Anti‐vascular endothelial growth factor for choroidal neovascularisation in people with pathological myopia

Ying Zhu, Ting Zhang, Gezhi Xu, Lijun Peng

Choroidal neovascularisation (CNV) is a common complication of pathological myopia. Once developed, most eyes with myopic CNV (mCNV) experience a progression to macular atrophy, which leads to irreversible vision loss. Anti-vascular endothelial growth factor (anti-VEGF) therapy is used to treat diseases characterised by neovascularisation and is increasingly used to treat mCNV. To assess the effects of anti-vascular endothelial growth factor (anti-VEGF) therapy for choroidal neovascularisation (CNV), compared with other treatments, sham treatment or no treatment, in people with pathological myopia. We searched a number of electronic databases including CENTRAL and Ovid MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP). We did not use any date or language restrictions in the electronic searches for trials. Electronic databases were last searched on 16 June 2016. We included randomised controlled trials (RCTs) and quasi-RCTs comparing anti-VEGF therapy with another treatment (e.g. photodynamic therapy (PDT) with verteporfin, laser photocoagulation, macular surgery, another anti-VEGF), sham treatment or no treatment in participants with mCNV. We used standard methodological procedures expected by Cochrane. Two authors independently screened records, extracted data, and assessed risk of bias. We contacted trial authors for additional data. We analysed outcomes as risk ratios (RRs) or mean differences (MDs). We graded the certainty of the evidence using GRADE. The present review included six studies which provided data on the comparison between anti-VEGF with PDT, laser, sham treatment and another anti-VEGF treatment, with 594 participants with mCNV. Three trials compared bevacizumab or ranibizumab with PDT, one trial compared bevacizumab with laser, one trial compared aflibercept with sham treatment, and two trials compared bevacizumab with ranibizumab. Pharmaceutical companies conducted two trials. The trials were conducted at multiple clinical centres across three continents (Europe, Asia and North America). In all these six trials, one eye for each participant was included in the study.When compared with PDT, people treated with anti-VEGF agents (ranibizumab (one RCT), bevacizumab (two RCTs)), were more likely to regain vision. At one year of follow-up, the mean visual acuity (VA) in participants treated with anti-VEGFs was -0.14 logMAR better, equivalent of seven Early Treatment Diabetic Retinopathy Study (ETDRS) letters, compared with people treated with PDT (95% confidence interval (CI) -0.20 to -0.08, 3 RCTs, 263 people, low-certainty evidence). The RR for proportion of participants gaining 3+ lines of VA was 1.86 (95% CI 1.27 to 2.73, 2 RCTs, 226 people, moderate-certainty evidence). At two years, the mean VA in people treated with anti-VEGFs was -0.26 logMAR better, equivalent of 13 ETDRS letters, compared with people treated with PDT (95% CI -0.38 to -0.14, 2 RCTs, 92 people, low-certainty evidence). The RR for proportion of people gaining 3+ lines of VA at two years was 3.43 (95% CI 1.37 to 8.56, 2 RCTs, 92 people, low-certainty evidence). People treated with anti-VEGFs showed no obvious reduction (improvement) in central retinal thickness at one year compared with people treated with PDT (MD -17.84 μm, 95% CI -41.98 to 6.30, 2 RCTs, 226 people, moderate-certainty evidence). There was low-certainty evidence that people treated with anti-VEGF were more likely to have CNV angiographic closure at 1 year (RR 1.24, 95% CI 0.99 to 1.54, 2 RCTs, 208 people). One study allowed ranibizumab treatment as of month 3 in participants randomised to PDT, which may have led to an underestimate of the benefits of anti-VEGF treatment.When compared with laser photocoagulation, there was more improvement in VA among bevacizumab-treated people than among laser-treated people after one year (MD -0.22 logMAR, equivalent of 11 ETDRS letters, 95% CI -0.43 to -0.01, 1 RCT, 36 people, low-certainty evidence) and after two years (MD -0.29 logMAR, equivalent of 14 ETDRS letters, 95% CI -0.50 to -0.08, 1 RCT, 36 people, low-certainty evidence).When compared with sham treatment, people treated with aflibercept had better vision at one year (MD -0.19 logMAR, equivalent of 9 ETDRS letters, 95% CI -0.27 to -0.12, 1 RCT, 121 people, moderate-certainty evidence). The fact that this study allowed for aflibercept treatment at 6 months in the control group might cause an underestimation of the benefit with anti-VEGF.People treated with ranibizumab had similar improvement in VA recovery compared with people treated with bevacizumab after one year (MD -0.02 logMAR, equivalent of 1 ETDRS letter, 95% CI -0.11 to 0.06, 2 RCTs, 80 people, moderate-certainty evidence).Of the included six studies, two studies reported no adverse events in either group and two industry-sponsored studies reported both systemic and ocular adverse events. In the control group, there were no systemic or ocular adverse events reported in 149 participants. Fifteen people reported systemic serious adverse events among 359 people treated with anti-VEGF agents (15/359, 4.2%). Five people reported ocular adverse events among 359 people treated with anti-VEGF agents (5/359, 1.4%). The number of adverse events was low, and the estimate of RR was uncertain regarding systemic serious adverse events (4 RCTs, 15 events in 508 people, RR 4.50, 95% CI 0.60 to 33.99, very low-certainty evidence) and serious ocular adverse events (4 RCTs, 5 events in 508 people, RR 1.82, 95% CI 0.23 to 14.71, very low-certainty evidence). There were no reports of mortality or cases of endophthalmitis or retinal detachment.There was sparse reporting of data for vision-related quality of life (in favour of anti-VEGF) in only one trial at one year of follow-up. The studies did not report data for other outcomes, such as percentage of participants with newly developed chorioretinal atrophy. There is low to moderate-certainty evidence from RCTs for the efficacy of anti-VEGF agents to treat mCNV at one year and two years. Moderate-certainty evidence suggests ranibizumab and bevacizumab are equivalent in terms of efficacy. Adverse effects occurred rarely and the trials included here were underpowered to assess these. Future research should be focused on the efficacy and safety of different drugs and treatment regimens, the efficacy on different location of mCNV, as well as the effects on practice in the real world.