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Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema

  • Comment
  • Review
  • Intervention




Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities has recently been proposed for improving vision in people with DMO.


To assess the effectiveness, safety and cost-effectiveness of anti-VEGF therapy for preserving or improving vision in people with DMO.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1946 to June 2012), EMBASE (January 1980 to June 2012), the metaRegister of Controlled Trials (mRCT) (, ( and the WHO International Clinical Trials Registry Platform (ICTRP) ( We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2012.

Selection criteria

We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment, or no treatment in patients with DMO. We also included economic evaluations to assess cost-effectiveness.

Data collection and analysis

Two review authors independently extracted the data. The risk ratio (RR) of visual loss and visual gain of three or more lines was estimated at least six months after treatment. Each economic analysis was described narratively using a structured format.

Main results

Eleven studies provided data on three comparisons of interest in this review. Compared with grid laser photocoagulation, there was evidence of moderate quality that antiangiogenic therapy (bevacizumab: two studies, 167 participants; ranibizumab: two studies, 300 participants; aflibercept: one study, 221 participants, 89 used for data extraction) more than doubled and, respectively, reduced by at least two thirds, the chance of gaining or losing 3 or more lines of vision (RR: 3.20, 95% confidence interval (CI) 2.07 to 4.95 and RR: 0.13, 95% CI: 0.05 to 0.34, respectively). In meta-analyses, no significant subgroup difference could be demonstrated between bevacizumab, ranibizumab and aflibercept regarding our primary outcome, but, again, there was little power to detect a difference. The quality of the evidence was moderate since the overall size was suboptimal for investigating between study, as well as between drug, heterogeneity.

Regarding absolute benefit, eight out of 100 patients with DMO would gain 3 or more lines of visual acuity using photocoagulation, whereas 26 would do so with antiangiogenic therapy, meaning that 100 patients need to be treated with antiangiogenic therapy to allow 18 more people (95% CI from 9 to 32) to markedly improve their vision after one year.

Using mean visual acuity outcome, the meta-analytic difference between antiangiogenic therapy and photocoagulation was 1.3 lines (1 to 1.6) after one year, favouring drug therapy.

In other analyses, ranibizumab was more effective than sham (three studies on 497 participants) and ranibizumab associated with laser was more effective than laser alone (three studies on 783 participants).

Systemic and ocular adverse events were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation (nine studies, 104 events in 2159 participants) did not show a significant difference regarding arterial thromboembolic events (RR: 0.85 (0.56 to 1.28). Similarly, no difference was suggested regarding overall mortality (53 events, RR: 0.95 (0.52 to 1.74), but clinically significant differences could not be ruled out.

Authors' conclusions

There is moderate quality evidence that antiangiogenic drugs provide a definite, but small, benefit compared to current therapeutic options for DMO, i.e. grid laser photocoagulation, or no treatment when laser is not an option. The quality and quantity of the evidence was larger for ranibizumab, but there was little power to investigate drug differences. Most data were obtained at one year, and a long-term confirmation is needed, since DMO is a chronic condition. Safety of both drug and the intravitreal injection procedure were good in the trials, but further long-term data are needed to exclude small, but clinically important differences regarding systemic adverse events.








CENTRAL(Cochrane Eyes and Vision Group Trials Register)(コクラン・ライブラリ2012年第6号)、MEDLINE(1946年1月~2012年6月)、EMBASE(1980年1月~2012年6月)、metaRegister of Controlled Trials(mRCT)(およびWHO(世界保健機関)International Clinical Trials Registry Platform(ICTRP)(を検索した。試験の電子検索に年月日および言語の制限を設けなかった。最後に電子データベースを検索したのは2012年6月13日であった。






11件の試験により本レビューで対象とした3件の比較に関するデータが得られた。約1年目の3ライン以上の視力改善または低下のRRに基づき結論を得て、追跡調査ではより一貫した報告が得られた。<br /><br />偽治療との比較では、3件の試験(参加者497名、追跡期間8~12ヵ月間)に、抗血管新生療法で(ペガプタニブ:2件の試験、参加者246名;ラニビズマブ:1件の試験、参加者151名)3ライン以上の視力の改善または低下する確率が2倍となり、さらに各々半減するという中等度の品質のエビデンスが認められた(RR:2.19、95%CI 1.36~3.53;RR:0.28、95%CI 0.13~0.59)。メタアナリシスでは、ペガプタニブに比しラニビズマブが有益であったが、主要アウトカムについて有意なサブグループの差は実証されなかった。<br /><br />グリッドレーザ光凝固療法との比較では、抗血管新生療法(ベバシズマブ:2件の試験、参加者167名;ラニビズマブ:2件の試験、参加者300名;アフリベルセプト:1件の試験、参加者221名、89名をデータ抽出に使用)で3ライン以上視力が改善または低下する確率が2倍を超えた後、各々3分の2以上低下した(RR:3.20、95%CI 2.07~4.95;RR:0.13、95%CI 0.05~0.34)。メタアナリシスでは、主要アウトカムについてはベバシズマブ、ラニビズマブおよびアフリベルセプト間に有意なサブグループの差を認めなかったが、ここでも差を検出する検出力が不足した。<br /><br />グリッドレーザ光凝固療法単独との比較では、ラニビズマブ+光凝固療法(3件の試験、参加者783名)により3以上のラインの視力が改善または低下する確率は2倍になり、その後各々少なくとも半減した(RR:2.11、95%CI 1.67~2.67;RR:0.29、95%CI 0.15~0.55)。<br /><br />全身および眼の有害事象は組み入れた試験ではまれにしか認められなかった。全抗血管形成薬について実施されたメタアナリシスでは、偽治療または光凝固療法を比較し(9件の試験、参加者2,159名中104件のイベント)、動脈血栓塞栓イベントについて有意差を認めなかった[RR 0.85(0.56~1.28)]。同様に、全死亡率[53件のイベント、RR:0.95(0.52~1.74)]に差を認めなかったが、臨床的に意味のある差を除外できなかった。



Plain language summary

Antiangiogenic therapy for diabetic macular oedema

Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. The retina at the macula thickens and this can cause gradual loss of central vision. Grid or focal laser photocoagulation is effective in treating DMO and has been used for several years, but vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities has recently been proposed to try to improve vision in people with DMO. Anti-VEGF drugs are delivered by an injection in the vitreous cavity of the eye and need to be repeated for maintenance.

We included 11 studies in this review comparing intravitreal antiangiogenic therapy with sham, laser photocoagulation or investigating its effect when added to photocoagulation. About one in five or seven more people gained a good amount of vision, i.e. 3 lines, using antiangiogenic therapy compared with laser, using seven to 10 intraocular injections in the first year, and two in the second year. Little is known about treatment needs beyond this term. Two related UK-based economic evaluations disagreed on whether ranibizumab was cost-effective compared with laser photocoagulation. The evaluation finding ranibizumab not cost-effective was revised while this review was being updated, leading the UK National Institute of Health and Clinical Excellence (NICE) to recommend ranibizumab for patients with visual impairment and more severe oedema on optical coherence tomography.

Antiangiogenic treatment was well tolerated in these studies, but since all studies were short- or medium-term, we were unable to investigate long-term effects as well as risks.



糖尿病性黄斑浮腫(DMO)は、糖尿病性網膜症の一般的な合併症です。黄斑の網膜が肥厚するため、中心視力の緩慢な低下が生じます。グリッドレーザ光凝固療法または限局性レーザ光凝固療法はDMO治療に有効で、数年使用されてきましたが、視力の改善はまれでした。抗血管内皮増殖因子(抗VEGF)モダリティを伴う抗血管新生療法は最近、DMO患者の視力改善の試みとして提案されています。抗VEGF薬は眼の硝子体腔内への注射で送達し、維持のため反復する必要があります。<br /><br />硝子体内抗血管新生療法を偽治療、レーザー光凝固療法と比較するかまたは、光凝固療法を併用しその効果を検討する11件の試験を本レビューに組み入れました。5または7名以上の患者中約1名が、レーザー療法より抗血管新生療法で、初年に7~10回、2年目に2回の眼内注射により十分な視力改善(3ライン以上)を認めました。この期間を超える治療の必要性については明らかになっていません。英国での2件の関連のある経済的評価では、ラニビズマブがレーザー光凝固療法より費用効果があるかという点について否定的でした。ラニビズマブに費用効果がないという評価所見は訂正されましたが、一方で本レビュー更新の結果、英国国立医療技術評価機構(NICE)は、視力障害および光コヒーレンストモグラフィでより重度の浮腫を認める患者対しラニビズマブ投与を推奨することにしました。<br /><br />抗血管新生療法は、上記試験で十分な忍容性を示しましたが、全試験が短期または中期であったため、長期の効果およびリスクを検討することができませんでした。


監  訳: 曽根 正好, 2014.3.14

実施組織: 厚生労働省委託事業によりMindsが実施した。

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オンライン公表: 2013/11/8