Background Central vision loss caused by age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Neovascular AMD is characterized by choroidal neovascularization (CNV). Growth of new blood vessels in patients with neovascular AMD is driven by a complex process that involves a signal protein called vascular endothelial growth factor A (VEGF-A). Anti-VEGF drugs that block this protein include ranibizumab, bevacizumab, and aflibercept. Objectives To assess and compare the effectiveness and safety of intravitreal injections of aflibercept versus ranibizumab, bevacizumab, or sham for treatment of patients with neovascular AMD. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (Issue 11, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched December 4, 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on November 30, 2015. Selection criteria We included randomized controlled trials (RCTs) in which aflibercept monotherapy was compared with ranibizumab, bevacizumab, or sham for participants with neovascular AMD who were treatment-naive. Data collection and analysis We used standard methodological procedures of The Cochrane Collaboration for screening, data abstraction, and study assessment. Two review authors independently screened records, abstracted data, and assessed risk of bias of included studies; we resolved discrepancies by discussion or with the help of a third review author when needed. Main results We included two RCTs (total of 2457 participants, 2457 eyes). Trial participants had neovascular AMD with active subfoveal choroidal neovascular lesions. Both trials followed the same protocol and compared aflibercept at various doses versus ranibizumab, but they were carried out in different countries. One trial enrolled participants from the United States and Canada, and the second trial was conducted at 172 sites in Europe, Asia Pacific, Latin America, and the Middle East. The overall quality of the evidence was high, and included trials were at low risk for most bias domains assessed; however, both trials were funded by the manufacturers of aflibercept. For the purposes of analysis, we combined aflibercept groups regardless of dosing and analyzed them as a single group. Visual acuity outcomes were similar between aflibercept and ranibizumab groups; at one year, participants in the aflibercept groups showed mean change in best-corrected visual acuity (BCVA) from baseline similar to that of participants in the ranibizumab groups (mean difference (MD) -0.15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (95% CI) -1.47 to 1.17; high-quality evidence). At two years, the mean change in BCVA from baseline was 7.2 ETDRS letters for aflibercept groups versus 7.9 for ranibizumab groups. Sufficient data were not available for calculation of confidence intervals. The proportion of participants who gained 15 or more letters of BCVA by one year of follow-up was approximately 32% for both aflibercept and ranibizumab (RR 0.97, 95% CI 0.85 to 1.11; high-quality evidence), and by two years of follow-up was approximately 31%(RR0.98, 95% CI 0.85 to 1.12; high-quality evidence). Similar small proportions of participants in the aflibercept and ranibizumab groups lost 15 or more letters of BCVA at one year (RR 0.89, 95% CI 0.61 to 1.30; high-quality evidence); this outcome was not reported for two-year follow-up. Data were not reported on the proportion of participants with BCVA worse than 20/200 at one-or two-year follow-up. Participants treated with aflibercept or ranibizumab showed similar improvement in morphological outcomes, as assessed from images (central retinal thickness and CNV size). At one year, the proportion of eyes that achieved dry retina was similar between aflibercept and ranibizumab groups (absence of cystic intraretinal fluid and subretinal fluid on optical coherence tomography (OCT); RR 1.06, 95% CI 0.98 to 1.14; high-quality evidence). In addition, investigators reported no difference in reduction of CNV area between aflibercept-and ranibizumab-treated eyes at one year (MD -0.24 mm(2), 95% CI -0.78 to 0.29; high-quality evidence). Data were not reported for the proportion of eyes with absence of leakage on fluorescein angiography at one-or two-year follow-up. Overall, occurrence of serious systemic adverse events was similar and comparable in aflibercept-and ranibizumab-treated groups at one year (RR 0.99, 95% CI 0.79 to 1.25). Risk of any serious ocular adverse event was lower in the aflibercept group than in the ranibizumab group, but the risk estimate is imprecise (RR 0.62, 95% CI 0.36 to 1.07). As the result of imprecision, we graded the quality of evidence for all adverse events as moderate. Authors' conclusions Results of this review document the comparative effectiveness of aflibercept versus ranibizumab for visual acuity and morphological outcomes in eyes with neovascular AMD. Current available information on adverse effects of each medication suggests that the safety profile of aflibercept is comparable with that of ranibizumab; however, the number of participants who experienced adverse events was small, leading to imprecise estimates of absolute and relative effect sizes. The eight-week dosing regimen of aflibercept represents reduced treatment requirements in comparison with monthly dosing regimens and thus has the potential to reduce treatment burden and risks associated with frequent injections.
