Virgili Gianni, Parravano Mariacristina, Evans Jennifer R, Gordon Iris, Lucenteforte Ersilia
Department of Translational Surgery and Medicine, Eye Clinic, University of Florence, Largo Brambilla, 3, Florence, Italy, 50134.
Cochrane Database Syst Rev. 2017 Jun 22;6(6):CD007419. doi: 10.1002/14651858.CD007419.pub5.
Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities can reduce oedema and thereby improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO.
The 2014 update of this review found high-quality evidence of benefit with antiangiogenic therapy with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO.The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods.
We searched various electronic databases on 26 April 2017.
We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO.
We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best-corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study.
Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate-certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 µm, 95% CI 2 µm to 76 µm; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 µm (95% CI -58 µm to -1 µm, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference.
AUTHORS' CONCLUSIONS: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms. Relative effects among anti-VEGF drugs at two years are less well known, since most studies were short term. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death.
糖尿病性黄斑水肿（DMO）是糖尿病视网膜病变的常见并发症。采用抗血管内皮生长因子（抗VEGF）方式进行抗血管生成治疗可减轻水肿，从而改善视力并防止视力进一步丧失。这些药物已取代激光光凝术，成为DMO患者的标准治疗方法。
本综述2014年的更新版发现，与激光光凝术相比，采用抗VEGF方式进行抗血管生成治疗对DMO治疗有益的高质量证据。本次更新综述的目的是使用网状Meta分析方法比较不同抗VEGF药物在保护和改善视力及生活质量方面的有效性和安全性。
我们于2017年4月26日检索了各种电子数据库。
我们纳入了随机对照试验（RCT），这些试验比较了任何具有抗血管生成作用机制的抗VEGF药物与另一种抗VEGF药物、另一种治疗方法、假治疗或不治疗在DMO患者中的效果。
我们使用Cochrane标准方法进行成对Meta分析，并使用网状Meta分析方法补充此证据。我们关注三种最常用药物作为直接用于实践的干预措施的相对疗效和安全性：阿柏西普和雷珠单抗，按标签使用；以及非标签使用的贝伐单抗。我们收集了关于三个疗效结局的数据（早期糖尿病性视网膜病变研究（ETDRS）视力表提高15行或更多；最佳矫正视力（BCVA）的平均变化；中心视网膜厚度（CRT）的平均变化）、三个安全性结局（所有严重全身性不良事件（SSAE）；全因死亡；动脉血栓栓塞事件）和生活质量。我们使用Stata“网状”Meta分析软件包进行所有分析。我们根据每项研究的方差贡献调查了混合比较的偏倚风险，并为每项研究分配了总体偏倚风险。
24项研究纳入了6007例有中度视力丧失的DMO患者，其中两项研究将230例患者的265只眼随机分组，一项是对56例患者（62只眼）的交叉研究，该研究被视为平行组试验。从三项关于阿柏西普的研究（975只眼）、八项关于贝伐单抗的研究（515只眼）和十四项关于雷珠单抗的研究（1518只眼）中收集了直接关注药物的数据。作为间接关注的治疗方法或传统治疗方法，我们纳入了三项关于培加替尼的研究（541只眼）、五项关于雷珠单抗加即刻激光的研究（557只眼）、一项关于雷珠单抗加延迟激光的研究（188只眼）、十三项关于激光光凝术的研究（936只眼）和六项关于假治疗的研究（793只眼）。一年后，阿柏西普、贝伐单抗和雷珠单抗在改善视力方面均比激光更有效（高确定性证据）。约十分之一的人通过激光改善了视力，约十分之三的人通过抗VEGF治疗改善了视力：阿柏西普与激光相比的风险比（RR）为3.66（95%置信区间（CI）2.79至4.79）；贝伐单抗的RR为2.47（95%CI 1.81至3.37）；雷珠单抗的RR为2.76（95%CI 2.12至3.59）。与抗VEGF治疗使视力提高1或2行相比，一年后激光治疗的视力平均无变化：激光与阿柏西普的平均差（MD）为-0.20（95%CI -0.22至-0.17）logMAR；与贝伐单抗的MD为-0.12（95%CI -0.15至-0.09）logMAR；与雷珠单抗的MD为-0.12（95%CI -0.14至-0.10）logMAR。阿柏西普和雷珠单抗与激光比较证据的确定性高，贝伐单抗与激光比较证据的确定性中等，因为间接证据和直接证据之间存在不一致。与阿柏西普相比，接受雷珠单抗治疗的人在一年时视力提高3行或更多行的可能性较小：RR为0.75（95%CI 0.60至0.94），中等确定性证据。每1000例接受阿柏西普治疗的人中，如果改用雷珠单抗治疗，一年时视力提高3行或更多行的人数将减少92例（减少22至148例）。平均而言，接受雷珠单抗治疗的人在一年时视力较差（MD为0.08 logMAR单位，95%CI 0.05至0.11），中等确定性证据；CRT较高（MD为39 µm，95%CI 2 µm至76 µm；低确定性证据）。雷珠单抗和贝伐单抗与阿柏西普相比具有可比性，在视力方面无差异：一年时视力提高3行或更多行的RR为1.11（95%CI 0.87至1.43），中等确定性证据，视力变化差异为0.00（95%CI -0.02至0.03）logMAR，中等确定性证据。CRT降低方面雷珠单抗更具优势，差值为-29 µm（95%CI -58 µm至-1 µm，低确定性证据）。我们的分析中没有总体统计不一致的证据。本综述的上一版发现抗血管生成药物与对照相比安全性良好的中等确定性证据。本次更新使用了最长可用随访期（一年或两年）的数据，发现阿柏西普、雷珠单抗和贝伐单抗在全身性严重不良事件（SSAE）方面无差异（中等或高确定性证据）。然而，偏倚风险存在差异，可发现循环不一致，对于动脉血栓栓塞事件或死亡等较少发生事件的相对安全性估计不够精确（低或极低确定性证据）。本综述中仅有四项RCT报告了两年的数据。大多数行业资助的研究在一年后为开放标签。一项大型公共资助研究在两年时比较了这三种药物，未发现差异。
抗VEGF药物对改善DMO患者的视力有效，每十人中约有三至四人可能在一年时视力提高至少3行。有中等确定性证据表明，在一年时，阿柏西普在视力和解剖学方面比雷珠单抗和贝伐单抗具有一定优势。由于大多数研究是短期的，抗VEGF药物在两年时的相对效果尚不太清楚。RCT的证据可能不适用于实际临床，因为需要抗血管生成治疗的患者往往治疗不足且监测不够。我们发现目前用于治疗DMO的三种抗血管生成药物在总体安全性上没有差异信号，但我们对心血管事件和死亡的估计不够精确。
