Elicit: Clinical Outcomes of Aflibercept in AMD and DME

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Clinical Outcomes of Aflibercept in AMD and DME

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May 5, 2026

What clinical outcomes support aflibercept treatment of wet AMD and diabetic macular edema?

Aflibercept treatment for wet AMD and diabetic macular edema is supported by visual acuity improvements equivalent to ranibizumab and superior to laser photocoagulation, significant anatomical improvements including central retinal thickness reductions and diabetic retinopathy severity improvements, clinically meaningful quality of life gains, and a safety profile comparable to other anti-VEGF agents with the advantage of less frequent dosing.

Abstract

Aflibercept treatment for wet age-related macular degeneration produces visual acuity outcomes equivalent to ranibizumab, with both treatments showing similar mean BCVA changes (within 0.5 letters) and approximately 32% of patients gaining ≥15 letters at one year. Anatomical outcomes were also similar, with comparable proportions achieving dry retina (RR 1.06, 95% CI 0.98 to 1.14) and equivalent choroidal neovascularization area reductions. For diabetic macular edema, aflibercept demonstrated statistically significant superiority over laser photocoagulation, with mean BCVA gains of 10.5-13.6 letters compared to -0.5 to 1.2 letters for laser (p<0.0001), and central retinal thickness reductions of 183-195 μm versus 66-73 μm for laser (p<0.0001). At 148 weeks, 35.8-42.9% of aflibercept-treated eyes gained ≥15 letters versus 13.6-18.9% with laser. Aflibercept showed non-inferiority to bevacizumab (mean improvement 15.0 versus 14.0 letters, p=0.37) and better anatomical outcomes than ranibizumab in real-world practice (central subfield thickness reduction -114.4 μm versus -87.8 μm, p<0.01). Quality of life improved meaningfully in both conditions, with NEI VFQ-25 total score gains of +6.11 points in DME and clinically significant improvements across multiple subscales in wet AMD. The safety profile was comparable to other anti-VEGF agents, with serious systemic adverse events similar to ranibizumab (RR 0.99, 95% CI 0.79 to 1.25) and no new safety signals identified in long-term use. The every-8-weeks maintenance dosing regimen after initial loading reduced treatment burden compared to monthly regimens while maintaining efficacy.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question. More on methods

Records from Elicit search

n = 200

Papers screened using: Target Population, Intervention, Clinical Outcomes, Study Design, Follow-up Duration, Aflibercept Analysis, Study Quality and Accessibility, Study Scope

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

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Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: “What clinical outcomes support aflibercept treatment of wet AMD and diabetic macular edema?”

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

Extract study design and population characteristics for aflibercept studies in wet AMD or diabetic macular edema, including:

Extract all visual acuity and functional vision outcomes for aflibercept treatment in wet AMD or diabetic macular edema, including:

Extract morphological and anatomical outcomes for aflibercept in wet AMD or diabetic macular edema, including:

Extract patient-reported outcomes and quality of life measures for aflibercept treatment in wet AMD or diabetic macular edema, including:

Extract safety and adverse event data for aflibercept in wet AMD or diabetic macular edema studies, including:

Extract aflibercept dosing and administration details for wet AMD or diabetic macular edema, including:

Extract comparative effectiveness data when aflibercept is compared to other treatments for wet AMD or diabetic macular edema, including:

Extract study limitations and factors affecting interpretation of aflibercept outcomes in wet AMD or diabetic macular edema, including:

Results

Characteristics of included studies

The systematic review included 10 sources examining aflibercept treatment for wet age-related macular degeneration (AMD) and diabetic macular edema (DME). These comprised randomized controlled trials, observational studies, and systematic reviews.

Study

Full text retrieved?

Study Type

Sample Size

Patient Population

Baseline Characteristics

Comparator

Follow-up Duration

J. Heier et al., 2012

Yes

RCT

2419 patients

Wet AMD

Active, subfoveal CNV

Ranibizumab

52 weeks

J. M. Ruiz-Moreno, 2015

No

Phase III RCT

461/402 patients

DME

Not specified

Laser

52 weeks

J. Heier et al., 2016

No

Phase III RCT

872 eyes

DME

Central-involved DME

Laser

148 weeks

Chirag Jhaveri et al., 2022

No

RCT

312 eyes (158 aflibercept)

DME

Moderate vision loss (VA 24-69 letters)

Bevacizumab first

2 years

You-Xin Chen et al., 2020

No

Phase III RCT

127 eyes per group

DME

Not specified

Laser

52 weeks

Pierre-Henry Gabrielle et al., 2022

No

Retrospective

534 eyes (267 aflibercept)

DME

Moderate (VA ≤68) and mild (VA ≥69) impairment

Ranibizumab

3 years

S. Sarwar et al., 2016

No

Cochrane review

2457 participants

Wet AMD

Treatment-naive, active subfoveal CNV

Ranibizumab

1-2 years

J. Carrasco et al., 2021

Yes

Meta-analysis

40-2506 patients/eyes

Wet AMD

Mean age 78.62 years, baseline BCVA 57.73 letters

None

2 years

M. Yuzawa et al., 2015

No

Phase III RCT

2419 patients (607 aflibercept)

Wet AMD

Treatment-naive, exudative AMD

Ranibizumab

52 weeks

J. Garweg et al., 2019

No

Phase IV single-arm

553 patients

DME

Mean BCVA 61.5 letters, mean CRT 464.81 μm

None

52 weeks

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The studies represented diverse designs, with five focusing on wet AMD and five on DME. Most studies were randomized controlled trials, with comparators including ranibizumab, bevacizumab, and laser photocoagulation. Follow-up durations ranged from 52 weeks to 3 years. Only two studies had full texts available for detailed extraction (J. Heier et al., 2012 and J. Carrasco et al., 2021).

Effects

Visual Acuity Outcomes in Wet AMD

Aflibercept demonstrated substantial and sustained visual acuity improvements in wet AMD across multiple studies. In the VIEW trials comparing aflibercept to ranibizumab, all aflibercept regimens were within 0.5 letters of ranibizumab for mean change in BCVA, demonstrating clinical equivalence. At one year, the mean change in BCVA was similar between aflibercept and ranibizumab groups (mean difference -0.15 ETDRS letters, 95% CI -1.47 to 1.17). This similarity persisted at two years, with mean changes of 7.2 letters for aflibercept versus 7.9 letters for ranibizumab.

Study

Time Point

Mean BCVA Change

Proportion Gaining ≥15 Letters

Proportion Achieving ≥70 Letters

Statistical Significance

S. Sarwar et al., 2016

1 year

-0.15 letters vs ranibizumab (95% CI -1.47 to 1.17)

~32% (RR 0.97, 95% CI 0.85 to 1.11)

Not reported

High-quality evidence

S. Sarwar et al., 2016

2 years

7.2 letters

~31% (RR 0.98, 95% CI 0.85 to 1.12)

Not reported

High-quality evidence

J. Carrasco et al., 2021

2 years

+4.49 letters

Not reported

47.39%

Not specified

M. Yuzawa et al., 2015

52 weeks

Similar improvements in NEI VFQ-25

Not reported

Not reported

Similar to ranibizumab

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The real-world meta-analysis reported a mean BCVA of 62.55 ETDRS letters at 2 years, with 47.39% of patients achieving visual acuity of ≥70 letters. The mean gain from baseline was +4.49 letters for the combined population and +5.91 letters for patients treated with a treat-and-extend regimen. Vision loss was minimal, with similar small proportions in aflibercept and ranibizumab groups losing ≥15 letters at one year (RR 0.89, 95% CI 0.61 to 1.30).

Visual Acuity Outcomes in Diabetic Macular Edema

Aflibercept demonstrated consistent superiority over laser photocoagulation and non-inferiority to other anti-VEGF agents in DME. In the VISTA and VIVID trials, mean BCVA gains with aflibercept were 12.5 and 10.7 letters versus 0.2 letters with laser in VISTA, and 10.5 and 10.7 letters versus 1.2 letters with laser in VIVID (p<0.0001 for all comparisons).

Study

Time Point

Aflibercept Regimen

Mean BCVA Gain

Proportion Gaining ≥15 Letters

Comparator BCVA Gain

p-value

J. M. Ruiz-Moreno, 2015

52 weeks

2q4 (VISTA)

12.5 letters

Significant vs laser

0.2 letters (laser)

p<0.0001

J. M. Ruiz-Moreno, 2015

52 weeks

2q8 (VISTA)

10.7 letters

Significant vs laser

0.2 letters (laser)

p<0.0001

J. M. Ruiz-Moreno, 2015

52 weeks

2q4 (VIVID)

10.5 letters

Significant vs laser

1.2 letters (laser)

p<0.0001

J. M. Ruiz-Moreno, 2015

52 weeks

2q8 (VIVID)

10.7 letters

Significant vs laser

1.2 letters (laser)

p<0.0001

J. Heier et al., 2016

148 weeks

2q4 (VISTA)

10.4 letters

42.9%

1.4 letters (laser)

p<0.0001

J. Heier et al., 2016

148 weeks

2q8 (VISTA)

10.5 letters

35.8%

1.4 letters (laser)

p<0.0001

J. Heier et al., 2016

148 weeks

2q4 (VIVID)

10.3 letters

41.2%

1.6 letters (laser)

p<0.0001

J. Heier et al., 2016

148 weeks

2q8 (VIVID)

11.7 letters

42.2%

1.6 letters (laser)

p<0.0001

You-Xin Chen et al., 2020

52 weeks

2q4

+13.6 letters

43.3%

-0.5 letters (laser)

p<0.0001

You-Xin Chen et al., 2020

52 weeks

2q8

+13.1 letters

36.5%

-0.5 letters (laser)

p<0.0001

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Long-term outcomes remained robust. At 148 weeks, mean BCVA gains with aflibercept 2q4 and 2q8 were 10.4 and 10.5 letters respectively in VISTA, and 10.3 and 11.7 letters in VIVID, compared to 1.4 and 1.6 letters with laser control (p<0.0001 for all). The proportion of eyes gaining ≥15 letters at 148 weeks ranged from 35.8% to 42.9% for aflibercept versus 13.6% to 18.9% for laser control.

In the VIVID-East study of Asian patients with DME, both aflibercept regimens (2q4 and 2q8) achieved mean BCVA gains of +13.6 and +13.1 letters respectively at 52 weeks, compared to -0.5 letters with laser (p<0.0001). A significantly higher proportion achieved ≥15-letter gains (43.3% for 2q4, 36.5% for 2q8, versus 12.1% for laser).

When compared to other anti-VEGF agents, aflibercept showed similar effectiveness. In the comparison of aflibercept monotherapy versus bevacizumab-first with potential switch to aflibercept, mean improvement was 15.0 letters for aflibercept versus 14.0 letters for bevacizumab-first (adjusted difference 0.8 letters, 95% CI -0.9 to 2.5, p=0.37). The real-world retrospective analysis found that at 3 years, the adjusted mean visual acuity change was +2.4 letters for aflibercept versus +1.3 letters for ranibizumab (p=0.001).

Anatomical Outcomes

Aflibercept produced significant anatomical improvements in both wet AMD and DME. In wet AMD, the proportion of eyes achieving dry retina (absence of fluid on OCT) was similar between aflibercept and ranibizumab (RR 1.06, 95% CI 0.98 to 1.14). Choroidal neovascularization area reduction showed no significant difference between the two agents (mean difference -0.24 mm², 95% CI -0.78 to 0.29). In one observational study, the proportion of active CNV lesions decreased from 80% to 58% over 12 months after switching to aflibercept.

For DME, central retinal thickness reductions were substantial and significantly greater than laser photocoagulation:

Study

Time Point

Aflibercept CRT Change (2q4)

Aflibercept CRT Change (2q8)

Comparator CRT Change

p-value

J. M. Ruiz-Moreno, 2015

52 weeks (VISTA)

-185.9 μm

-183.1 μm

-73.3 μm (laser)

p<0.0001

J. M. Ruiz-Moreno, 2015

52 weeks (VIVID)

-195.0 μm

-192.4 μm

-66.2 μm (laser)

p<0.0001

You-Xin Chen et al., 2020

52 weeks

Significantly greater

Significantly greater

Laser

Not specified

J. Garweg et al., 2019

52 weeks

-175.38 μm (SD 132.62)

N/A

N/A

N/A

Pierre-Henry Gabrielle et al., 2022

3 years

N/A

-114.4 μm (95% CI -134.4 to -94.3)

-87.8 μm (ranibizumab)

p<0.01

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The real-world comparison to ranibizumab showed aflibercept had significantly better anatomical outcomes, with adjusted mean central subfield thickness change remaining significantly different throughout the 3-year period (-114.4 μm for aflibercept versus -87.8 μm for ranibizumab, p<0.01).

Diabetic retinopathy severity also improved with aflibercept treatment. Greater proportions of eyes treated with aflibercept showed improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale compared to laser control in both VISTA (29.9% for 2q4, 34.4% for 2q8, versus 20.1% for laser, p=0.0350 and p=0.0052 respectively) and VIVID (44.3% for 2q4, 47.8% for 2q8, versus 17.4% for laser, p<0.0001 for both). The proportion of patients with improvement >2 levels in diabetic retinopathy severity was significant for aflibercept groups versus laser.

Vision-Related Quality of Life

Quality of life assessments demonstrated clinically meaningful improvements with aflibercept treatment. In wet AMD, the NEI VFQ-25 scores showed similar improvements across all subscales over 52 weeks for aflibercept 2q8 and ranibizumab, with the greatest improvements in mental health and general vision (9.0-11.6 points for both treatments). Improvements of ≥4 points were observed for near vision, distance vision, role difficulties, and dependency subscales. Mean change from baseline in composite NEI VFQ-25 score showed meaningful improvement only in patients who gained ≥5 ETDRS letters (7.3 points for aflibercept 2q8 and 7.8 points for ranibizumab).

For DME, the AQUA study reported substantial quality of life improvements at 52 weeks:

Quality of Life Measure

Baseline Score

Week 52 Change

Clinical Significance

NEI VFQ-25 total score

70.12

+6.11 (SD 11.46)

Clinically meaningful

Near activities subscale

Not specified

+11.37 (SD 18.01)

More pronounced than distance

Distance activities subscale

Not specified

+7.33 (SD 17.32)

Clinically meaningful

Better-seeing eye

Not specified

+7.74 (SD 13.59)

Comprehensive improvement

Worse-seeing eye

Not specified

+5.48 (SD 9.70)

Clinically meaningful

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The improvements were more pronounced for near activities than for distant activities, suggesting significant impact on daily functioning. These quality of life improvements support aflibercept use in DME as they were clinically meaningful.

Safety Profile

The safety profile of aflibercept was generally favorable and comparable to other anti-VEGF agents. In wet AMD trials, ocular and systemic adverse events were similar across aflibercept and ranibizumab treatment groups. The Cochrane review reported that serious systemic adverse events were similar between aflibercept and ranibizumab (RR 0.99, 95% CI 0.79 to 1.25), while the risk of serious ocular adverse events was lower in the aflibercept group, though with an imprecise estimate (RR 0.62, 95% CI 0.36 to 1.07). However, the quality of evidence for adverse events was graded as moderate due to imprecision.

For DME, safety profiles were consistent across studies:

Study

Serious Ocular Adverse Events

Treatment-Emergent Adverse Events

Deaths

Safety Conclusion

J. M. Ruiz-Moreno, 2015

Similar across groups

Similar ocular and nonocular events

Not reported

Comparable to laser

J. Heier et al., 2016

Cataract: 3.1% (2q4), 2.1% (2q8), 0.3% (control)

Consistent with known profile

Not reported

Known safety profile maintained

Chirag Jhaveri et al., 2022

Not specified

52% (aflibercept) vs 36% (bevacizumab)

Not reported

More events with aflibercept

You-Xin Chen et al., 2020

Not specified

Conjunctival hemorrhage (11.8%), retinal hemorrhage (8.7%), retinal aneurysm (7.5%), retinal exudates (5.5%)

Not reported

Low and similar across groups

Pierre-Henry Gabrielle et al., 2022

Low rate

Not specified

Not reported

Safe with low serious events

J. Garweg et al., 2019

Endophthalmitis (0.5%)

53.6% overall; 26.8% ocular

5 (0.9%), not treatment-related

Consistent with known profile

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In the comparison of aflibercept monotherapy to bevacizumab-first, serious adverse events (52% versus 36%) and hospitalizations for adverse events (48% versus 32%) were more common in the aflibercept-monotherapy group. The real-world meta-analysis indicated no new safety signals were identified in long-term use, though comprehensive safety data were limited. The most common serious ocular adverse event in the AQUA study was endophthalmitis, occurring in 0.5% of patients.

Long-term safety over 148 weeks showed that the incidence of adverse events remained consistent with the known safety profile of aflibercept. Overall, 53.6% of DME patients experienced treatment-emergent adverse events, with 26.8% being ocular events in the study eye.

Treatment Regimens

Aflibercept was administered at a dose of 2 mg across all studies. Two primary dosing regimens emerged:

Every 4 weeks regimen (2q4): Monthly injections throughout the treatment period.

Every 8 weeks regimen (2q8): The more common regimen involved 3-5 initial monthly loading doses followed by maintenance dosing every 8 weeks. Specifically, wet AMD studies used 3 initial monthly doses, while DME studies used 5 initial monthly doses.

The eight-week dosing regimen represented reduced treatment requirements compared to monthly dosing regimens and offered the potential to reduce treatment burden and risks from frequent injections. Over 2 years in real-world practice, patients received a mean of 12.34 injections, with a reduction in injections in Year 2 versus Year 1. In the AQUA study, patients received a mean of 8.8 injections over 52 weeks. One observational study showed a decrease in mean number of injections from 7.4 in the 12 months before switching to aflibercept to 6.6 in the 12 months after switching.

Rescue treatment protocols allowed flexibility in dosing. From week 24 in some DME trials, aflibercept patients could receive active laser if rescue criteria were met, while laser control patients could receive aflibercept 2q8. From week 100, laser control patients who had not received rescue treatment could receive aflibercept as needed per retreatment criteria. The treat-and-extend regimen in real-world practice achieved a mean BCVA gain of +5.91 letters at 2 years.

Comparative Effectiveness

Aflibercept demonstrated non-inferiority to ranibizumab in wet AMD and superiority to laser photocoagulation in DME, while showing comparable effectiveness to bevacizumab.

Versus Ranibizumab in Wet AMD:

In the VIEW trials, aflibercept regimens were noninferior and clinically equivalent to ranibizumab, with all aflibercept groups within 0.5 letters of ranibizumab for mean change in BCVA. Visual acuity outcomes were similar at one and two years, with approximately 32% and 31% of patients in both groups gaining ≥15 letters respectively. The proportion of eyes achieving dry retina was similar (RR 1.06, 95% CI 0.98 to 1.14), and CNV area reduction showed no significant difference (mean difference -0.24 mm², 95% CI -0.78 to 0.29). The similarity in morphological outcomes and visual acuity, combined with aflibercept’s less frequent dosing schedule, supported its use as an alternative to ranibizumab.

Versus Laser in DME:

Aflibercept demonstrated statistically significant superiority over laser photocoagulation in improving BCVA and reducing DME. Mean BCVA gains were significantly higher for aflibercept groups (10.5-12.5 letters) compared to laser (0.2-1.2 letters). Significant improvements were also seen in central retinal thickness reductions and the proportion of patients gaining ≥15 letters. At 148 weeks, aflibercept groups showed sustained superior outcomes in BCVA gain and DRSS score improvements compared to laser control. In the VIVID-East study of Asian patients, aflibercept showed significant improvements in BCVA and central retinal thickness reduction compared to laser.

Versus Bevacizumab in DME:

In the direct comparison of aflibercept monotherapy versus bevacizumab-first with potential switch to aflibercept, no significant difference in visual outcomes was found over 2 years (mean improvement 15.0 versus 14.0 letters, adjusted difference 0.8 letters, p=0.37). This indicated non-inferiority of aflibercept compared to a bevacizumab-first strategy.

Versus Ranibizumab in DME:

The real-world retrospective analysis found that visual acuity change was not clinically different between aflibercept and ranibizumab, but aflibercept had better anatomical outcomes. The adjusted mean central subfield thickness change remained significantly different throughout the 3-year period in favor of aflibercept (p<0.01). When baseline visual impairment was moderate (VA ≤68 ETDRS letters), aflibercept showed faster improvement in visual acuity up to 18 months compared to ranibizumab, though outcomes were similar by 36 months.

Real-World Versus Clinical Trial Results:

The real-world meta-analysis reported mean BCVA gains of +4.49 ETDRS letters at 2 years, which was higher than ranibizumab’s real-world results (1.2 to 3.4 ETDRS letters), though direct comparative effectiveness data between aflibercept and ranibizumab in real-world settings at 2 years were not available. The switching study showed that when patients transitioned from ranibizumab to aflibercept, mean visual acuity remained unchanged but with a modest increase in treatment intervals, suggesting real-world effectiveness similar to clinical trial results.

References

J. Heier, David M. Brown, V. Chong, J. Korobelnik, P. Kaiser, and 15 more\ (2012).Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology (Rochester, Minn.)

Chirag Jhaveri, A. Glassman, F. Ferris, Danni Liu, M. Maguire, and 11 more\ (2022).Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. New England Journal of Medicine

You-Xin Chen, Xiao-Xin Li, Y. Yoon, Xiaodong Sun, Y. Astakhov, and 4 more\ (2020).Intravitreal Aflibercept versus Laser Photocoagulation in Asian Patients with Diabetic Macular Edema: The VIVID-East Study. Clinical Ophthalmology

J. M. Ruiz-Moreno\ (2015).[New perspectives in the approach to diabetic macular edema. Aflibercept therapy]. Archivos de la Sociedad Española de Oftalmología

J. Heier, J. Korobelnik, David M. Brown, U. Schmidt-Erfurth, D. Do, and 16 more\ (2016).Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology (Rochester, Minn.)

Pierre-Henry Gabrielle, V. Nguyen, C. Creuzot-Garcher, J. Arnold, H. Mehta, and 7 more\ (2022).THREE-YEAR TREATMENT OUTCOMES OF AFLIBERCEPT VERSUS RANIBIZUMAB FOR DIABETIC MACULAR EDEMA. Retina

S. Sarwar, E. Clearfield, Mohamed Kamel Soliman, M. Sadiq, Andrew J Baldwin, and 5 more\ (2016).Aflibercept for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews

J. Carrasco, V. Daien, B. Eldem, J. Spoorendonk, Jisu Yoon\ (2021).2-Year Real-World Outcomes with Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: Literature Review and Meta-analysis of Patient-Relevant Outcomes. Ophthalmology and Therapy

M. Yuzawa, K. Fujita, K. Wittrup-jensen, C. Norenberg, O. Zeitz, and 6 more\ (2015).Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration. Ophthalmology (Rochester, Minn.)

J. Garweg, J. Štefanickova, C. Hoyng, T. Schmelter, T. Niesen, and 2 more\ (2019).Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study. Ophthalmology Retina

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2-Year Real-World Outcomes with Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: Literature Review and Meta-analysis of Patient-Relevant Outcomes

J. Carrasco, V. Daien, B. Eldem, J. Spoorendonk, Jisu Yoon

Ophthalmology and Therapy·

2021·

8 citations

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Study Design

- Study type: Literature review and meta-analysis of observational studies - Sample size: Ranges from 40 to 2506 patients/eyes - Patient population: Treatment-naïve patients with neovascular age-related macular degeneration (nAMD) - Baseline disease characteristics: Mean age of 78.62 years, mean baseline BCVA of 57.73 ETDRS letters - Comparator group: None - Follow-up duration: 2 years

Visual Outcomes

- Best-corrected visual acuity (BCVA) changes from baseline: Mean gain of +4.49 ETDRS letters at 2 years - Proportion achieving specific visual acuity thresholds: 47.39% of patients achieved a BCVA ≥70 ETDRS letters at 2 years - Time points assessed: 2 years - Whether outcomes support aflibercept effectiveness: Yes, the visual gains achieved during the first year are maintained through the second year.

Anatomical Outcomes

Not mentioned (the paper does not provide specific anatomical outcomes such as central retinal thickness changes, proportion achieving dry retina, choroidal neovascularization area changes, diabetic retinopathy severity scale improvements, fluorescein angiography leakage findings, or optical coherence tomography findings)

Quality of Life

Not mentioned (the paper does not include information on quality of life measures such as NEI VFQ-25 scores, functional vision assessments, patient satisfaction measures, or vision-related disability assessments)

Safety Profile

- Serious ocular adverse events: Endophthalmitis (1 case), non-infectious inflammation (1 case), dehiscence of conjunctiva on the injection site (2 cases) - Serious systemic adverse events: Not mentioned - Treatment-emergent adverse events by category: Not detailed - Rates and risk ratios compared to control groups: Not provided - Deaths and relationship to treatment: Not mentioned - Injection-related complications: Not detailed - Long-term safety findings: Limited data; no new safety signals identified - Whether safety profile supports aflibercept use in these conditions: Generally favorable but lacks comprehensive data

Treatment Regimen

- Dose administered: Not explicitly mentioned, but typically 2mg. - Initial loading schedule: Implied to be monthly for 3 doses, similar to the VIEW studies. - Maintenance schedule: Fixed bimonthly regimen in Year 1, variable dosing regimen in Year 2, with some patients on a treat-and-extend regimen. - Total number of injections over study period: Mean of 12.34 injections over 2 years. - Rescue treatment protocols: Not mentioned. - Treatment burden compared to other regimens: Injection frequency decreases from Year 1 to Year 2. - Retreatment criteria used: Not mentioned. - Whether dosing regimen is practical and effective: Supported by significant gains in visual acuity.

Comparative Effectiveness

- Aflibercept maintains visual gains from the first year to the second year with reduced injections. - Mean gain in VA for aflibercept is higher than ranibizumab in real-world studies (4.49 ETDRS letters vs. 1.2 to 3.4 ETDRS letters). - No direct comparison of relative effectiveness between aflibercept and ranibizumab in real-world data at 2 years. - No mention of comparisons to bevacizumab, laser photocoagulation, non-inferiority/superiority findings, head-to-head efficacy outcomes, or cost-effectiveness considerations.

Key Limitations

- Limited database search (only MEDLINE) - Search conducted in 2019, missing recent studies - Use of retrospective studies with associated biases - Arbitrary cutoff for study inclusion (40 patients/eyes) - Low number of studies included in meta-analysis (11) - Analysis based on aggregate data, introducing ecological bias - Lack of comprehensive adverse event reporting - High heterogeneity between studies - No new human or animal studies included - Lack of direct comparison with other treatments (e.g., ranibizumab) - Need for further research to understand outcomes

The 96 weeks’ assessment from the VIEW studies provided insights into the long-term efficacy of intravitreal aflibercept (IVT-AFL) in neovascular age-related macular degeneration (nAMD) and demonstrated that it was possible to maintain long-term outcomes while moving from a fixed bimonthly regimen in Year 1 to a variable dosing regimen in Year 2. The aim of this analysis was to perform a literature review and meta-analysis assessing the use of IVT-AFL and real-world outcomes in treatment-naïve patients with nAMD treated with IVT-AFL for 2 years, as per label. A literature review and meta-analysis were performed to provide an overview of the baseline characteristics of the population, the 2-year outcomes, the associated treatment burden, and safety. Eleven publications providing data from patients with nAMD who had treatment initiated with IVT-AFL between 2012 and 2016 were identified. The mean baseline age of patients was 78.62 years, with a baseline best-corrected visual acuity (BCVA) of 57.73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Patients reported a mean BCVA at 2 years of 62.55 ETDRS letters, with 47.39% of patients having a BCVA ≥ 70 ETDRS letters. Mean gain in BCVA versus baseline was + 4.49 ETDRS letters for the combined population (+ 5.91 letters for patients treated with a treat-and-extend regimen). Over the 2 years of the study, patients received an average of 12.34 injections, with a reduction in injections in Year 2 versus Year 1. The qualitative assessment of the safety data suggested that no new safety signals were identified. Patients treated with IVT-AFL reported significant gains in visual acuity versus baseline after 2 years. The evidence identified indicates that the visual gains achieved during the first year of treatment are maintained through the second year and that these were achieved with a reduction in the mean number of IVT-AFL injections administered in Year 2 of treatment.

The 96 weeks' assessment of the VIEW studies provided insights regarding the long-term efficacy of intravitreal aflibercept (IVT-AFL) in the treatment of neovascular age-related macular degeneration (nAMD) and demonstrated that it was possible to maintain long-term outcomes while moving from a fixed bimonthly regimen in Year 1 to a variable dosing regimen in Year 2 in a clinical trial setting.

Because clinical trial treatment protocols and clinical trial results may not always be replicable in real-world settings, our objective was to conduct a systematic literature review and meta-analysis of the published evidence describing 2-year outcomes in treatment-naı ¨ve patients with nAMD treated with IVT-AFL.

The aim of the analysis was to describe the characteristics of the population treated with IVT-AFL in routine clinical practice, the IVT-AFL treatment approaches used, and how key patient relevant outcomes, such as change in visual acuity (VA) evolved.

The analysis showed that, after 2 years, patients treated with IVT-AFL reported significant gains in VA versus baseline. The evidence identified shows that it was possible to achieve good long-term outcomes with IVT-AFL in clinical practice and maintain the VA gains achieved during the first year of treatment in the second year.

Patients were primarily treated using proactive treatment approaches that included fixed bimonthly regimens in Year 1 and variable dosing regimens in Year 2; as well as treat-and-extend posologies. In most cases, the injection frequency decreased significantly from Year 1 to Year 2 without compromising the patients' VA.

A qualitative assessment of the safety data reported in the literature suggests that there were no new safety signals identified during the studies and very few adverse events were identified.

INTRODUCTION

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness worldwide [1]. Most of the AMD-related blindness that occurs is associated with the neovascular (or ''wet'') form of AMD (nAMD) [2]. Anti-vascular endothelial growth factor (anti-VEGF) agents have been demonstrated to be efficacious and safe treatment options for managing patients with nAMD [3][4][5][6] and have changed the treatment paradigm of the disease [7]. Anti-VEGF agents are currently considered to be a preferred option for managing patients with nAMD [7] and set the benchmark for all new treatment options in nAMD. The VIEW 1 & 2 studies assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in nAMD and established that a regimen comprising fixedinterval treatment with IVT-AFL during the Year-1 interval was non-inferior to the monthly intravitreal ranibizumab regimen [5,6]. The short-term efficacy and safety of the bimonthly regimen with IVT-AFL was well established in the pivotal trials [5,6], and the 2-year data from the VIEW studies provided the first insights into the long-term efficacy of IVT-AFL in nAMD [6], demonstrating that it was possible to maintain the visual acuity (VA) gains achieved in the first year of treatment while moving from a fixed bimonthly regimen to a modified quarterly dosing regimen [6].

The evidence from the randomized clinical trials was supplemented with real-world evidence describing the short-term effectiveness and safety of the proactive bimonthly regimen with IVT-AFL [8][9][10][11][12]. A study by Talks et al. [8] provided the first insight into the real-world effectiveness of IVT-AFL in treatment-naı ¨ve patients with nAMD. The implementation of a ''VIEW-like'' treatment regimen of three consecutive initial monthly doses followed by a bimonthly regimen helped to significantly improve patients' VA, with mean gains in VA at Week 52 being comparable to the VA gains observed in the randomized trials [8]. Comprehensive literature reviews and meta-analysis of real-world data support the findings and conclusions of the individual studies and characterize the value of the proactive bimonthly regimen with IVT-AFL in clinical practice [13][14][15]. Researchers, including Eleftheriadou et al. [16], have provided insights into the 2-year effectiveness of IVT-AFL in a population that was primarily treated with the fixed bimonthly treatment approach in Year 1 and with a variable dosing regimen in Year 2 of treatment. The implementation of a variable dosing regimen with IVT-AFL in Year 2 reduced the injection frequency without compromising the patient's VA gains [16]. Evidence describing the 2-year use and 2-year effectiveness of IVT-AFL in nAMD has increased significantly over the past few years, and there is value in performing a review of 2-year outcomes in treatment-naı ¨ve patients with nAMD. The aim of this analysis was to conduct a literature review and meta-analysis of the published evidence describing 2-year outcomes in treatment-naı ¨ve patients with nAMD who were treated with IVT-AFL in clinical practice.

METHODS

A literature review and meta-analysis were performed to provide a comprehensive overview of the population treated with IVT-AFL, including baseline characteristics, 2-year outcomes, associated treatment burden, and overall safety.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Literature Review

A literature search identified publications of observational studies describing the 2-year use of IVT-AFL in treatment-naı ¨ve patients with nAMD. The search strategy that was the basis for the literature review included a variety of synonyms for nAMD and IVT-AFL (Electronic Supplementary Material [ESM] Digital Content 1). The search was conducted in the MEDLINE Ò database using ProQuest. The search string considered Medical Subject Headings (MeSH) terms and search syntax aiming to search in the title or abstract and free text, using quotation marks and Boolean operators. The search date for the literature was 8 July 2019 and studies published earlier were included.

Study Selection and Data Extraction

The literature review targeted observational studies with a prospective or retrospective study design describing the use of IVT-AFL in treatment-naı ¨ve patients with nAMD. Studies had to report a minimum follow-up period of 2 years and had to enroll at least 40 patients/eyes (see ESM Digital Content 1 for full inclusion and exclusion criteria). Studies were selected based on population, intervention, comparator, outcomes, and study design (PICOS) criteria [17]. Title, abstract, and full-text screening were performed by one reviewer. Inclusion and exclusion per stage was reported according to a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart [18]. The data extraction template was developed considering various aspects of the Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) guidelines [19]. The authors referred to the PRISMA [18] and MOOSE [19] guidelines for guidance and support at different stages of the analysis but did not adhere to all of the recommendations and activities described in the guidelines. Study duplicates were also removed (e.g., if there was more than one publication describing the same population or overlapping populations, only one was selected).

Variables of Interest and Statistical Analyses

The meta-analysis used aggregate data from the studies identified in the literature review and followed a similar approach as that of a previous meta-analysis assessing real-world effectiveness of anti-VEGF [20]. Variables of interest included patient baseline characteristics (defined as baseline best-corrected VA [BCVA] and age at baseline), 2-year outcomes (defined as BCVA change from baseline to Year 2, percentage of patients achieving a VA C 70 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at Year 2, and VA at Year 2), treatment burden (defined as mean number of injections over the 2 years of treatment), and safety (any drugrelated event reported in the publications). If sufficient data were available, subgroup analysis was conducted, considering study design (prospective non-interventional vs. retrospective non-interventional), country/region, and treatment approach (proactive bimonthly followed by variable dosing regimen vs. other). To account for possible heterogeneity in outcome between studies, a random-effects model in addition to a fixed-effects model was used to produce estimates for all variables of interest. When necessary, data from individual studies were converted to the units of interest (e.g., ETDRS letters is the unit of interest for measuring the change in VA; ESM Digital Content 2). When studies did not report the standard errors necessary for the meta-analysis, these values were imputed via the multivariate imputation by chained equations (MICE) algorithm [21]. Multiple imputation was used; as such, the confidence interval (CI) considers the uncertainty of imputation. Heterogeneity was measured using the I 2 statistic [22]. The metaanalyses were performed using the metafor package [23] and the MICE algorithm with the software environment R (R Foundation for Statistical Computing, Vienna, Austria). Outcomes are reported as means (with 95% CI).

Meta-Regression

To assess the potential heterogeneity associated with pooled estimates from the meta-analysis, a meta-regression was conducted for each aforementioned outcome using region and study design as covariates. Additionally, meta-regressions were assessed if there were associations between 2-year outcomes with IVT-AFL (VA change from baseline to Year 2) and other covariates: region; VA at baseline; age at baseline; central retinal thickness (CRT) at baseline; mean number of injections in Year 1; and mean number of injections over the 2 years. The meta-regression investigated each of these covariates separately per regression.

Literature Review

The results of the literature review are presented in Fig. 1 . A total of 823 publications were identified in the initial search. After screening for title and abstract, 63 publications were eligible for full-text review. After a full-text review, 17 publications were selected for data extraction.

During the data extraction, six of the 17 publications were excluded (due to \ 40 patients, overlapping populations, and lack of data availability), leaving 11 publications [24][25][26][27][28][29][30][31][32][33][34] (Table 1 ). These 11 publications report realworld data for patients who initiated treatment with IVT-AFL between 2012 and 2016 [25][26][27][28][29][30][31][32][33][34]. Study sizes ranged from 40 patients/eyes [32] to 2506 patients/eyes [27], with some studies reporting subpopulations [27,30,31]. The publications described outcomes achieved following a fixed bimonthly (every 8 weeks) regimen in Year 1 and a variable regimen in Year 2 (2q8), using treat-and-extend (T&E) and pro re nata (PRN; as needed) regimens (Table 1 ).

Patients' Baseline Characteristics

Patients' baseline age ranged between 75.1 years [30] and[ 90 years [27,33]. The pooled analysis estimated a mean age of 78.62 years (95% CI 76.18-81.07; I 2 96.55%) for the combined population (random-effects estimate; Table 2 ). No clinically significant differences in baseline age were observed between the combined population and the subgroup analysis (random-effects estimate; Table 2 ). BCVA ranged between 52.5 ETDRS letters [27] and 75.0 ETDRS letters [30], with the majority of the studies reporting patients with a mean baseline VA of \ 60.00 ETDRS letters [24,25,27,28,[31][32][33][34]. The pooled analysis estimated a mean baseline BCVA of 57.73 ETDRS letters (95% CI 54.23-61.24; I 2 93.52%) for the combined population (Table 2 ). When compared with the combined population, patients included in studies that implemented T&E regimens had a higher mean baseline BCVA of 60.21 ETDRS letters (95% CI 54.87-65.56; I 2 82.16; randomeffects estimate; Table 2 ). The evidence identified in the literature review only allowed for a subgroup analysis assessing the characteristics of the European-based studies versus the combined population. No clinically significant differences for the baseline BCVA were identified between the combined population and the population included in the European studies (Table 2 ). Due to the limited number of prospective studies [30], the analysis focusing on addressing prospective or retrospective studies had limited validity; therefore, this is not reported. The previously mentioned limitations for the subgroup analysis assessing potential differences in the populations based on study design and region were also present for the effectiveness and treatment burden analysis.

2-Year Outcomes with IVT-AFL

The BCVA at 2 years varied between 52.0 ETDRS letters [27] and 78.0 ETDRS letters [30] (Table 1 ). The pooled analysis estimated a mean BCVA of 62.55 ETDRS letters (95% CI 58.06-67.05) for the combined population at 2 years (randomeffects estimate; Table 2 ). When compared with the combined population, patients included in 2 ). No clinically significant differences were identified between the combined population and the population included in the European studies for the mean gain in BCVA at Year 2 (Table 2 ). Mean gains in VA after 2 years of IVT-AFL ranged from -0.80 ETDRS letters [27] to ? 9.00 ETDRS letters [30], with four studies reporting 2 ).

Treatment Burden with IVT-AFL

The mean number of injections with IVT-AFL over 2 years varied depending on the treatment regimen (Table 1 ). Patients on a PRN regimen received a mean of 6.7 injections over the 2 years [33] and patients on 2q8 received between 9.9 and 12.0 injections [32,34]. Injection frequency ranged between 10.5 [29] and 13.8 [30] for the patients on T&E regimens. The analysis of the individual studies indicates that the injection frequency decreased from Year 1 (between 7.2 injections [28] and 8.4 injections [31]) to Year 2 (between 2.5 injections and 6.1 injections [31]) in patients treated following 2q8 or T&E regimens. The pooled analysis estimated that patients received a mean of 12.34 injections (95% CI 10.47-14.22; I 2 94.37%; random-effects estimate; Table 2 ) over 2 years. When compared with the combined population, patients included in studies that implemented T&E regimens received a higher mean of 13.59 injections (95% CI 11.76-15.45, I 2 0.00; random-effects estimate; Table 2 ).

2-Year Safety

When assessing 2-year safety, several limitations were identified. Few of the publications identified in the literature review included a safety assessment and those that included safety data primarily only provided a qualitative description (Table 3 ). Considering this lack of information, it was not possible to complete a formal meta-analysis on safety and provide pooled estimates. The assessment of the 2-year safety was therefore primarily based on the qualitative assessments made by the original study teams (Table 3 ).

Meta-regression Analysis

The meta-regression did not identify any statistically significant association between the variables analyzed (region, baseline BCVA and age, baseline CRT, mean number of injections over the 2 years, and mean number of injections in the first year of treatment) and 2-year outcomes with IVT-AFL (Table 4 ). There was a No safety assessment included Augsburger [25] No safety assessment included Barthelmes [26] ' 'Over the course of the study period, 10 adverse events resulting from 2415 injections were observed in all eyes, including non-completers and switchers: 2 eyes had hemorrhage reducing best-corrected visual acuity by 0.15 letters, and 3 eyes had retinal pigment epithelium tears.''

Chatziralli [27] No safety assessment included Eleftheriadou [28] No safety assessment included Garweg [29] No safety assessment included Matsumoto [30] ' 'None of our subjects experienced severe adverse events, such as cerebral infarction, myocardial infarction, infectious endophthalmitis, and rhegmatogenous retinal detachment.' '

Mekjavic ´ [31] ' 'The following ocular-specific AEs were observed: endophthalmitis (n = 1, severe; treated with vitrectomy and intravitreal antibiotics); non-infectious inflammation (n = 1, severe; treated with local corticosteroids for several days); dehiscence of conjunctiva on the injection site (n = 2, both mild; treated with local antibiotic ointment for a few days). Vitreous opacities (bubbles) were anecdotally reported and considered mild. Precise numbers were not tabulated.' ' Siempsis [32] In terms of safety, there were no cases of endophthalmitis reported in our cohort during the study period Subhi [33] No safety assessment included

Traine [34] No safety assessment included

DISCUSSION

This analysis aimed to review and summarize evidence from observational studies describing real-world 2-year outcomes with IVT-AFL in nAMD. The analysis summarized data from treatment-naı ¨ve patients with nAMD who initiated treatment with IVT-AFL between 2012 and 2016, providing an overview of clinical practice experience with IVT-AFL in different geographic locations and multiple populations.

The data identified in the literature review describe 2-year outcomes with IVT-AFL prior to the landmark ALTAIR study [35] and the inclusion of the T&E posology in the IVT-AFL label, in which, after the three initial monthly doses, the 2-month injection interval can be increased by 2-or 4-week intervals to maintain stable visual and/or anatomic outcomes [36]. The analysis provides an overview of clinical practice and outcomes at a time when the initial IVT-AFL label (three initial monthly doses followed by a fixed bimonthly regimen in the first year and variable regimen in the second year) was the primary treatment approach. The data identified did not allow for characterization of the impact associated with the implementation of the IVT-AFL T&E label, whereby the 2-month injection interval can be increased by 2-or 4-week intervals to maintain stable visual and/ or anatomic outcomes.

Despite not having an approved T&E posology in the label at the time (2012-2016), and despite the scarce evidence from randomized clinical trials describing the efficacy of T&E regimens with IVT-AFL, the literature review identified real-world data describing 2-year outcomes in patients treated with IVT-AFL using flexible regimens and T&E approaches [25,26,[29][30][31]34]. The studies identified in the literature review do not reflect the current IVT-AFL T&E label [36], nor do they follow the learnings from the ALTAIR study [37], in which injection intervals were extended by 2-or 4-week intervals.

Our analysis showed that, after 2 years, patients treated with IVT-AFL report significant gains in VA versus baseline. The pooled analysis (all studies) estimated a mean gain in VA versus baseline of ? 4.49 ETDRS letters for the combined population. The subanalysis of the studies describing patients treated using flexible T&E regimens estimated a higher gain in VA versus baseline, with a mean gain of ? 5.91 ETDRS letters. Mean VA after 2 years was 62.55 ETDRS letters for the combined population, with 47.39% of the patients reporting a BCVA C 70 ETDRS letters. The results of the pooled analysis and the T&E subanalysis provide additional evidence that a proactive treatment approach with IVT-AFL in clinical practice significantly improves a patient's visual acuity versus baseline.

The mean gain in VA registered in clinical practice for the combined population at 2 years was lower than the mean gain registered at Week 96 in the VIEW studies (? 4.49 vs. ? 7.60 ETDRS letters in VIEW [5]), but the mean gain in VA for the T&E group was of a similar magnitude to the outcomes registered in the VIEW trials (? 5.91 vs. ? 7.60 ETDRS letters in VIEW [5]). Although the mean gains in VA observed in clinical practice are significant, there are differences versus the mean gains observed in randomized trials.

When reviewing the baseline characteristics of the real-world population and the clinical trial population, we observed that the realworld patients were older (78.62 vs. 75.80 years, respectively) and had a higher baseline VA (57.73 vs. 53.60 ETDRS letters, respectively). The analysis did not provide a pooled estimate for lesion type or size, but from studies, such as that of Barthelmes et al. [26], we know that some of the real-world populations reported significant differences in the size and type of lesions (59% occult lesions in the real world vs. 37.6% in the clinical trial population). The analysis did not quantify how the different baseline characteristics impacted the mean VA gain in the real-world population and to what extent the older population, the higher baseline VA, and the higher proportion of patients with occult lesions justify the lower mean gains in VA observed in clinical practice.

A previous meta-analysis has assessed 2-year real-world data with other anti-VEGF agents [30]. In a meta-analysis of ranibizumab realworld studies, Kim et al. [20] estimated a mean gain in VA after 1 and 2 years of treatment with ranibizumab. After 2 years of treatment with ranibizumab, the mean gain in VA ranged from ? 1.2 to ? 3.4 ETDRS letters for the overall population [30]. The mean gain estimated by Kim et al. [20] was lower than the mean gain estimated by the authors for patients treated with IVT-AFL (? 4.49 ETDRS letters for the combined population). Patient baseline characteristics were similar in both studies (mean baseline age of 78.8 years and mean baseline VA of 53.6 ETDRS letters in the ranibizumab-treated patients) [20], but ranibizumab was primarily used following reactive treatment approaches such as PRN [20]. This contrasts with the IVT-AFL studies that primarily report proactive treatment approaches [27,33]. The authors are not aware of any publication assessing the relative effectiveness of IVT-AFL versus ranibizumab at 2 years using real-world data. In that context, and to minimize any bias associated with naı ¨ve comparisons of different metaanalyses, we focus only on reporting the mean VA gains for the combined population and defer any conclusions on relative effectiveness for future research.

The evidence identified in the literature review indicates that it was possible to achieve good 2-year outcomes with IVT-AFL in clinical practice and to maintain the VA gains achieved during the first year of treatment in the second year [24,26,28,[30][31][32][33][34]. This was achieved by moving from the proactive bimonthly regimen to a variable dosing regimen and with a significant reduction in the number of IVT-AFL injections in Year 2 [24,26,28,[30][31][32][33][34]. A published meta-analysis of real-world outcomes with IVT-AFL estimated mean VA gains after 1 year at between ? 5.97 ETDRS letters [13] and ? 5.30 ETDRS letters [15]. Our analysis estimated a mean gain after 2 years of ? 4.49 ETDRS letters. A naı ¨ve comparison of the 1-year and 2-year meta-analyses suggests that the outcomes achieved during the first year with IVT-AFL are sustained over the second year.

A mean injection frequency of 12.34 injections over 2 years calculated in this study is consistent with the initial IVT-AFL label (3 initial monthly doses followed by a fixed bimonthly regimen in the first year and a variable regimen in the second year), and in line with what was reported in the VIEW 96-week assessment (11.2 injections) [7]. When assessing the differences in injection frequency, it is important to take into consideration that the VIEW studies reported the mean number of injections at 96 weeks [7], whereas the observational studies reported the mean number of injections at 2 years (104 weeks). The analysis of the individual studies confirms that the injection frequency decreased from Year 1 (between 7.2 injections [28] and 8.4 injections [31]) to Year 2 (between 2.5 injections and 6.1 injections [31]) in patients treated following the initial label or the early T&E regimens. When compared with the combined population, patients treated with T&E regimens reported a higher mean injection frequency of 13.59 injections over 2 years. The higher number of injections could be driven by how T&E was defined and implemented. Most studies defined similar anatomic criteria for extending the interval (absence of intraretinal fluid or absence of both intraretinal and subretinal fluid) but took different approaches to the initial monthly doses and the extension. Two of the studies used a T&E approach similar to the current label [29,34], administering the three monthly initial doses and extending the injection interval by 2 weeks to a maximum of 14 weeks, with patients receiving (on average) 11.1 and 10.5 injections, respectively. In other studies, the injection interval was extended by 2 weeks, but the maximum injection interval was limited to 12 weeks, with patients receiving an average of 13.8 injections [30]. A study that reported a higher mean number of injections, 14.5 injections over 2 years [31], considered an approach whereby patients received monthly injections until the macula became dry, and afterwards the injection interval was extended by 2 weeks up to a maximum of 14 weeks. In the ALTAIR study [35], after the three consecutive monthly doses, the injection intervals were extended by 2 and 4 weeks to a maximum of 16 weeks, reducing the mean number of injections to 10.5 over 2 years. Further research is warranted to determine the outcomes associated with the implementation of an ALTAIR-like [35] approach in clinical practice and the impact associated with the new T&E label.

Few studies reported 2-year safety data: Barthelmes et al. [26] reported ten adverse events after administering 2415 injections; Matsumoto et al. [30] reported no severe adverse events; Mekjavic ´et al. [31] reported four ocular-specific adverse events (endophthalmitis, non-infection inflammation, and dehiscence of conjunctiva on the injection site); and Siempsis et al. [32] did not report any cases of endophthalmitis. The qualitative assessment of the conclusions provided by the authors of the individual studies suggests that there were no new safety signals identified during the studies and very few adverse events were reported; however, the data reported did not allow us to complete a formal meta-analysis and to provide a pooled estimate of the 2-year safety associated with the use of IVT-AF. The absence of comprehensive reporting of adverse events is a limitation and should be considered in future research.

The analysis identified a high heterogeneity (I 2 ) that is indicative of high between-study variation. In this situation, it is recommended to focus on the random-effects estimate rather than the fixed-effects estimate [37]. Both estimates are reported for completeness, but in the Results section of this article, only the randomeffects estimate is described. The aim of the meta-regression analysis was to identify how key variables, such as patient baseline characteristics (age, baseline BCVA, and CRT) and injection frequency, are associated with 2-year outcomes with IVT-AFL. However, there were limited data to conduct these analyses (due to a limited number of studies and data reported). Further research is warranted to confirm or refute the results of the meta-regression.

There are limitations associated with this analysis. The literature review was conducted with the MEDLINE Ò database using ProQuest and did not include other data sources. Although MEDLINE Ò has extensive coverage and is commonly used, not including other databases is a limitation of the analysis. The literature search was conducted in July 2019 and may not capture more recent publications describing 2-year outcomes with IVT-AFL. The data used originate primarily from retrospective studies that have an associated bias and are associated with increased imprecision, incomplete follow-up, and recall bias [38,39]. There was an attempt to reduce publication bias [40] and uncertainty associated with small sample sizes [41] by excluding studies that reported \ 40 patients/eyes from the meta-analysis. The choice to set the cutoff at 40 patients was arbitrary and defined by the authors, as there is no formal reference that can be used to define what constitutes a ''small sample size'' study. Another limitation of this analysis is that only 11 studies were identified, which is low for assessing interstudy differences in a meta-analysis. It should be considered that this low number of studies was the result of strict selection criteria that aimed to reduce bias that is traditionally associated with meta-analyses using real-world research (e.g., imprecision, publication bias, etc.). Furthermore, the analysis was based on aggregate (mean) data and not patient-level data, which are not free from ecological bias.

CONCLUSION

Patients treated with IVT-AFL reported significant 2-year gains in VA versus baseline. The evidence indicates that the visual gains achieved during the first year of treatment are maintained through the second year. This outcome was achieved with a significant reduction in the mean number of IVT-AFL injections administered in Year 2 of treatment.

Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions. Joao Carrasco developed the hypothesis and overall concept. Joao Carrasco, Jisu Yoon, and Jelle Spoorendonk contributed to the data collection and analysis. Vincent Daien and Bora Eldem contributed to the review and assessment of the clinical data used in the analysis. All authors were involved in the analysis, interpretation of the results, and the review and development of the manuscript. All authors have provided final approval of the manuscript to be published and agree to be accountable for all aspects of the work by ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Medical Writing, Editorial, and Other Assistance. Editorial support was provided by ApotheCom (London, UK) and was funded by Bayer Consumer Care AG, Pharmaceuticals, Switzerland.

Disclosures. Joao Carrasco is a paid employee of Bayer Consumer Care AG, Basel, Switzerland. Vincent Daien reports consulting fees, travel support, and financial and non-financial support outside the submitted work from Alcon, Bayer, Horus, Novartis, and Thea. Bora Eldem reports consulting fees, travel support, and financial and non-financial support outside the submitted work from Alcon, Allergan, Novartis, Bayer, Bausch & Lomb, Ophthotech, Pfizer, Roche, Sanofi, Santen, Servier, and Thea. Jelle Spoorendonk is a paid employee of Pharmerit International, an OPEN Health Company, which was contracted by Bayer to assist in the analysis. Jisu Yoon was a paid employee of Pharmerit International, an OPEN Health Company, at the time that this study was completed and was contracted by Bayer to assist in the analysis. The authors thank Walter Bouwmeester from Pharmerit International, an OPEN Health Company, for his contribution to the literature review and meta-analysis.

Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Data Availability. All data generated or analyzed during this study are included in this published article or as supplementary information files.

Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/bync/4.0/.\
Acknowledgements

ACKNOWLEDGEMENTSFunding.This research was funded by Bayer Consumer Care AG, Basel, Switzerland.Bayer Consumer Care AG is also responsible for funding the journal's Rapid Service and Open Access Fees.

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