Zhu Ying, Zhang Ting, Xu Gezhi, Peng Lijun
Department of Ophthalmology, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, Hunan, China, 410008.
Department of Ophthalmology, Eye and Ear Nose Throat Hospital, Shanghai Medical School, Fudan University, No. 83, Fenyang Road, Shanghai, China, 200032.
Cochrane Database Syst Rev. 2016 Dec 15;12(12):CD011160. doi: 10.1002/14651858.CD011160.pub2.
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.
AUTHORS' CONCLUSIONS: 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.
脉络膜新生血管（CNV）是病理性近视的常见并发症。一旦发生，大多数患有近视性CNV（mCNV）的眼睛会进展为黄斑萎缩，从而导致不可逆转的视力丧失。抗血管内皮生长因子（anti-VEGF）疗法用于治疗以新生血管形成为特征的疾病，并且越来越多地用于治疗mCNV。
评估抗血管内皮生长因子（anti-VEGF）疗法与其他治疗、假治疗或不治疗相比，对病理性近视患者脉络膜新生血管（CNV）的治疗效果。
我们检索了多个电子数据库，包括Cochrane系统评价数据库、Ovid MEDLINE、ClinicalTrials.gov和世界卫生组织（WHO）国际临床试验注册平台（ICTRP）。在电子检索试验时，我们未设置任何日期或语言限制。电子数据库的最后检索日期为2016年6月16日。
我们纳入了比较抗VEGF疗法与另一种治疗（如维替泊芬光动力疗法（PDT）、激光光凝、黄斑手术、另一种抗VEGF）、假治疗或不治疗的随机对照试验（RCT）和半随机对照试验，受试者为患有mCNV的患者。
我们采用Cochrane期望的标准方法程序。两位作者独立筛选记录、提取数据并评估偏倚风险。我们联系试验作者获取更多数据。我们将结局分析为风险比（RRs）或均值差（MDs）。我们使用GRADE对证据的确定性进行分级。
本综述纳入了六项研究，这些研究提供了抗VEGF与PDT、激光、假治疗和另一种抗VEGF治疗之间比较的数据，共有594例mCNV患者。三项试验比较了贝伐单抗或雷珠单抗与PDT，一项试验比较了贝伐单抗与激光，一项试验比较了阿柏西普与假治疗，两项试验比较了贝伐单抗与雷珠单抗。两项试验由制药公司开展。试验在三大洲（欧洲、亚洲和北美洲）的多个临床中心进行。在所有这六项试验中，每位受试者的一只眼睛被纳入研究。与PDT相比，接受抗VEGF药物（雷珠单抗（一项RCT）、贝伐单抗（两项RCT））治疗的患者更有可能恢复视力。在随访一年时，接受抗VEGF治疗的患者的平均视力（VA）比接受PDT治疗的患者好-0.14 logMAR，相当于7个早期糖尿病性视网膜病变研究（ETDRS）视力字母（95%置信区间（CI）-0.20至-0.08，3项RCT，263人，低确定性证据）。视力提高3行及以上的受试者比例的RR为1.86（95%CI 1.27至2.73，2项RCT，226人，中等确定性证据）。在两年时，接受抗VEGF治疗的患者的平均VA比接受PDT治疗的患者好-0.26 logMAR，相当于13个ETDRS视力字母（95%CI -0.38至-0.14，2项RCT，92人，低确定性证据）。两年时视力提高3行及以上的患者比例的RR为3.43（95%CI 1.37至8.56，2项RCT，92人，低确定性证据）。与接受PDT治疗的患者相比，接受抗VEGF治疗的患者在一年时中央视网膜厚度没有明显降低（改善）（MD -17.84μm，95%CI -41.98至6.30，2项RCT，226人，中等确定性证据）。有低确定性证据表明，接受抗VEGF治疗的患者在1年时CNV血管造影闭合的可能性更大（RR 1.24，95%CI 0.99至1.54，2项RCT，208人）。一项研究允许将雷珠单抗治疗用于随机分配至PDT组的受试者，从第3个月开始使用，这可能导致对抗VEGF治疗益处的低估。与激光光凝相比，贝伐单抗治疗组患者在一年后（MD -0.22 logMAR，相当于11个ETDRS视力字母，95%CI -0.43至-0.01，1项RCT，36人，低确定性证据）和两年后（MD -0.29 logMAR，相当于14个ETDRS视力字母，95%CI -0.50至-0.08，1项RCT，36人，低确定性证据）的视力改善情况优于激光治疗组。与假治疗相比，接受阿柏西普治疗的患者在一年时视力更好（MD -0.19 logMAR，相当于9个ETDRS视力字母，95%CI -0.27至-0.12，1项RCT，121人，中等确定性证据）。该研究允许对照组在6个月时接受阿柏西普治疗，这可能导致对抗VEGF治疗益处的低估。与接受贝伐单抗治疗的患者相比，接受雷珠单抗治疗的患者在一年后视力恢复情况的改善相似（MD -0.02 logMAR，相当于1个ETDRS视力字母，95%CI -0.11至0.06，2项RCT，80人，中等确定性证据）。在纳入的六项研究中，两项研究报告两组均无不良事件，两项由行业赞助的研究报告了全身和眼部不良事件。在对照组中，149名受试者未报告全身或眼部不良事件。在359名接受抗VEGF药物治疗的患者中，15人报告了全身严重不良事件（15/359，4.2%）。在359名接受抗VEGF药物治疗的患者中，5人报告了眼部不良事件（5/359，1.4%）。不良事件数量较少，关于全身严重不良事件（4项RCT，508人中有15起事件，RR 4.50，95%CI 0.60至33.99，极低确定性证据）和严重眼部不良事件（4项RCT，508人中有5起事件，RR 1.82，95%CI 0.23至14.71，极低确定性证据）的RR估计不确定。没有关于死亡、眼内炎或视网膜脱离病例的报告。在仅一项试验的一年随访中，关于视力相关生活质量（支持抗VEGF）的数据报告较少。这些研究未报告其他结局的数据，如新发脉络膜视网膜萎缩的受试者百分比。
随机对照试验提供了低至中等确定性的证据，证明抗VEGF药物在治疗mCNV一年和两年时的疗效。中等确定性证据表明，雷珠单抗和贝伐单抗在疗效方面相当。不良反应很少发生，且此处纳入的试验评估这些不良反应的能力不足。未来的研究应侧重于不同药物和治疗方案的疗效和安全性、对不同部位mCNV的疗效，以及对现实世界临床实践的影响。
