentis)

Dosage: 0.5 mg for AMD/RVO, 0.3 mg for DME 1, 2
FDA Status: Approved for neovascular AMD, DME, RVO, and diabetic retinopathy 1, 2
Pharmacokinetics: Clears from bloodstream more quickly than bevacizumab or aflibercept, with smallest decreases in plasma free-VEGF 4

Aflibercept (Eylea)

Dosage: 2.0 mg intravitreal injection 1, 2
FDA Status: Approved for neovascular AMD, macular edema following RVO, DME, diabetic retinopathy, and retinopathy of prematurity 2
Extended Dosing: After three loading doses at 4-week intervals, maintenance every 8 weeks has comparable efficacy to monthly dosing for AMD 1
Pharmacodynamics: Results in greatest reductions in plasma free-VEGF relative to baseline levels 4

Pegaptanib (Macugen)

Dosage: Administered with follow-up examinations approximately 6 weeks after each injection 1
Clinical Use: Rarely used in current practice due to inferior visual outcomes compared to ranibizumab and bevacizumab 5, 6

Brolucizumab (Beovu)

FDA Approval: October 2019 1
Efficacy: Achieved noninferiority to aflibercept at week 48 in HAWK and HARRIER trials, with superior reductions in central subfield thickness 1

Indications by Disease

Neovascular (Wet) Age-Related Macular Degeneration

Anti-VEGF therapy is the standard of care for neovascular AMD, with ranibizumab, bevacizumab, and aflibercept all demonstrating substantial visual improvement. 1, 5

Initial Treatment: Approximately 4-week intervals for all agents 1
Maintenance Regimens: Three protocols exist—monthly/bimonthly injections, treat-and-extend, or PRN (as-needed) 1
Comparative Efficacy: Visual acuity outcomes are similar between bevacizumab and ranibizumab when using the same regimens (RR 0.95 for gain of ≥15 letters, 95% CI 0.81-1.12) 5
Long-term Outcomes: 50% of patients maintained VA of 20/40 at 5-year follow-up 1

Treatment Algorithm:

Start with three loading doses at 4-week intervals 1
For aflibercept: transition to every 8 weeks after loading phase 1
For ranibizumab/bevacizumab: use treat-and-extend or PRN based on clinical findings 1
Monitor with OCT at each visit to detect active exudation 1

Diabetic Macular Edema

For center-involving DME with vision loss (20/30 or worse), intravitreal anti-VEGF treatment is the initial treatment choice. 1

Agent Selection Based on Baseline Vision:
- Vision 20/40 or better: All three agents (bevacizumab, ranibizumab, aflibercept) provide similar visual gains 1
- Vision 20/50 or worse: Aflibercept provides superior outcomes to bevacizumab (mean gain 18.3 vs 13.3 letters at 2 years), with ranibizumab intermediate (16.1 letters) 1
Dosing Protocol (DRCR.net):
- Monthly injections for 4-6 months initially 1
- Hold treatment if no improvement in vision/thickness OR if 20/20 vision achieved 1
- Resume if worsening occurs 1
- Double follow-up interval (up to 4 months) if consecutive visits require no treatment 1
Adjunctive Therapy: Focal laser for persistent edema despite anti-VEGF treatment may reduce injection burden (41% aflibercept, 64% bevacizumab, 52% ranibizumab patients required laser over 2 years) 1
Alternative First-Line: Macular laser or intravitreal corticosteroids for patients not candidates for anti-VEGF (e.g., pregnancy) 1

Proliferative Diabetic Retinopathy

Anti-VEGF therapy (ranibizumab and aflibercept FDA-approved) provides noninferior or superior visual outcomes compared to panretinal laser over 2 years. 1

Advantages over Laser:
- Less peripheral visual field loss 1
- Fewer vitrectomy surgeries for complications 1
- Lower risk of developing diabetic macular edema 1
Disadvantage: Requires greater number of visits and treatments than panretinal laser 1
Non-Proliferative DR: Anti-VEGF reduces subsequent neovascularization and DME development but does not improve visual outcomes over 2 years, therefore not routinely recommended 1

Retinal Vein Occlusion (Branch and Central)

Anti-VEGF agents are effective for macular edema associated with both BRVO and CRVO, with ranibizumab and aflibercept FDA-approved. 1, 7, 2

Branch Retinal Vein Occlusion

Ranibizumab Efficacy (BRAVO trial): Monthly 0.5 mg injections resulted in 18-letter gain vs 7.3 letters in sham group at 6 months; 61% gained ≥15 letters vs 29% sham 1
Aflibercept Efficacy (VIBRANT trial): Superior to grid laser for macular edema in BRVO 1
Bevacizumab: Demonstrated efficacy in smaller studies 1
Critical Timing: Delay in treatment is deleterious—eyes initially treated with sham then switched to ranibizumab did not achieve same visual gains as those treated from onset 1

Central Retinal Vein Occlusion

Neovascularization Management: Dense peripheral panretinal photocoagulation is primary treatment, with anti-VEGF as adjunctive therapy when complete PRP insufficient 7
Immediate Benefit: Anti-VEGF provides immediate benefit and may improve ability to deliver complete laser treatment 7
Goal: Prevent progression to iris neovascularization and neovascular glaucoma 7

Dosing Regimens Across Indications

Fixed Monthly Dosing

Maintains initial visual gains but requires frequent visits 1
Used in major trials (ANCHOR, MARINA, VIEW) 1

Treat-and-Extend

Interval adjusted based on treatment response 1
Comparable efficacy to monthly dosing with fewer injections at 2 years 1
Frequently used in clinical practice 1

PRN (As-Needed)

Based on presence/absence of subretinal or intraretinal fluid 1
Comparable efficacy to fixed monthly regimens over 1 year for ranibizumab, but may not maintain initial gains with longer follow-up 1
Caution: PRN bevacizumab may be slightly less effective than other regimens 1

Comparative Effectiveness

High-quality evidence demonstrates no clinically important difference (≥5 letters) in visual acuity gains between bevacizumab and ranibizumab for NVAMD and DME. 5, 8

AMD: Nine trials provide high-strength evidence of no difference between bevacizumab and ranibizumab 8
DME: Three trials provide moderate-strength evidence of no difference between bevacizumab and ranibizumab 8
Anatomic Outcomes: Bevacizumab less effective at reducing retinal thickening than aflibercept or ranibizumab in DME (difference of 11.6 μm, within measurement error range) 1, 5
Cost-Effectiveness: Aflibercept and ranibizumab significantly less cost-effective than repackaged bevacizumab 8

Safety Profile

Ocular Adverse Events

Endophthalmitis: <1% of anti-VEGF-treated participants (cumulative ≤1.0% over 1 year for aflibercept) 1, 5
Retinal Detachment: Rare complication of intravitreal injection 1, 2
Increased Intraocular Pressure: Most frequently reported serious ocular adverse event 1, 2
Retinal Vasculitis with/without Occlusion: Reported complication 2
RPE Tears: May occur with or without treatment, not a contraindication to continued anti-VEGF therapy 1

Systemic Adverse Events

Arterial Thromboembolic Events: Theoretical risk, but clinical trial results remain inconclusive 1
Comparative Safety: No statistically significant differences in death, arteriothrombotic events, or venous thrombotic events between ranibizumab and aflibercept at 1 year 1
DME Exception: One trial reported more arterial thrombotic events with ranibizumab versus aflibercept 8
Overall Assessment: Favorable risk-to-benefit profile with minimal systemic risks; severe adverse effects uncommon 7, 5

Special Populations

Pregnancy/Lactation: Risks not studied; avoid unless no alternative exists 1
Retinopathy of Prematurity: Aflibercept FDA-approved for this indication 2

Biosimilars

Biosimilars of aflibercept (including Pavblu/aflibercept-ayyh) are recognized as appropriate alternatives and therapeutically equivalent for approved indications. 7

Monitoring Requirements

Follow-Up Intervals

Initial Treatment Phase: Approximately 4-week intervals for all agents 1
AMD Maintenance: Variable based on regimen (monthly, every 8 weeks for aflibercept, or treat-and-extend) 1
DME: 1-3 months for center-involving DME; 3-6 months for stable DME 1
RVO: Based on clinical findings and treating ophthalmologist judgment 1

Essential Monitoring

OCT: Simple, noninvasive, well-accepted; provides critical management information 1
Fluorescein Angiography: Used when clinically indicated to detect active exudation 1
OCTA: May be useful for evaluating high-risk fellow eyes 1
Amsler Grid: Patient self-monitoring for metamorphopsia 1

Critical Clinical Pearls

Pitfall: Delaying anti-VEGF treatment in RVO results in inferior visual outcomes even when treatment is eventually initiated. 1

Pitfall: Sample sizes in clinical trials insufficient to estimate differences in rare safety outcomes; post-marketing surveillance remains important. 5

Pitfall: Patients with AMD often have cognitive impairment; family members or care assistants should prompt self-testing. 1

Pitfall: Bevacizumab provides similar outcomes to other agents in eyes with mild visual impairment (20/32-20/40) but not as effective at reducing retinal thickening. 1

What are the anti-Vascular Endothelial Growth Factor (VEGF) agents used in ophthalmology, including their indications and dosages?

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