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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 34  |  Issue : 2  |  Page : 133-147

Efficacy and safety of aflibercept therapy for diabetic macular edema: A systematic review and meta-analysis


1 Faculty of Medicine, McGill University, Montreal, Canada
2 Department of Ophthalmology, Faculty of Medicine, McGill University, Montreal, Canada
3 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal; Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

Date of Submission13-Oct-2021
Date of Decision24-Apr-2022
Date of Acceptance28-Apr-2022
Date of Web Publication26-Jul-2022

Correspondence Address:
Sangeetha Santhakumaran
3605 Rue de la Montagne, Montreal, Quebec, H3G 2M1
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joco.joco_308_21

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  Abstract 


Purpose: To assess the real-world efficacy and safety of aflibercept for the treatment of diabetic macular edema (DME).
Methods: A systematic search was conducted across multiple databases. Articles were included if participants had DME and received aflibercept treatment for a minimum of 52 ± 4 weeks. Primary outcomes included changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). A risk of bias assessment of studies was completed, pooled estimates were obtained, and a meta-regression was performed. Information on adverse events was collected.
Results: The search yielded 2112 articles, of which 30 were included. Aflibercept was more effective than laser photocoagulation functionally (12-month BCVA-weighted mean difference [WMD] = 10.77 letters, P < 0.001; 24 months = 8.12 letters, P < 0.001) and anatomically (12-month CMT WMD = –114.12 μm, P < 0.001; 24 months = –90.4 μm, P = 0.004). Compared to bevacizumab, aflibercept was noninferior at improving BCVA at 12 months (WMD = 1.71 letters, P = 0.34) and 24 months (WMD = 1.58 letters, P = 0.083). One study found that aflibercept was more effective than bevacizumab anatomically at 1 and 2 years (P < 0.001 at 12 and 24 months). Compared to ranibizumab, aflibercept rendered a greater improvement in BCVA at 1 year (WMD = 1.76 letters, P = 0.001), but not 2 years (WMD = 1.66 letters, P = 0.072). CMT was not significantly different between both therapies at 12 months (WMD = −14.30 μm, P = 0.282) and 24 months (P = 0.08). One study reported greater functional improvement with aflibercept compared with dexamethasone (P = 0.004), but inferiority in reducing CMT (P < 0.001). Meta-regression analysis demonstrated that dosing schedule was found to impact outcomes at 12 and 24 months, while study design and sample size did not impact outcomes at 12 months. There were minimal safety concerns using aflibercept therapy.
Conclusions: Aflibercept is a safe and effective therapy option for DME in the clinical setting, performing superiorly to laser photocoagulation. Evidence regarding comparisons with bevacizumab, ranibizumab, and dexamethasone is mixed and limited.

Keywords: Aflibercept, Antivascular endothelial growth factor, Diabetic macular edema, Eylea, Retina


How to cite this article:
Santhakumaran S, Salimi A, Brunetti VC, Galic J. Efficacy and safety of aflibercept therapy for diabetic macular edema: A systematic review and meta-analysis. J Curr Ophthalmol 2022;34:133-47

How to cite this URL:
Santhakumaran S, Salimi A, Brunetti VC, Galic J. Efficacy and safety of aflibercept therapy for diabetic macular edema: A systematic review and meta-analysis. J Curr Ophthalmol [serial online] 2022 [cited 2022 Dec 7];34:133-47. Available from: http://www.jcurrophthalmol.org/text.asp?2022/34/2/133/352486




  Introduction Top


Diabetic macular edema (DME) is a significant cause of vision loss, affecting 7% of diabetic individuals.[1] The standard of care for DME was previously focal laser photocoagulation, and intravitreal corticosteroids have also been used.[2] However, studies have demonstrated that antivascular endothelial growth factor (anti-VEGF) therapies have superior outcomes and an improved safety profile compared to laser photocoagulation.[2] Bevacizumab (Avastin®) is an anti-VEGF therapy that was introduced for the treatment of colorectal cancer, currently used off-label for the treatment of macular edema.[3] Ranibizumab (Lucentis®) is among the approved anti-VEGF treatments for DME, targeting neovascularization.[4] Aflibercept (Eylea®) has also been approved for DME, bearing similar efficacy to ranibizumab.[5],[6] Aflibercept is a recombinant fusion protein that acts as a decoy receptor, with a higher affinity for VEGF-A, VEGF-B, and placental growth factor than their natural receptors.

Most reviews evaluating the efficacy of anti-VEGF treatments for DME have focused on randomized control trials (RCTs), as this is considered one of the highest levels of evidence.[7] However, the external validity of RCTs is often limited due to strict inclusion/exclusion criteria and highly controlled testing parameters. A meta-analysis including non-RCT sources of information may, thus, highlight the real-world complexities of the disease and its management. In addition, the comparison of anti-VEGF, intravitreal corticosteroid, and laser photocoagulation therapy within a single meta-analysis has yet to be completed. This meta-analysis aims to evaluate the real-world efficacy of aflibercept for the treatment of DME in comparison to other DME treatments, including results from both RCT and non-RCT sources. The following questions were addressed:

  1. What is the effect of aflibercept therapy on best-corrected visual acuity (BCVA), as a functional outcome, and central macular thickness (CMT), as an anatomical outcome, in patients with DME?
  2. How does aflibercept compare to alternative therapies for DME?
  3. Are there safety concerns associated with aflibercept use in DME?



  Methods Top


This research was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [Supplemental File 1]. A literature search was conducted on PubMed, Ovid MEDLINE, EMBASE, and ClinicalTrials.gov. The search strategy included key terms related to anti-VEGF, aflibercept, Eylea, diabetic retinopathy, and DME [Supplemental File 2]. The search included studies that were written in English or French and published before February 2020.



Articles were included in the meta-analysis if participants had DME and received aflibercept in at least one of the study arms. Studies were required to report change in BCVA and/or anatomical retinal changes before and after treatment with a minimum follow-up duration of 52 weeks ± 4 weeks. The mean baseline and endpoint data with their respective standard deviations were required for aflibercept monotherapy statistical analysis purposes. The mean change in primary outcome with an associated standard deviation was required for comparative analysis purposes. Studies with incomplete data were included as part of the systematic review but excluded from the meta-analysis. Anatomical retinal changes were specific to the macular region, including the fovea (i.e., CMT, central foveal thickness, central subfield thickness, and central retinal thickness if only the macular region was considered [hereto collectively referred to as CMT]). Post hoc analyses, conference abstracts, viewpoints/opinion papers, reviews, meta-analyses, extension studies, and studies evaluating the efficacy of ziv-aflibercept were excluded. Data were extracted independently by two reviewers and organized into the following categories: study details, length of follow-up, treatment regimen, assessment of study endpoints, and adverse events.

Primary outcomes included changes in BCVA and CMT. Secondary outcomes consisted of safety, particularly ocular adverse events, Antiplatelet Trialists' Collaboration (APTC)-defined adverse events (myocardial infarction, stroke, or vascular death), serious/systematic adverse events, and death.

Version 2 of the Cochrane risk-of-bias tool assessed the risk of bias in RCTs. Each item was rated as low risk, having some concerns, or high risk. Total score was calculated by two reviewers based on the Cochrane Collaboration algorithm.[8] Risk of bias in the non-RCTs was assessed using the Newcastle–Ottawa Scale (NOS) on a nine-point scale.[9] A modified six-point version of the NOS was used to evaluate studies with no control group, omitting questions regarding the comparability of both the groups.[10] An overall NOS score of 7 and above was considered low risk, 5–7 was considered to have some concerns, and under 5 was considered high risk. For the modified version, a score of 6 was considered low risk, 4–5 was considered to have some concerns, and 3 and under was considered high risk.

Estimates were pooled using the DerSimonian and Laird random-effects models with inverse variance weighting.[11] Heterogeneity was quantitatively assessed using the I[2] statistic. Subgroup analyses by comparator and further subdivision by randomization versus nonrandomization were performed. A meta-regression was performed to assess any factors that contributed to BCVA and CMT outcomes other than comparator group, evaluating the effect of dosing schedule, study design, and sample size. Publication bias was assessed via visual inspection of funnel plots.[12] All analyses were performed using StataCorp. (2017). Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC.[13]


  Results Top


The literature search of the selected databases resulted in 2112 titles (PubMed 548, Ovid MEDLINE 762, EMBASE 788, and ClinicalTrials.gov 14). After removal of 1255 duplicates, 857 studies remained. There was exclusion of 368 records based on title, 489 abstracts were screened, and 105 full-text articles were assessed for eligibility. Thirty studies were included in this review. The selection process is illustrated in [Figure 1]. Detailed study characteristics are given in [Supplemental File 3].
Figure 1: Flow diagram of studies included in this meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart outlining number of studies screened, assessed for eligibility, and included in review

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Bias among 12 RCTs was assessed using the Cochrane Collaboration's Risk of Bias 2 tool. Four studies were evaluated as having low risk of bias, four studies had some concerns, and four studies were high risk. A traffic plot and a summary plot of the included studies assessed using the Risk of Bias 2 tool are shown in [Figure 2]. The biases of seven cohort studies were assessed using the original NOS. Of a total score of 9, three studies were low-risk, and the remaining four studies had some concerns. A traffic plot and a summary plot of the included studies assessed using the NOS are shown in [Figure 3]. Of 11 noncohort studies, evaluated using the modified NOS, two studies were found to be low risk, and the remaining studies had some concerns. A traffic plot and a summary plot of the included studies assessed using the modified NOS are shown in [Figure 4].[14]
Figure 2: Traffic plot and summary plot of the included randomized controlled trials (RCTs). Risk of bias assessment of RCT studies using version 2 of the Cochrane risk-of-bias tool. Total score calculated based on the algorithm suggested by the Cochrane Collaboration.

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Figure 3:A traffic plot and summary plot of the included cohort studies. Risk of bias assessment of non-randomized controlled trial studies using the Newcastle-Ottawa Scale (NOS). An overall NOS score of 7 and above is considered low risk, a score of 5 to 7 is considered to have some concerns, and a score under 5 is considered high risk.

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Figure 4: Traffic plot and summary plot of the included non-cohort studies. Risk of bias assessment of non-cohort, non-randomized controlled trial studies without a comparator group using a modified version of the Newcastle-Ottawa Scale. A score of 6 is considered low risk, a score of 4 or 5 is considered to have some concerns, and a score of 3 and under is considered high risk.

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Meta-regression analysis demonstrated that dosing schedule was found to impact BCVA outcomes at 12 and 24 months and CMT outcomes at 12 and 24 months. Study design and sample size did not significantly impact results at 12 months for BCVA and CMT. There were insufficient data to perform study design and sample size analyses for 24-month data. Detailed results are given in [Supplemental File 4].



Visual examination of the funnel plots evaluating BCVA and CMT outcomes revealed symmetrical scattering of the included studies around the overall effect line, suggesting absence of publication bias [Figure 5].
Figure 5:Funnel plots assessing publication bias of studies evaluating best-corrected visual acuity (pictured top) and central macular thickness (pictured bottom). Afl: Aflibercept, SD: Standard deviation, CI: Confidence interval

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Of eighteen studies with complete 12-month data relating to BCVA, a significant pooled mean improvement of 9.31 Early Treatment Diabetic Retinopathy Study (ETDRS) letters was noted with aflibercept (weighted mean difference [WMD] = 9.31 ETDRS letters; 95% confidence interval [CI]: 6.87–11.74 ETDRS letters; P < 0.001, I[2] = 94.0%) [Figure 6]. Three studies were not included in the 12-month analysis due to missing baseline, 12-month mean, or standard deviation data. Among these three studies, the mean BCVA was reported to be significantly improved with aflibercept monotherapy in two studies (mean difference of 6.1 ± 7.1 ETDRS letters, P = 0.006;[15] mean difference of 3.7 ETDRS letters, P = 0.024),[16] and an improvement in BCVA (with no reported P value) was found in one study (mean difference of 9.3 ± 9.3 ETDRS letters).[17] Of the eighteen studies, six RCTs showed a significant improvement of 13.16 ETDRS letters with aflibercept (WMD = 13.16 ETDRS letters; 95% CI: 7.99–18.32 ETDRS letters; P < 0.001, I[2] = 97.7%) [Figure 7], and twelve non-RCTs showed a significant improvement of 7.55 ETDRS letters with aflibercept (WMD = 7.55 ETDRS letters; 95% CI: 5.54–9.57 ETDRS letters; P < 0.001, I[2] = 72.9%) [Figure 7].
Figure 6:Estimated weighted mean difference of baseline to 12-month (pictured top), and baseline to 24-month best-corrected visual acuity (pictured bottom) with aflibercept therapy as measured using Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Dashed line represents weighted mean difference. 12-month weighted mean difference: 9.31 ETDRS letters, P < 0.001. 24-month weighted mean difference: 6.76 ETDRS letters, P = 0.056. Values reported as crude mean difference, without adjustment for covariates. CI: Confidence interval

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Figure 7: Estimated weighted mean difference of baseline to 12-month (pictured top), and baseline to 24-month best-corrected visual acuity (pictured bottom) with aflibercept therapy stratified by study design as measured using Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Dashed line represents weighted mean difference. 12-month weighted mean difference randomized controlled trial (RCT) 13.16 ETDRS letters, P < 0.001. 12-month weighted mean difference non-RCT: 7.55 ETDRS letters, P < 0.001. 24-month weighted mean difference RCT: 6.80 ETDRS letters, P = 0.261. 24-month weighted mean difference non-RCT: 6.98 ETDRS letters, P = 0.006. Values reported as crude mean difference, without adjustment for covariates. CI: Confidence interval.

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Of four studies that reported complete 24-month mean BCVA outcomes, a marginally significant improvement in BCVA with a pooled mean gain of 6.76 ETDRS letters was noted with aflibercept (WMD = 6.76 ETDRS letters; 95% CI: –0.19–13.70 ETDRS letters; P = 0.056, I[2] = 97.1%) [Figure 6]. Two studies were not included in the 24-month analysis due to missing data. Among these two studies, the mean BCVA was reported to be nonsignificantly increased with aflibercept monotherapy in one (mean difference of 6.4 ± 10.6 ETDRS letters, P = 0.1)[15] and significantly increased in the other (mean difference of 4.9 ETDRS letters, P = 0.01).[16] One study reported a statistically significant increase in BCVA at 18 months (mean difference 18.9 ± 7.0 ETDRS letters, P < 0.005).[18] Of the four studies, two RCTs showed a mean improvement of 6.80 ETDRS letters with aflibercept (WMD = 6.80 ETDRS letters; 95% CI: –5.05–18.66 ETDRS letters; P = 0.261, I[2] = 98.8%) [Figure 7] while two non-RCTs showed a mean improvement of 6.98 ETDRS letters (WMD = 6.98 ETDRS letters; 95% CI: 2.02–11.93 ETDRS letters; P = 0.006, I[2] = 67.5%) [Figure 7].

Among four studies comparing aflibercept and laser photocoagulation, aflibercept was superior in improving BCVA at 1 year (WMD = 10.77 ETDRS letters, 95% CI: 7.19–14.35 ETDRS letters, P < 0.001, I[2] = 94.4%) [Figure 8]. All studies comparing aflibercept and laser photocoagulation were RCTs; therefore, weighted mean results remained the same with study type stratification. The 2-year results included two studies which continually evidenced the superiority of aflibercept (WMD = 8.12 ETDRS letters, 95% CI: 2.97–13.28 ETDRS letters, P < 0.001, I[2] = 96.0%) [Figure 8]. Heier et al. reported a statistically significant improvement of BCVA with aflibercept over laser photocoagulation at 3 years (P < 0.001 for all aflibercept groups versus laser control, using the last observation carried forward [LOCF] method).[19]

Two trials compared visual outcomes related to aflibercept and bevacizumab at 1 and 2 years. No significant differences were found between the two therapies at 1 year (WMD = 1.71 ETDRS letters, 95% CI: –1.81–5.24 ETDRS letters, P = 0.341, I[2] = 88.1%) [Figure 8] and 2 years (WMD = 1.58 ETDRS letters, 95% CI: –0.20–3.37 ETDRS letters, P = 0.083, I[2] = 44.1%) [Figure 8]. There was insufficient power in the bevacizumab comparator group to undergo RCT versus non-RCT stratification analyses.
Figure 8:Estimated weighted mean difference of improvement in best-corrected visual acuity with aflibercept in comparison with other therapies at 12 months (pictured top) and 24 months (pictured bottom) as measured using Early Treatment Diabetic Retinopathy Study (ETDRS) letters. At 12 months: Weighted mean difference between aflibercept and laser photocoagulation: 10.77 ETDRS letters, P < 0.001, weighted mean difference between aflibercept and ranibizumab: 1.76 ETDRS letters, P = 0.001, weighted mean difference between aflibercept and bevacizumab: 1.71 ETDRS letters, P = 0.341. Single-study comparisons (not pictured): Weighted mean difference between aflibercept and dexamethasone: 2.90 ETDRS letters, P = 0.004. At 24 months: Weighted mean difference between aflibercept and laser photocoagulation: 8.12 ETDRS letters, P < 0.001, weighted mean difference between aflibercept and ranibizumab: 1.66 ETDRS letters, P = 0.072, weighted mean difference between aflibercept and bevacizumab: 1.58 ETDRS letters, P = 0.083. Note: Only comparator groups with more than one study were included in forest plots. Afl: Aflibercept, 2q4: 2 mg every 4 weeks, 2q8: 2 mg every 8 weeks, 0.5q: 0.5 mg every 4 weeks, 2PRN: 2 mg as needed; CI: Confidence interval.

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When comparing aflibercept with ranibizumab, the overall 1-year improvement in BCVA across all six studies was significantly better with aflibercept (WMD = 1.76 ETDRS letters, 95% CI: 0.75–2.76 ETDRS letters, P = 0.001, I[2] = 0) [Figure 8]. Two studies were not included in the analyses due to missing standard deviation data; however, these studies reported no significant difference in BCVA improvement between aflibercept and ranibizumab at 12 months (P = 0.237[20] and P = 0.8).[21] Of the six studies, two RCTs demonstrated that the overall 1-year improvement in BCVA was significantly better with aflibercept (WMD = 2.19 ETDRS letters; 95% CI: 0.25–4.12 ETDRS letters; P = 0.027, I[2] = 0.0%) [Figure 9] and four non-RCTs demonstrated a 1-year improvement in BCVA which was nonsignificantly better with aflibercept compared with ranibizumab (WMD = 1.53 ETDRS letters; 95% CI: –0.05–3.11 ETDRS letters; P = 0.058, I[2] = 21.5%) [Figure 9]. At 2 years, visual outcomes related to aflibercept were no longer found to be superior to ranibizumab (WMD = 1.66 ETDRS letters, 95% CI: –0.15–3.48 ETDRS letters, P = 0.072, I[2] = 48.3%) [Figure 8]. There was insufficient power in the 24-month ranibizumab comparator group to undergo RCT versus non-RCT stratification analyses.

One study compared the outcomes of aflibercept to dexamethasone, which evidenced superiority of aflibercept in improving BCVA at 1 year (P = 0.004).[22] There was insufficient power in the dexamethasone comparator group to undergo RCT versus non-RCT stratification analyses.

Of twenty studies that reported both baseline and 12-month mean CMT outcomes, a significant improvement in CMT with a pooled mean reduction of 133.76 μm was noted with aflibercept therapy (WMD = –133.76 μm; 95% CI: –158.74 to –108.78 μm; P < 0.001, I[2] = 94.8%) [Figure 10]. In the two studies that were not included in the 12-month pre-post analysis due to missing baseline or 12-month mean or standard deviation, the mean CMT was significantly reduced with aflibercept monotherapy (mean difference –175.38 ± 132.62 μm, P = 0.006;[23] mean difference –117.7 ± 103.3 μm, P = 0.0003).[15] Of the twenty studies, six RCTs showed a significant pooled mean reduction of 147.52 μm with aflibercept (WMD = –147.52 μm; 95% CI: –211.45 to –83.60 μm; P < 0.001, I[2] = 98.1%) [Figure 11] while fourteen non-RCTs showed a significant pooled mean reduction of 127.48 μm with aflibercept (WMD = –127.48 μm; 95% CI: –147.77 to –107.19 μm; P < 0.001, I[2] = 83.3%) [Figure 11].
Figure 9: Estimated weighted mean difference of improvement in best-corrected visual acuity with aflibercept in comparison with ranibizumab at 12 months stratified by randomized controlled trial (RCT) (pictured top) vs. non-RCT (pictured bottom) as measured using Early Treatment Diabetic Retinopathy Study (ETDRS) letters. 12-month RCTs: Weighted mean difference between aflibercept and ranibizumab: 2.19 ETDRS letters, P = 0.027. 12-month non-RCTs: Weighted mean difference between aflibercept and ranibizumab: 1.53 ETDRS letters, P = 0.058. Note: Only comparator groups with more than one study in both RCT and non-RCT groups were represented in stratified analyses; thus, no comparator groups were represented in stratified analyses at 24 months. Afl: aflibercept, CI: Confidence interval.

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Figure 10:Estimated weighted mean difference of baseline to 12-month (pictured top), and baseline to 24-month central macular thickness (μm) (pictured bottom). Dashed line represents weighted mean difference. 12-month weighted mean difference: –133.76 μm, P < 0.001. 24-month weighted mean difference: –109.21 μm, P = 0.001. Values reported as crude mean difference, without adjustment for covariates. CI: Confidence interval

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Figure 11: Estimated weighted mean difference of baseline to 12-month (pictured top), and baseline to 24-month central macular thickness (μm) (pictured bottom) stratified by study design. Dashed line represents weighted mean difference. 12-month randomized controlled trial (RCT) weighted mean difference: –147.52 μm, P < 0.001. 12-month non-RCT weighted mean difference: –127.48 μm, P < 0.001. 24-month RCT weighted mean difference: –111.66 μm, P = 0.072. 24-month non-RCT weighted mean difference: –106.64 μm, P < 0.001. Values reported as crude mean difference, without adjustment for covariates. CI: Confidence interval.

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Of five studies that reported 24-month CMT outcomes, a significant improvement in CMT with a pooled mean reduction of 109.21 μm was noted with aflibercept therapy (WMD = –109.21 μm; 95% CI: –174.59 to –43.84 μm; P = 0.001, I[2] = 96.6%) [Figure 10]. One study was not included in the meta-analysis due to missing endpoint standard deviation data; however, this study reported a significant reduction in CMT at 2 years (mean difference –123.3 ± 104.2 μm, P = 0.02).[15] Khattab et al. reported an 18-month statistically significant reduction in CMT (mean difference –212.5 ± 55.7 μm, P < 0.005).[18] Of the five studies, two RCTs showed a nonsignificant pooled mean reduction of 111.66 μm with aflibercept (WMD = −111.66 μm; 95% CI: –233.18–9.86 μm; P = 0.072, I[2] = 99.1%) [Figure 11] while three non-RCTs showed a significant pooled mean reduction of 106.64 μm with aflibercept (WMD = −106.64 μm; 95% CI: –134.05 to –79.23 μm; P < 0.001, I[2] = 0.0%) [Figure 11].

Aflibercept was superior to laser photocoagulation in improving CMT at both 1 year (WMD = −114.12 μm, 95% CI: –154.55 to –73.68 μm, P < 0.001, I[2] = 91.9%) [Figure 12] and 2-year follow-ups (WMD = −90.47 μm, 95% CI = −151.80 to –29.15 μm, P = 0.004, I[2] = 95.4%, respectively) [Figure 12]. Heier et al. reported a statistically significant improvement of CMT with aflibercept over laser photocoagulation at 3 years (P < 0.0001 for all aflibercept groups versus laser control, using the LOCF method).[19] All studies comparing aflibercept and laser photocoagulation were RCTs; therefore, there was no subgroup analysis performed based on study design.
Figure 12:Estimated weighted mean difference of reduction in central macular thickness (μm) with aflibercept in comparison with other therapies at 12 months (pictured top) and 24 months (pictured bottom). At 12 months: Weighted mean difference between aflibercept and laser photocoagulation: –114.12 μm, P < 0.001, weighted mean difference between aflibercept and ranibizumab: –14.30 μm, P = 0.282. Single-study comparisons (not pictured): Weighted mean difference between aflibercept and bevacizumab –68.00 μm, P < 0.001, weighted mean difference between aflibercept and dexamethasone: 108.40 μm, P < 0.001. At 24 months: Weighted mean difference between aflibercept and laser photocoagulation: –90.47 μm, P = 0.004. Single-study comparisons (not pictured): Weighted mean difference between aflibercept and ranibizumab: –22.00 μm, P = 0.008, weighted mean difference between aflibercept and bevacizumab: –45.00 μm, P < 0.001. Note: Only comparator groups with more than one study were included in forest plots. Afl: Aflibercept; 2q4: 2 mg every 4 weeks, 2q8: 2 mg every 8 weeks, 0.5q: 0.5 mg every 4 weeks, 2PRN: 2 mg as needed, CI: Confidence interval

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Wells et al. reported a greater degree of CMT reduction with aflibercept compared with bevacizumab at both the one and 2-year time points (P < 0.001 for both years).[5],[24] There was insufficient power in the bevacizumab comparator group to undergo RCT versus non-RCT stratification analyses.

When comparing aflibercept with ranibizumab, the overall improvement in CMT across six studies at 1 year was not significantly different between the two groups (WMD = −14.30 μm, 95% CI = −40.36-11.76 μm, P = 0.282, I[2] = 72.8%) [Figure 12]. A study by Ozkaya et al. displayed similar results at 1 year (P = 0.3).[21] Of the six studies, two RCTs demonstrated a nonsignificantly increased reduction in CMT with aflibercept compared to ranibizumab (WMD = −21.55 μm, 95% CI = −44.02–0.92 μm, P = 0.060, I[2] = 0.0%) [Figure 13]. Four non-RCTs demonstrated a nonsignificantly increased reduction in CMT with aflibercept compared to ranibizumab (WMD = −10.12 μm, 95% CI = −51.71–31.47 μm, P = 0.633, I[2] = 83.6%) [Figure 13]. A nonsignificant difference in CMT outcomes was also reported at 2 years by Wells et al. (P = 0.08).[24] There was insufficient power in the 24-month ranibizumab comparator group to undergo RCT versus non-RCT stratification analyses.
Figure 13: Estimated weighted mean difference of improvement in central macular thickness (μm) with aflibercept in comparison with ranibizumab at 12 months stratified by randomized controlled trial (RCT) (pictured top) vs. non-RCT (pictured bottom). 12-month RCTs: Weighted mean difference between aflibercept and ranibizumab: –21.55 μm, P = 0.060. 12-month non-RCTs: Weighted mean difference between aflibercept and ranibizumab: –10.12 μm, P = 0.633. Note: Only comparator groups with more than one study in RCT and non-RCT groups were represented in stratified analyses; thus, no comparator groups were represented in stratified analyses at 24 months. Afl: Aflibercept, CI: confidence interval

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Ozsaygili and Duru, in the same study that showed superiority of aflibercept in improving BCVA, demonstrated the superiority of dexamethasone over aflibercept in reducing the CMT at 1 year (P < 0.001).[22] There was insufficient power in the dexamethasone comparator group to undergo RCT versus non-RCT stratification analyses.

Twenty-four studies commented on safety outcomes, including 14 studies reporting ocular adverse events[5],[17],[18],[19],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32] and 10 reporting no ocular adverse events with aflibercept.[15],[16],[20],[21],[22],[33],[34],[35],[36],[37] The most commonly reported ocular adverse event was subconjunctival hemorrhage (164 cases of 2516 aflibercept-treated eyes with ocular safety data available, representing a prevalence of 6.5%).[24],[26],[27],[30],[31],[32] Twelve studies reported APTC-defined adverse events with aflibercept treatment.[5],[17],[19],[23],[24],[25],[26],[27],[28],[29],[30],[32] Four studies reported no APTC-defined events having occurred during the study with aflibercept treatment.[15],[16],[35],[37] The most commonly reported APTC-defined event was vascular or other unknown cause (107 cases reported of 2212 aflibercept-treated eyes, with APTC-defined data available, representing a prevalence of 4.8%).[5],[19],[24],[26],[27],[28],[29],[30] Twelve studies reported systemic or other serious adverse events associated with aflibercept treatment.[5],[17],[19],[23],[24],[25],[26],[27],[28],[29],[30],[32] Five studies reported no systemic or other serious events during the study.[5],[15],[16],[31],[35],[37] The most commonly reported adverse event was hypertension (52 cases reported of 2232 aflibercept-treated eyes with available data, representing a prevalence of 2.3%).[19],[26],[27],[30] All-cause mortality was reported in 7 studies,[17],[19],[23],[24],[26],[30],[38] ranging from 0.9% to 5.5%, with one study reporting no deaths due to aflibercept treatment.[35] In studies that reported the causes of death, most deaths were related to cardiovascular events.[19],[23],[30] Among the studies comparing aflibercept with laser photocoagulation, most studies did not find a significant difference in adverse events between the two groups. Baker et al. reported a significantly increased intraocular pressure with aflibercept compared with observation.[26] In the VISTA/VIVID studies, all-cause mortality was more frequent in the groups treated with aflibercept at the 100 and 148-week time points.[19],[28] Compared to aflibercept, there was a higher incidence of increased intraocular pressure and cataract formation in patients treated with dexamethasone.[22],[34] Wells et al., who compared safety outcomes between aflibercept, bevacizumab, and ranibizumab, found a higher rate of APTC-defined events for ranibizumab compared to aflibercept at 2 years,[5],[24] but no difference between groups in other categories of adverse events.






  Discussion Top


This meta-analysis summarizes the evidence regarding the efficacy and safety of aflibercept for treatment of DME. A wide variety of study types were incorporated, from controlled environments such as RCTs, to retrospective studies with heterogenous samples of DME patients in real-life clinical settings. Aflibercept therapy rendered a significant improvement in BCVA at 1 year and a marginally significant improvement at 2 years. Similar results were obtained at 12 months when studies were stratified by randomization status. However, at 24 months, RCTs demonstrated that the improvement in BCVA was nonsignificant while non-RCTs demonstrated a significant improvement. There was also a reduction in macular thickness at both 1 and 2 years. Similar to BCVA, the results obtained at 12 months with RCTs were similar to nonstratified results. Conversely, at 24 months, RCTs demonstrated that the improvement in CMT was nonsignificant while non-RCTs demonstrated that the improvement was significant. In comparison with laser photocoagulation, there was a significantly greater improvement in BCVA and anatomical outcomes with aflibercept therapy, similar to the results of previous meta-analyses comparing the two therapies.[7],[39],[40]

Aflibercept has been reported to have superior visual acuity outcomes compared to bevacizumab.[40],[41],[42] Our analysis failed to reveal any differences between aflibercept therapy and bevacizumab with respect to the functional outcome. The lack of significant BCVA improvement in the present study suggests that aflibercept might be superior in a specific subpopulation of patients, such as patients with a poor baseline BCVA. Only one trial reported a significantly greater degree of CMT reduction with aflibercept compared with bevacizumab at both the 1 and 2-year time points.[5],[24]

Aflibercept provided a significant advantage over ranibizumab therapy at 1 year in terms of BCVA, mirroring results from previous meta-analyses.[41],[42] When stratified based on randomization status, RCTs maintained this significance; however, non-RCTs reported nonsignificance. The overall 1-year advantage was no longer observed at the 2-year time point. It is important to consider that two studies were not included in the analyses due to missing standard deviation information, both of which reported no differences between aflibercept and ranibizumab BCVA outcomes.[20],[21] CMT outcomes were not significantly different at 1 or 2 years between ranibizumab and aflibercept, and these outcomes were consistent irrespective of study design.

Ozsaygili and Duru demonstrated functional superiority of aflibercept over dexamethasone; however, dexamethasone was shown to be anatomically superior to aflibercept.[22] Although a correlation between visual acuity and macular thickness is usually observed, the relationship has been described as modest.[43] This suggests that there are additional variables affecting BCVA in the setting of DME other than macular thickness, such as HbA1C and age.[43] Damage to photoreceptors may also be irreversible; therefore, despite reduction in macular edema, visual acuity may remain compromised.

Aflibercept has demonstrated considerable safety across multiple study designs when compared to various treatment modalities. Two other meta-analyses found no significant adverse events occurring under aflibercept therapy.[39],[42] This contrasts to a safety study evaluating aflibercept, ranibizumab, and laser therapies found an increased risk of death, cerebrovascular accident, and vascular death among patients using aflibercept and ranibizumab compared with laser and sham.[44] Zhang et al. found more frequent systemic adverse events in groups treated with anti-VEGF therapy, whereas steroid therapy resulted in more frequent ocular adverse events, including cataracts and increased intraocular pressure.[41] Similarly, the present study found that in both studies evaluating dexamethasone, there were elevations in intraocular pressure after dexamethasone therapy. These findings suggest that steroid therapy should be employed cautiously.

In this study, meta-regression analysis demonstrated dosing schedule as a predictor of outcomes in addition to comparator group. This aligns with findings of previously published data demonstrating the variability of different dosing schedules on patient outcomes.[45] It is important to consider that the risk of bias tools used to evaluate RCTs and non-RCTs vary in their standards of assessment. RCTs are inherently of higher quality; therefore, a low risk score for a non-RCT study may only equate to an RCT with some concerns. Although including multiple study designs resulted in a more comprehensive and clinically relevant review, there were several limitations: (1) studies with small sample sizes were not powered enough to undergo meaningful statistical analyses; (2) there were a limited number of comparison studies for certain treatments, particularly bevacizumab and dexamethasone; and (3) the methodological quality and the nonblinding of participants in non-RCTs may have introduced selection bias and confounding factors. However, the real-life data contributed by such studies provides a more realistic representation of the efficacy of aflibercept in practice; and (4) a significant amount of heterogeneity was present across comparator studies, likely due to differences in experimental protocols. To address this variability, a random-effects model was used to calculate pooled estimates.

Aflibercept is effective at improving visual and anatomical outcomes in patients with DME, both in highly controlled settings and in a real-life environment. Aflibercept shows greater improvements when compared to laser photocoagulation overall. Individual studies have shown an advantage of aflibercept when compared to bevacizumab anatomically, ranibizumab functionally at 1 year, and dexamethasone functionally. Aflibercept is shown to be noninferior compared to bevacizumab functionally and ranibizumab anatomically. Aflibercept demonstrates a considerable safety profile in patients with DME. Future research should assess the predictors of response to aflibercept. Furthermore, given the substantial differences in the cost associated with each treatment modality, cost-effectiveness studies taking into consideration the findings of the present study are warranted.[50]

Availability of data and material

The present manuscript has data included as electronic Supplementary Material.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13]



 

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