Aflibercept for neovascular age-related macular degeneration

Review question
How well does aflibercept work, and how safe is it for the treatment of individuals with neovascular age-related macular degeneration compared with other currently used treatments (ranibizumab and bevacizumab) or no treatment?

One cause of loss of sight in the center of the eye is a disease called age-related macular degeneration (AMD). AMD causes blindness in many older people in developed countries. Around the world, nearly 9% (one in 11) of people 45 to 85 years of age are estimated to have AMD. About 10% of people with AMD develop a type of AMD called neovascular (wet) AMD, which results from new blood vessels that develop in an inner layer of the eye called the choroid. If a patient with this type of AMD is not treated, the affected eye may lose sight and may develop other problems related to blindness.

New blood vessels grow when they are signaled by a protein called vascular endothelial growth factor A (VEGF-A). Medicines that block this protein, called anti-VEGF drugs, are injected into the eye and have been shown to reduce fluid in the back of the eye while causing new blood vessels to slow down growth or to shrink. Ranibizumab and bevacizumab were the most commonly used anti-VEGF drugs from 2006 to 2011, when aflibercept became available. Aflibercept was created to bond more strongly with VEGF; therefore, aflibercept acts longer after an injection, so patients should need fewer injections of aflibercept than of ranibizumab or bevacizumab.

Study details
We found two trials that enrolled a total of 2457 participants with neovascular AMD. These trials were similar in most respects, but they were conducted at different locations. One was completed only in North America, and the other took place in many countries in many parts of the world. Both trials compared injections of aflibercept into the eye versus ranibizumab injections and were funded by the company that makes aflibercept. No trial was found that compared aflibercept versus bevacizumab injections into the eye. We last searched for trials on November 30, 2015.

Key results
Participants treated with aflibercept or ranibizumab experienced similar improvements in visual acuity one year after the start of treatment. Serious vision loss did not occur in many eyes given either treatment and did not occur more often with either aflibercept or ranibizumab. Serious adverse effects in the eye were reported rarely in both aflibercept and ranibizumab groups. The incidence of serious adverse health effects, such as internal bleeding, stroke, and high blood pressure, was comparable between aflibercept and ranibizumab groups; however, such reported events were few. Thus, we are uncertain about possible differences in adverse effects reported among individuals given aflibercept or ranibizumab.

Quality of the evidence
The two identified trials were well designed, and we judged the quality of evidence as high for vision-related outcomes. A judgement of high quality means that we believe future research is very unlikely to change our conclusions. Because of uncertainty regarding adverse effects due to the small number of occurrences, we judged the quality of evidence for adverse effects as moderate. A judgement of moderate quality means that we believe future research may have an important impact on our conclusions.

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.

Read the full abstract...

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.


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 strategy: 

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) ( (last searched December 4, 2014), (, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( 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% (RR 0.98, 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 mm2, 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.