Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion

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Authors


Abstract

Background

Central retinal vein occlusion (CRVO) is a relatively common retinal vascular disorder in which macular oedema may develop, with a consequent reduction in visual acuity. Until recently there has been no treatment of proven benefit, but growing evidence supports the use of anti-vascular endothelial growth factor (anti-VEGF) agents.

Objectives

To investigate the effectiveness and safety of anti-VEGF therapies for the treatment of macular oedema secondary to CRVO.

Search methods

We searched CENTRAL (which contains the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 10), Ovid MEDLINE (January 1950 to October 2013), EMBASE (January 1980 to October 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2013), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to October 2013), OpenGrey, OpenSIGLE (January 1950 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and Web of Science Conference Proceedings Citation Index-Science (CPCI-S). There were no language or date restrictions in the electronic search for trials. The electronic databases and clinical trials registers were last searched on 29th October 2013.

Selection criteria

We considered randomised controlled trials (RCTs) that compared intravitreal anti-VEGF agents of any dose or duration to sham injection or no treatment. We focused on studies that included individuals of any age or gender and a minimum of six months follow-up.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data. The primary outcome was the proportion of participants with a gain in best-corrected visual acuity (BCVA) from baseline of greater than or equal to 15 letters (3 lines) on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Secondary outcomes included the proportion of participants with a loss of 15 letters or more of BCVA, the mean change from baseline BCVA, the mean change in central retinal thickness (CRT), the number and type of complications or adverse outcomes, and the number of additional interventions administered. Where available, we also presented quality of life and economic data.

Main results

We found six RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs included 937 participants and compared outcomes at six months to sham injection for four anti-VEGF agents: aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) and ranibizumab (Lucentis). Three trials were conducted in Norway, Sweden and the USA, and three trials were multicentre, one including centres in the USA, Canada, India, Israel, Argentina and Columbia, a second including centres in the USA, Australia, France, Germany, Israel, and Spain, and a third including centres in Austria, France, Germany, Hungary, Italy, Latvia, Australia, Japan, Singapore and South Korea. We performed meta-analysis on three key visual outcomes, using data from up to six trials. High-quality evidence from six trials revealed that participants receiving intravitreal anti-VEGF treatment were 2.71 times more likely to gain at least 15 letters of visual acuity at six months compared to participants treated with sham injections (risk ratio (RR) 2.71; 95% confidence intervals (CI) 2.10 to 3.49). High-quality evidence from five trials suggested anti-VEGF treatment was associated with an 80% lower risk of losing at least 15 letters of visual acuity at six months compared to sham injection (RR 0.20; 95% CI 0.12 to 0.34). Moderate-quality evidence from three trials (481 participants) revealed that the mean reduction from baseline to six months in central retinal thickness was 267.4 µm (95% CI 211.4 µm to 323.4 µm) greater in participants treated with anti-VEGF than in participants treated with sham. The meta-analyses demonstrate that treatment with anti-VEGF is associated with a clinically meaningful gain in vision at six months. One trial demonstrated sustained benefit at 12 months compared to sham. No significant ocular or systemic safety concerns were identified in this time period.

Authors' conclusions

Compared to no treatment, repeated intravitreal injection of anti-VEGF agents in eyes with CRVO macular oedema improved visual outcomes at six months. All agents were relatively well tolerated with a low incidence of adverse effects in the short term. Future trials should address the relative efficacy and safety of the anti-VEGF agents and other treatments, including intravitreal corticosteroids, for longer-term outcomes.

摘要

抗血管內皮生長因子用於視網膜中央靜脈阻塞繼發性黃斑水腫

背景

視網膜中央靜脈阻塞(CRVO)是一種相當常見的視網膜血管疾病,有形成黃斑水腫並且視力隨之下降的可能。直到目前尚無可證實功效的療法,但越來越多的證據支持使用抗血管內皮生長因子(anti-VEGF)。

目的

評估anti-VEGF用於CRVO繼發性黃斑水腫治療上的有效性及安全性。

搜尋策略

我們搜尋了CENTRAL (包括 Cochrane Central Register of Controlled Trials (CENTRAL) 以及科藍眼與視力群組臨床試驗註冊) (The Cochrane Library 2013, Issue 10)資料庫, Ovid MEDLINE (1950 年1月至2013年10月), EMBASE (1980 年1月至2013年10月), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982年1月至2013年10月), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1937年1月至2013年10月), OpenGrey, OpenSIGLE (1950年1月至2013年10月), metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en)及Web of Science Conference Proceedings Citation Index-Science (CPCI-S). 在電子搜索試驗時並未設定任何日期或語言限制。2013年10月29日為最後的電子數據庫及臨床試驗註冊搜尋日期。

選擇標準

我們將比較玻璃體內注射anti-VEGF藥物的隨機對照試驗(RCT)列入考量,包括任何anti-VEGF劑量或持續時間,相較於模擬治療(sham injection)或不予治療。並著重於包括所有年齡與性别,以及至少六個月隨訪的研究。

資料收集與分析

由兩位回顧作者獨立評估試驗品質並提取數據。主要結果為受試者獲得最佳矯正視力改善(BCVA)所佔比例-在早期治療糖尿病視網膜病變研究(ETDRS)視力表(Early Treatment of Diabetic Retinopathy Study (ETDRS) chart )由基線進步至大於或等於15個字母(3行)。次要結果為喪失BCVA15個字母以上的受試者比例,以BCVA基線為基準的平均改變,中央視網膜厚度(CRT)平均改變,併發症或負面醫療結果的數量與種類,以及附加施藥干預。在許可情況下我們也提出生活質素和經濟數據。

主要結果

在獨立及重複審核搜尋結果後,我們發現6個符合納入標準的RCT。這些RCT包括937受試者以及比較了模擬治療和4種anti-VEGF藥劑:aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) 和 ranibizumab (Lucentis) 在6個月後的治療結果。三個試驗分别在挪威、瑞典和美國獨立進行;以及三個多中心的試驗,其中第一個包括美國、加拿大、印度、以色列、阿根廷和哥倫比亞,第二個包括美國、澳大利亞、法國、德國、以色列中心和西班牙,第三個包括奧地利、法國、德國、匈牙利、義大利、拉脫維亞、澳大利亞、日本、新加坡和韓國。我們利用來自6個試驗的數據進行了三項關鍵視覺醫療結果的統合分析。來自6個高品質臨床試驗證據顯示,相較於接受模擬治療的受試者,接受玻璃體内anti-VEGF治療的受試者在6個月時獲得至少「15個字母的視力」結果的比例高達2.71倍(風險比(RR)2.71;95%信賴區間(CI)2.10至3.49)。來自5個高品質臨床試驗證據顯示,相較於接受模擬治療的受試者,接受玻璃體内anti-VEGF治療的受試者在6個月時有80%較低喪失「15個字母的視力」的風險(RR 0.20; 95% CI 0.12 至 0.34 )。 來自3個中品質臨床試驗證據顯示(481受試者),從基準到6個月期間接受玻璃體内anti-VEGF受試者中央視網膜厚度减低程度平均為267.4 µm(95% CI 211.4 µm to 323.4 µm)高於模擬治療受試者。統合分析顯示於六個月時呈現具臨床意義的視力增進與anti-VEGF治療有關。一組試驗顯示相較於模擬治療,anti-VEGF在12個月時有持續的效益。在此期間并未發現明顯的眼部或全身安全疑慮。

作者結論

比起不作任何治療,重複性的在患有CRVO黃斑水腫的病眼玻璃體内注射抗VEGF藥劑於6個月後改善視力結果。所有藥劑相對耐受皆為良好並且短期内不良效果發生率低。為觀察長期結果,應再針對anti-VEGF藥劑及其他療法,包括玻璃體內注射皮質類固醇的相對功效和安全性進行下一步臨床試驗。

譯註

翻譯者:吳心文(Hsin-wen Wu)
服務單位:自由譯者
翻譯領域:general medicine, ophthalmology, commerce, technology and tourism

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Résumé scientifique

Facteur de croissance endothélial antivasculaire pour le traitement de l'œdème maculaire secondaire à l'occlusion de la veine centrale de la rétine

Contexte

L'occlusion de la veine centrale de la rétine (OVCR) est une pathologie vasculaire rétinienne relativement fréquente au cours de laquelle un œdème maculaire peut se développer, avec une baisse consécutive de l'acuité visuelle. Jusqu'à récemment, aucun traitement n’avait pu prouver un effet bénéfique, mais de plus en plus de preuves sont favorables à l'utilisation d’agents à base de facteur de croissance endothélial antivasculaire (anti-VEGF, pour Anti-Vascular Endothelial Growth Factor).

Objectifs

Examiner l'efficacité et l'innocuité des traitements par anti-VEGF pour le traitement de l'œdème maculaire secondaire à une OVCR.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (qui contient le registre Cochrane des essais contrôlés (CENTRAL) et le registre des essais du groupe Cochrane sur l'ophtalmologie) (Bibliothèque Cochrane 2013, numéro 10), Ovid MEDLINE (de janvier 1950 à octobre 2013), EMBASE (de janvier 1980 à octobre 2013), LILACS (Latin American and Caribbean Health Sciences Literature Database) (de janvier 1982 à octobre 2013), CINAHL (Cumulative Index to Nursing and Allied Health Literature) (de janvier 1937 à octobre 2013), OpenGrey, OpenSIGLE (de janvier 1950 à octobre 2013), le méta-registre des essais contrôlés (mREC) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), le système d'enregistrement international des essais cliniques (ICTRP) de l'OMS (www.who.int/ictrp/search/en) et CPCI-S (Web of Science Conference Proceedings Citation Index). Aucune restriction concernant la langue ou la date n'a été appliquée aux recherches électroniques d'essais. La dernière recherche des bases de données électroniques et des registres d'essais cliniques a été effectuée le 29 octobre 2013.

Critères de sélection

Nous avons pris en compte les essais contrôlés randomisés (ECR) ayant comparé des agents anti-VEGF intravitréens, quelque soit la dose ou la durée, à une injection simulée ou à l'absence de traitement. Nous avons privilégié les études ayant inclus des individus indépendamment de l’âge ou du sexe et ayant réalisé un suivi d'au moins six mois.

Recueil et analyse des données

Deux auteurs de la revue ont évalué la qualité méthodologique des essais et extrait des données de manière indépendante. Le critère de jugement principal était la proportion de participants présentant un gain de la meilleure acuité visuelle corrigée (MAVC) par rapport aux valeurs initiales supérieure ou égale à 15 lettres (3 lignes) sur le tableau de l'étude Early Treatment of Diabetic Retinopathy Study (ETDRS). Les critères de jugement secondaires incluaient la proportion de participants présentant une perte de 15 lettres ou plus de la MAVC, la variation moyenne par rapport aux valeurs initiales de la MAVC, la variation moyenne dans l'épaisseur centrale de la rétine (CRT pour central retinal thickness), le nombre et le type de complications ou de résultats indésirables, et le nombre d'interventions supplémentaires administrées. Lorsqu'elles étaient disponibles, nous avons également présenté les données concernant la qualité de vie et les données économiques.

Résultats principaux

Nous avons trouvé six ECR répondant aux critères d'inclusion après une revue indépendante en double des résultats des recherches. Ces ECR ont inclus 937 participants et comparaient les résultats à six mois par rapport à une injection simulée pour quatre agents anti-VEGF : l'aflibercept (VEGF Trap-Eye, Eylea), le bevacizumab (Avastin), le pegaptanibest de sodium (Macugen) et le ranibizumab (Lucentis). Trois essais ont été réalisés en Norvège, en Suède et aux États-Unis, et trois essais étaient multicentriques, dont un avec des centres aux États-Unis, au Canada, en Inde, en Israël, en Argentine et en Colombie, un deuxième avec des centres aux États-Unis, en Australie, en France, en Allemagne, en Israël et en Espagne, et un troisième avec des centres en Autriche, en France, en Allemagne, en Hongrie, en Italie, en Lettonie, en Australie, au Japon, à Singapour et en Corée du Sud. Nous avons effectué une méta-analyse sur trois critères de jugement visuels clés, en utilisant les données de jusqu'à six essais. Des preuves de qualité élevée issues de six essais ont révélé que les participants recevant un traitement anti-VEGF par injection intravitréenne avaient 2,71 fois plus de chances de gagner au moins 15 lettres d’acuité visuelle à six mois par rapport aux participants traités avec des injections simulées (risque relatif (RR) 2,71 ; intervalle de confiance (IC) à 95 % de 2,10 à 3,49). Des preuves de qualité élevée issues de cinq essais suggéraient que le traitement anti-VEGF était associé à une diminution de 80 % du risque de perte d'au moins 15 lettres de l'acuité visuelle à six mois par rapport à une injection simulée (RR 0,20 ; IC à 95 % de 0,12 à 0,34). Des preuves de qualité modérée issues de trois essais (481 participants) ont révélé que la réduction moyenne, de l'inclusion à six mois, de l'épaisseur centrale de la rétine était supérieure de 267,4 µm (IC à 95 % de 211,4 µm à 323,4 µm) chez les participants traités aux anti-VEGF que chez les participants traités avec un traitement simulé. Les méta-analyses démontrent que le traitement aux anti-VEGF est associé à une amélioration cliniquement appréciable de l’acuité visuelle à six mois. Un essai démontrait un effet bénéfique prolongé à 12 mois par rapport à un traitement simulé. Aucun effet indésirable significatif, oculaire ou systémique, n’a été identifié pendant cette période.

Conclusions des auteurs

Par rapport à l'absence de traitement, l'injection intravitréenne répétée d'agents anti-VEGF améliore le pronostic visuel à six mois des patients atteints d'OVCR avec un œdème maculaire. Tous les agents étaient relativement bien tolérés avec une faible incidence d'effets indésirables à court terme. Les futurs essais devront examiner l'efficacité et l'innocuité relatives des agents anti-VEGF et d'autres traitements, y compris l'injection intravitréenne de corticostéroïdes, pour les résultats à plus long terme.

Plain language summary

Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion

Review question
We reviewed the evidence about the effect of anti-vascular endothelial growth factor (anti-VEGF) agents in people with macular oedema secondary to central retinal vein occlusion (CRVO).

Background
CRVO affects approximately one person per 1000 at any one time, and is associated with increasing age, high blood pressure, diabetes, glaucoma and various disorders of the blood. It frequently causes sudden, painless vision loss in one eye, although sometimes the vision loss may be minimal. If the vein blockage leads to inadequate oxygen delivery to the sensitive retinal tissue, the CRVO is the 'non-perfused' or 'ischaemic' subtype. More commonly, blood flow and oxygen delivery are restored following the vein blockage and the CRVO is the 'perfused' or 'non-ischaemic' subtype, and has a better visual outcome. Various other complications may develop over hours, days, weeks or months. These include macular oedema, in which fluid collects within the retina and causes reduction in vision. Until relatively recently there has been no evidence-based treatment for this condition. Anti-VEGF agents have been used successfully to treat patients with other retinal vascular disorders, including several conditions associated with macular oedema.

Study characteristics
This systematic review identified six trials which included 937 participants with macular oedema secondary to CRVO (as of 29 October 2013). The trials compared sham injections with one of four types of anti-VEGF agents: aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) and ranibizumab (Lucentis). All trials treated participants for at least six months. Three trials were multicentre, international trials and three were conducted in Norway, Sweden or the USA.

Key results
Overall, treatment with anti-VEGF agents increased the chance of a significant gain in vision (at least 3 lines on the vision chart) at six months by more than two and a half times, compared to no treatment. Furthermore, the risk of losing significant vision (at least 3 lines on the vision chart) was reduced by 80% in those receiving anti-VEGF therapy compared to those receiving no treatment. No significant safety concerns were identified at six or 12 months, but the available studies do not allow a conclusion about their long-term effectiveness and safety to be drawn. Nevertheless, the availability of anti-VEGF treatment for CRVO macular oedema represents an important advance in the clinical management options for this sight-threatening disease.

Quality of the evidence
The six trials included in this review were high quality and consistently demonstrated visual benefit from anti-VEGF injections.

淺顯易懂的口語結論

抗血管內皮生長因子用於視網膜中央靜脈阻塞繼發性黃斑水腫

回顧問題
我們回顧了關於抗血管內皮生長因子(anti-VEGF)藥劑對視網膜中央靜脈阻塞(CRVO)繼發性黃斑水腫病患產生療效的證據。

背景資料
在一千人中約有一人會受到CRVO的影響,此症與年齡增長、高血壓、糖尿病、青光眼以及各種血液疾病有關。通常造成突發無痛的單眼視力减退,有時症狀甚至微乎其微。如果静脈阻塞導致運送至敏感視網膜組織的氧氣不足,屬於「非灌流型」或「缺氧型」CRVO。在比較普遍的情況下,血液流動和供氧功能在静脈阻塞後會自主復原,此為「灌流型」或「非缺氧型」CRVO。許多其他種類的併發症可能會在數小時、數日或數個月之後形成。黃斑水腫為其中之一,因液體屯積在視網膜内而引起視力减退。直到目前對此病症仍無具實證基礎的療法。Anti-VEGF已成功的應用在治療其他視網膜血管疾病的病例上,包括幾種與黃斑水腫有關的疾病。

研究特色
此系統回顧發現六個臨床試驗總共有937名CRVO繼發性黃斑水腫的受試者(直到2013年10月29日)。這些試驗比較了模擬治療和其他四種之一的anti-VEGF藥劑:aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) 和 ranibizumab (Lucentis)。 所有試驗皆為受試者提供至少6個月的治療。其中三個為國際性多中心試驗,另外三個分别在挪威、瑞典和美國進行。

關鍵結果
大致上,比起不予治療,使用anti-VEGF藥劑治療在6個月後提高2.5倍以上顯著視力增進的比例(至少視力表上三行)。而且相較於不予治療,使用anti-VEGF藥劑治療使得喪失顯著視力(至少視力表上的三行)的風險降低80%。分别在6個月或12個月時並無發現顯著的安全顧慮,但現有的研究無法提出有關這些治療的長期效果以及安全的結論。雖然如此,CRVO黄斑水腫anti-VEGE治療的可得性代表了在這種危害視力疾病的臨床管理選擇上的一項重要進步。

證據品質
納入回顧的這六項試驗皆屬高品質,並穩定地展現anti-VEGF注射帶來的視力益處。

譯註

翻譯者:吳心文(Hsin-wen Wu)
服務單位:自由譯者
翻譯領域:general medicine, ophthalmology, commerce, technology and tourism

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Résumé simplifié

Facteur de croissance endothélial antivasculaire pour le traitement de l'œdème maculaire secondaire à l'occlusion de la veine centrale de la rétine

Question de la revue
Nous avons examiné les preuves concernant l'effet du facteur de croissance endothélial antivasculaire (anti-VEGF, pour Anti-Vascular Endothelial Growth Factor) chez les personnes présentant un œdème maculaire secondaire à l'occlusion de la veine centrale de la rétine (OVCR).

Contexte
L'OVCR affecte environ une personne sur 1 000 à tout moment, et sa fréquence augmente avec l'âge, une pression artérielle élevée, le diabète, le glaucome et diverses maladies du sang. Elle provoque fréquemment une perte soudaine et indolore de la vue d'un œil, mais parfois la perte de la vision peut être minime. Si l'obstruction veineuse est responsable d’un apport insuffisant en oxygène dans le tissu rétinien sensible, l'OVCR est du sous-type « non-perfusé » ou « ischémique aigu ». Plus fréquemment, le débit sanguin et l'apport en oxygène sont rétablis à la suite de l’épisode d'obstruction veineuse et l'OVCR est du sous-type « perfusé » ou « non ischémique », et a un meilleur pronostic visuel. Diverses autres complications peuvent se développer au fil des heures, jours, semaines ou mois. Elles comprennent l'œdème maculaire, dans lequel du liquide s'accumule au sein de la rétine et provoque une baisse de la vision. Jusqu'à relativement récemment, il n'y avait pas de traitement fondé sur des preuves pour cette affection. Des agents anti-VEGF ont été utilisés avec succès pour traiter des patients atteints d'autres maladies vasculaires rétiniennes, dont plusieurs pathologies associées à un œdème maculaire.

Les caractéristiques de l’étude
Cette revue systématique a identifié six essais qui incluaient 937 participants présentant un œdème maculaire secondaire à une OVCR (au 29 octobre 2013). Les essais avaient comparé des injections simulées avec l'un des quatre types d'agents anti-VEGF : l'aflibercept (VEGF Trap-Eye, Eylea), le bevacizumab (Avastin), le pegaptanibest de sodium (Macugen) et le ranibizumab (Lucentis). Dans tous les essais, les participants ont été traités pendant au moins six mois. Trois essais étaient multicentriques et internationaux et trois ont été réalisés en Norvège, en Suède ou aux États-Unis.

Résultats principaux
Dans l'ensemble, le traitement aux agents anti-VEGF a augmenté les chances d'une amélioration significative de la vision (au moins 3 lignes sur le tableau optométrique) à six mois d’un facteur de plus de deux fois et demi, par rapport à l'absence de traitement. En outre, le risque de perte significative de la vision (au moins 3 lignes sur le tableau optométrique) a été réduit de 80 % chez les personnes recevant un traitement aux anti-VEGF par rapport à ceux ne recevant aucun traitement. Aucun problème significatif concernant l'innocuité du traitement n’a été identifié à six ou à 12 mois, mais les études disponibles ne permettent pas de conclure quant à leur efficacité et leur innocuité à long terme. Néanmoins, la disponibilité des anti-VEGF pour le traitement de l'œdème maculaire secondaire à l’OVCR représente une avancée importante dans les options de prise en charge clinique de cette pathologie qui menace la vision.

Qualité des preuves
Les six essais inclus dans cette revue étaient de qualité élevée et ont clairement démontré le bénéfice visuel des injections anti-VEGF.

Notes de traduction

Traduit par: French Cochrane Centre 12th October, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. *Assumed risk was taken from the mean baseline risk from studies in the meta-analysis and was equal to the total number of events in the control groups divided by the total number of participants in the control groups.

    Judgement of high quality: most evidence comes from RCTs at low risk of bias, with no unexplained heterogeneity and consistent results, low probability of publication bias, a large magnitude of effect or an apparent dose-response gradient.

    Judgement of moderate quality: most of the evidence comes from RCTs with some limitations. For example, limitations include an unclear risk of bias in one or several domains or few participants and wide confidence intervals suggesting imprecision of evidence.

Anti-VEGF compared with sham injection for CRVO macular oedema

Patient or population: participants with CRVO macular oedema of duration less than 9 months (mean < 3 months) and no prior treatment

Settings: presenting baseline visual acuity ranging from 6 (< 6/120) letters to 73 letters (˜6/12), both non-ischaemic and ischaemic eyes (% ischaemic at baseline of included trials ranged from 0% to 16%)

Intervention: intravitreal injection with ranibizumab, bevacizumab, aflibercept or pegaptanib sodium

Comparison: sham injection

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Sham injectionAnti-VEGF injection

BCVA gain of 15 letters or more

(follow-up: 6 months)

182 per 1000 493 per 1000
(382 to 635)
RR 2.71 (2.10 to 3.49)937
(6 studies)
⊕⊕⊕⊕
high
Includes all 4 anti-VEGF agents

BCVA loss of 15 letters or more

(follow-up: 6 months)

219 per 1000 44 per 1000
(26 to 74)
RR 0.20 (0.12 to 0.34)766
(5 studies)
⊕⊕⊕⊕
high
Includes all 4 anti-VEGF agents

Mean change in BCVA from baseline

(follow-up: 6 months)

The mean change across control groups ranged from loss of 4 letters to gain of 3 lettersThe mean gain across treatment groups ranged from +7.1 letters to + 18.0 letters MD 15.23 letters (11.57 to 18.89)937
(6 studies)
⊕⊕⊕⊝
moderate
Standard deviation or 95% CI not reported in 2 studies (aflibercept and pegaptanib sodium)

Mean change from baseline in central retinal thickness

(follow-up: 6 months)

The mean reduction from baseline in CRT across control groups ranged from
-102 to -169 microns (6 studies, 937 participants)
The mean reduction from baseline in CRT in the intervention groups was -267 microns greater (-211 to -323 microns) MD -267.4 µm (211.4 to 323.4)481
(3 studies)
⊕⊕⊕⊝
moderate
Standard deviation or 95% CI not reported in 3 studies (aflibercept and pegaptanib sodium)

Complication: iris or retinal neovascularisation

(follow-up: 6 months)

75 per 1000

14 per 1000

(7 to 27)

RR 0.18 (0.09 to 0.36)

936

(6 studies)

⊕⊕⊕⊕
high
Includes all 4 anti-VEGF agents
Ocular adverse events: endophthalmitis at 6 monthsNo cases in 347 participants treated with sham injection1 case in 590 participants treated with intravitreal injection of anti-VEGF-

937

(6 studies)

⊕⊕⊕⊕
high
Includes all 4 anti-VEGF agents
Mean change from baseline in quality of life score (NEI VFQ-25 instrument)The mean gain in quality of life score from baseline across control groups ranged from +0.8 to +3.5 pointsThe mean gain in quality of life score from baseline across control groups ranged from +6.2 to +7.5 points-

743

(3 studies)

⊕⊕⊕⊝
moderate
Standard deviation or 95% CI not reported in 2 studies (aflibercept)
> 4-point increase is considered a clinically relevant improvement
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Anti-VEGF: anti-vascular endothelial growth factor; BCVA: best-corrected visual acuity; CI: confidence interval;CRT: central retinal thickness; CRVO: central retinal vein occlusion; MD: mean difference; NEI-VFQ 25: National Eye Institute Visual Functioning Questionnaire 25 question instrument; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Central retinal vein occlusion (CRVO) is a common retinal vascular disorder in which macular oedema, including the cystoid type, may develop with a consequent reduction in visual acuity (Guex-Crosier 1999; Hayreh 1983). Cystoid macular oedema is characterised by the collection of fluid in intercellular spaces within the outer plexiform layer of the retina and results from the breakdown of the capillary endothelium blood-retinal barrier and leakage of fluid from the vasculature (Guex-Crosier 1999; Vinores 1999). This process is promoted by vascular endothelial growth factor (VEGF) (Vinores 1999), and the aqueous concentration of VEGF has been found to be significantly elevated in patients with CRVO macular oedema compared to controls (Funk 2009). Furthermore, there is a significant inverse association between duration since onset of CRVO macular oedema and the aqueous VEGF concentration (Funk 2009). Macular oedema can be visualised with slit-lamp biomicroscopy and its thickness and pattern of distribution can be investigated and quantified using optical coherence tomography (OCT) (Catier 2005; Hee 1995).

Central retinal vein occlusion is classified into two subtypes, 'non-ischaemic' (also called 'perfused') and 'ischaemic' (also called 'non-perfused'), although it is unlikely that the disease process is binary. No single test reliably differentiates the two subtypes with 100% sensitivity and specificity during the early acute phase of CRVO (Hayreh 1990a). Fundus fluorescein angiography (FFA) is frequently used to define ischaemic CRVO (Clarkson 1994; CVOS Group 1997). However, standard FFA may be reliable in fewer than 60% of cases (Hayreh 1990a), on account of masking from extensive retinal haemorrhages, which frequently persist in the first six months, poor images resulting from media opacities (vitreous haemorrhage or lens opacities, which are frequent in the affected age group), and inadequate assessment of the peripheral retina (Hayreh 1990a). However, ultra wide-field FFA is increasingly used in clinical practice to provide up to 200º imaging of the retina using a non-contact lens-based system (Prasad 2010).

Epidemiology

The burden of CRVO macular oedema in the population and the incidence of macular oedema following CRVO are unknown (McIntosh 2010), and there is still a paucity of data on risk factors for developing macular oedema following CRVO (Hayreh 1994).

The age- and sex-standardised prevalence of CRVO has been estimated at 0.80 per 1000 persons (95% confidence interval (CI) 0.61 to 0.99), giving an estimated global burden (for the 2008 population) of 2.5 million affected adults (Rogers 2010). In this pooled analysis, including 11 population-based studies on 49,869 participants in the United States, Asia, Europe and Australia, the prevalence of CRVO was found to increase with age, with a crude prevalence ranging from 0.27 per 1000 (95% CI 0 to 0.65) in those aged 40 to 49 years, to 5.44 per 1000 (95% CI 2.78 to 8.10) in those aged 80 years and over (Rogers 2010). Of these participants, 43.7% were male, 48.4% were white, 27.1% were Asian, 17.2% were Hispanic and 7.2% were black, and the prevalence did not differ by race or by gender. In another study of 1302 people diagnosed with CRVO in the USA, black people had a 58% increased risk of CRVO compared to white people (hazard ratio (HR) 1.58; 95% CI 1.25 to 1.99) and women had a 25% decreased risk compared to men (HR 0.75; 95% CI 0.66 to 0.85), after adjustment for known confounders (Stem 2013). Numerous other factors increase the hazard of CRVO, including a hypercoagulable state (HR 2.92; 95% CI 1.52 to 2.42), a diagnosis of stroke (HR 1.44; 95% CI 1.23 to 1.68), end-organ damage from hypertension (HR 1.92; 95% CI 1.52 to 2.42) and end-organ damage from diabetes mellitus (HR 1.53; 95% CI 1.28 to 1.84), relative to people without these conditions (Stem 2013). After developing a CRVO there is a 1% chance per year of a retinal vein occlusion in the fellow eye (CVOS Group 1997). CRVO is associated with an increase in mortality on account of its statistical association with comorbid diabetes or cardiovascular disease (Bertelsen 2013).

Natural history and prognosis

There is a paucity of population-level data on the prevalence and incidence of ischaemic versus non-ischaemic CRVO macular oedema, but the distinction is important because their presentation and natural history differ (Hayreh 2011). The ischaemic subtype of CRVO accounts for approximately 20% of acute presentations (Hayreh 1983; Hayreh 1994) and is associated with worse baseline acuity and a poor visual prognosis, even after the resolution of macular oedema (CVOS Group 1997; Hayreh 2011). In a natural history cohort study (n = 697 eyes with CRVO), baseline visual acuity was 6/30 (20/100) or better in 78% of patients with non-ischaemic CRVO and in only 1% with ischaemic CRVO, and visual field defects were mild in 91% and 8%, respectively (Hayreh 2011). Final visual acuity, after resolution of macular oedema, was 6/30 (20/100) or better in 83% with non-ischaemic CRVO and 12% with ischaemic CRVO (Hayreh 2011). In non-ischaemic CRVO, development of foveal pigmentary degeneration, epiretinal membrane or both has been identified as the main cause of poor final acuity (Hayreh 2011). Visual morbidity, including blindness, may also result from persistent macular oedema, ocular neovascularisation or secondary glaucoma (Campochiaro 2008). The risk of developing these complications also differs between the subtypes, with 16.6% of eyes with more than 5.5 disc areas of non-perfusion on FFA at baseline, versus 4.0% of eyes with less than 5.5 disc areas of non-perfusion, developing neovascular glaucoma at 36 months (Chan 2011). The non-ischaemic type may convert to the ischaemic type in an estimated one-third of cases within three years, and conversion is most frequent in the initial four months (CVOS Group 1997).

Presenting visual acuity is also a key predictor of visual outcome at three years, considering ischaemic and non-ischaemic subtypes together (CVOS Group 1997). Out of 714 eyes with CRVO, 65% of patients with presenting visual acuity better than or equal to 6/12 (20/40) were found to maintain this level of vision; those with presenting visual acuity 6/12 to 6/60 (20/40 to 20/200) have a variable prognosis with 19% improving to better than 6/15 (20/50), 44% showing no improvement and 37% worsening to less than 6/60 (20/200); whilst 80% of those with vision less than 6/60 (20/200) at presentation have no visual improvement. In another natural history study, amongst non-ischaemic eyes (n = 588) with an initial visual acuity of approximately 6/24 (20/70) or worse, 59% improved, 27% showed no change and 14% deteriorated on resolution of macular oedema, whereas amongst those with ischaemic CRVO (n = 109), 41% improved, 41% did not change and 18% deteriorated (Hayreh 2011). An intact external limiting membrane in the outer retina at baseline, which can be visualised with spectral-domain OCT, has also been found to predict better visual outcomes after treatment (Wolf-Schnurrbusch 2011).

History of the management of CRVO macular oedema

Historically, there was no evidence-based treatment for CRVO macular oedema. Various medical and surgical interventions had been tried, including argon laser panretinal photocoagulation (Hayreh 1990b), macular grid photocoagulation (CVOS Group 1995), tissue plasminogen activator (Everett 2006), oral pentoxifylline (Park 2007), hyperbaric oxygen therapy (Wright 2007) and pars plana vitrectomy with internal limiting membrane peeling (DeCroos 2009; Park 2010; Raszewska-Steglinska 2009), but these were not effective. Evidence for the effect of optic neurotomy has been mixed (Arevalo 2008; Hasselbach 2007; Opremcak 2006; Zambarakji 2005), with one recent randomised controlled trial (RCT) suggesting possible benefit (Aggermann 2012). A RCT comparing laser-induced chorioretinal venous anastomosis to sham treatment in adults with non-ischaemic CRVO macular oedema of three to 12 months' duration demonstrated moderate efficacy, especially in the 76% who developed a functioning anastomosis following laser treatment, and the visual acuity advantage compared to control was maintained at 18 months (McAllister 2010). However, 18% in the treatment arm developed neovascularisation at the treatment site and 9% required vitrectomy surgery for macular traction or non-resolving vitreous haemorrhage (McAllister 2010).

More significantly, two RCTs on corticosteroids for CRVO macular oedema demonstrated short-term effectiveness, but concerns have been raised about the incidence of complications (Gewaily 2009). Firstly, the 'Standard Care vs. Corticosteroid for Retinal Vein Occlusion' trial treated participants with non-ischaemic CRVO macular oedema with either 1 mg or 4 mg intravitreal triamcinolone (IVTA) injections repeated every four months, or observation alone (SCORE 2009). Both treatment doses were associated with a five times increase in the odds of achieving a 15 letter gain in visual acuity at 12 months (P = 0.001). However, 35% of patients treated with 4 mg, and 20% of patients treated with 1 mg, required intraocular pressure lowering treatment by 12 months compared to 8% in the observation group (SCORE 2009). Similarly, at 12 months there was new lens opacity, or progression of existing lens opacity, in 33% of the 4 mg group and 26% of the 1 mg group, compared to 18% of the observation group (SCORE 2009). Secondly, the Ozurdex GENEVA trial compared a single dexamethasone implant (Ozurdex, Allergan, Inc., Irvine, CA) at a dose of 0.7 mg or 0.35 mg, to a sham implant, in adults with non-ischaemic branch retinal vein occlusion (BRVO) or CRVO macular oedema of six weeks to nine months duration, and baseline acuity of 6/15 (68 letters, 20/50) to 6/60 (34 letters, 20/20) (Ozurdex GENEVA 2010). The percentage of eyes with CRVO macular oedema achieving a 15 letter improvement in visual acuity was significantly higher in both Ozurdex groups at day 30 and day 60 than in the sham group (P < 0.001), with the maximal effect at day 60. However, by days 90 and 180 there was no significant difference between groups (Ozurdex GENEVA 2010). The incidence of ocular adverse events was not reported for CRVO macular oedema separately, but did not differ significantly between the 0.35 mg and 0.7 mg dose groups. In both groups there was a higher incidence of ocular hypertension at day 60 (P < 0.002), and by day 180 approximately 24% of patients with dexamethasone implants required intraocular pressure (IOP)-lowering medication, and five patients required a surgical or laser procedure to reduce IOP (Ozurdex GENEVA 2010). There was also a significant increase in anterior chamber activity in the 0.35 mg (P = 0.007) and 0.7 mg (P = 0.03) treatment groups compared to sham (P = 0.03), but no significant increase in the risk of incident cataract at 180 days (Ozurdex GENEVA 2010). In a subsequent six-month, open-label extension, all patients were eligible for a single 0.7 mg Ozurdex implant, regardless of initial treatment assignment, if BCVA was < 84 letters (6/6, 20/20) or CRT was > 250 μm (Ozurdex GENEVA 2011). Amongst patients who received two treatments with 0.7 mg implants for CRVO, six months apart (n = 114), mean BCVA improvements were similar after the first and second injections, with a peak improvement of approximately 8 to 10 letters at 60 days. Patients randomised to receive sham injection in the first six months who subsequently received 0.7 mg dexamethasone (n = 117) had an average gain of approximately 6 to 7 letters at 60 days. There was no apparent sustained visual acuity gain at 12 months in either group. Summed safety data for CRVO and BRVO patients who received a 0.7 mg implant at day 180 (n = 997) were reported. Over 12 months, cataract progression occurred in 29.8% of phakic eyes that received two 0.7 mg implants, versus 5.7% of sham-treated phakic eyes. In the former treatment group (n = 341), a > 10 mmHg IOP rise was observed in 12.6% after the first treatment and 15.4% after the second treatment, and in the majority this was transient or controlled with topical medication. However, a laser or surgical procedure to reduce IOP was required for 14 treated eyes compared to no eyes in the untreated group (Ozurdex GENEVA 2011). There are currently no RCTs exploring the efficacy or safety of more frequent treatment with dexamethasone implants, or with follow-up beyond 12 months. Despite this, the UK National Institute of Clinical Excellence (NICE) have recently approved Ozurdex implants as a treatment option for CRVO macular oedema, with a suggested repeat interval of six months, to a total of six implants per patient.

Description of the intervention

Monoclonal antibodies against VEGF were first developed as an intravenous treatment for metastatic colorectal cancer (Homsi 2007; Los 2007). The first drug licensed for this purpose was bevacizumab (Avastin®), which received Food and Drug Administration (FDA) approval in 2004 (Genentech/Roche 2009b). Bevacizumab is a 149kDa recombinant humanised monoclonal whole immunoglobulin G1 antibody that binds to VEGF and blocks the binding of VEGF to receptors (Flt-1 and KDR) on endothelial cells (Genentech 2009). It is not licensed for intraocular use, although there has been widespread off-licence intravitreal use in the USA and Europe. Pegaptanib sodium (Macugen®) is a 50kDa aptamer; a pegylated modified oligonucleotide, which adopts a three-dimensional configuration in vivo that allows it to bind to extracellular VEGF-165 and antagonise its biological effects (Eyetech 2008; Gragoudas 2004). It was approved by the FDA in 2004, and the European Medicines Agency in 2006, for use in neovascular age-related macular degeneration (wet AMD) (Eyetech 2008). Ranibizumab (Lucentis®) is a 48kDa recombinant humanised monoclonal immunoglobulin G1 antibody fragment (kappa isotype) that binds to the receptors of all biologically active isoforms of VEGF-A and blocks the binding of VEGF-A to VEGFR1 and VEGFR2 receptors on endothelial cells (Genentech 2008). Ranibizumab has a binding affinity for VEGF approximately 100 times greater than bevacizumab (Ferrara 2006). It was approved for the treatment of wet AMD by the FDA in 2006 and by NICE in 2008 (Genentech/Roche 2009a); for the treatment of retinal vein occlusion by the FDA in June 2010; and for the treatment of diabetic macular oedema by the FDA in August 2012, and by NICE in October 2012. Aflibercept (Eylea®, vascular endothelial growth factor Trap-Eye; Regeneron Pharmaceuticals, Tarrytown, NY) is a 115kDa decoy receptor fusion protein comprising the second domain of human VEGF receptor 1 and the third domain of VEGF receptor 2 fused to the constant Fc domain of human immunoglobulin G1 (Economides 2003). It has a greater binding affinity for VEGF than bevacizumab and ranibizumab (Stewart 2012), and mathematical modelling indicates that it may require less frequent dosing than shorter-acting anti-VEGF agents (Stewart 2008). It was approved by the FDA for the treatment of wet AMD in November 2011 and for CRVO macular oedema in September 2012.

The pharmacokinetics of 1.25 mg bevacizumab and 0.5 mg ranibizumab intravitreal injections have been investigated in an experimental rabbit model (Bakri 2007a; Bakri 2007b). The vitreous concentration of both drugs declined in a monoexponential function, with a half-life of 4.32 days for bevacizumab, and 2.88 days for ranibizumab. At 30 days both drugs persisted in the vitreous, at a concentration of > 0.1 μg/ml for ranibizumab versus > 10 μg/ml for bevacizumab. No ranibizumab was detected in the fellow eye or serum, whilst a peak serum concentration of bevacizumab of 3.3 μg/ml was reached at eight days, with a half-life of 6.86 days, and very low concentrations (ng/ml) were detected in the fellow eye throughout the 29-day study. The aqueous half-life of a single 1.5 mg intravitreal injection of bevacizumab has also been studied in humans with various causes of macular oedema and has been found to be approximately 9.8 days (Krohne 2008). Patients with CRVO demonstrate moderate variability in the aqueous concentration of ranibizumab measured one month after a first intravitreal injection of 0.3 mg or 0.5 mg, but measurements one month following subsequent injections are highly correlated for a given patient (Campochiaro 2009).

The anti-VEGF agents have demonstrated promise in treating CRVO macular oedema in many retrospective and prospective case series, and in a number of RCTs in recent years.

How the intervention might work

Vascular endothelial growth factor is a cytokine produced by cells in response to hypoxia that promotes vascular leakage by binding to receptors on endothelial cells. It has been observed that transgenic mice over-expressing VEGF in the photoreceptors exhibited blood-retina barrier failure (Vinores 1999). Another study observed that injecting VEGF intravitreally induces a time and dose-dependent breakdown of the blood-aqueous and blood-retinal barriers in a rabbit model, with maximal vascular leakage occurring 48 hours after injection (Edelman 2005). Animal and human studies have identified that the expression of VEGF mRNA is significantly upregulated in regions of ischaemic retina of various causes, including CRVO (Pe'er 1995; Pe'er 1998; Shima 1996). Serum amyloid A, a major acute phase protein, and the cytokine IL-6, which is derived from activated T lymphocytes and induces expression of VEGF and vascular permeability, have been found to be significantly elevated in the aqueous humour of eyes with CRVO macular oedema compared to control eyes (Feng 2013). In a rat model of CRVO, injection of bevacizumab fully prevented the upregulation of VEGF-A after one day and the upregulation of pigment-epithelium-derived factor after three days, which is known to influence the development of vascular oedema (Drechsler 2012). Bevacizumab also decreased the upregulation of the proinflammatory cytokine interleukin (IL)-1B which otherwise developed one day after a CRVO (Drechsler 2012). Furthermore, the concentration of VEGF in human aqueous demonstrates close temporal correlation with the course of neovascularisation and permeability in CRVO, and injecting anti-VEGF antibodies inhibits VEGF-driven neovascularisation both in vitro and in vivo (Adamis 1996; Aiello 1995; Boyd 2002). Significant correlations have been identified between the aqueous VEGF concentration in patients with CRVO macular oedema and different components of the full-field electroretinography (ERG) including the b/a ratio of the single flash ERG, implicit times of the cone a-wave, cone b-wave and 30 Hz flicker ERG leading to the suggestion that full-field ERGs could be used to detect patients at high risk of developing neovascularisation (Yasuda 2011).

Whilst VEGF-A has been identified as an important anti-angiogenic target in retinal diseases, it has more recently also been recognised to play an important role in neuroprotection in the retina (Nishijima 2007). In a model of ischaemia-reperfusion injury VEGF-A exposure resulted in a dose-dependent reduction in retinal neuron apoptosis. Furthermore, ischaemic preconditioning, which increases VEGF-A levels, was found to reduce the number of apoptotic retinal cells after injury, suggesting its role in the adaptive response to retinal ischaemia, and this protective effect was reversed with VEGF-A inhibition (Nishijima 2007). Chronic VEGF-A inhibition in adult animals was also found to result in a significant loss of retinal ganglion cells, and the requirement for VEGF-A in the maintenance of normal vasculature has now been recognised (Nishijima 2007). Interestingly, pegaptanib sodium, which does not bind to VEGF-120, did not reduce retinal ganglion cell viability in this animal model (Nishijima 2007). In a small RCT of 19 participants with neovascular glaucoma secondary to ischaemic CRVO and poor baseline visual acuity, six months after randomisation to a single bevacizumab injection with panretinal photocoagulation (PRP) (n = 10) versus PRP alone (n = 9), neovascularisation had resolved in the bevacizumab group, but the a- and b-wave amplitudes of the combined rod-cone response and the b-wave amplitudes of the 30 Hz flicker response were markedly reduced, suggesting a potential adverse effect of anti-VEGF treatment on photoreceptor function (Wittstrom 2012). These basic science and clinical studies illustrate that it should not be assumed that different anti-VEGF agents will have the same biological and clinical effects, or that all effects of VEGF blockade are beneficial.

Why it is important to do this review

The visual prognosis in CRVO macular oedema is poor in a substantial proportion of patients, especially those with the ischaemic subtype, and until recently there was no treatment of proven benefit (Everett 2006; Hayreh 2003; Prisco 2002). Ranibizumab and aflibercept have now been approved in the US for the treatment of CRVO macular oedema, and clinicians internationally are increasingly using various anti-VEGF agents both on- and off-label for the treatment of CRVO macular oedema, based on emerging clinical experience and short-term trial evidence. This systematic review was therefore designed to investigate the effectiveness and safety of anti-VEGF agents for the treatment of CRVO macular oedema.

Objectives

To investigate the effectiveness and safety of anti-VEGF therapies for the treatment of macular oedema secondary to CRVO.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs with a minimum of six months follow-up.

Types of participants

We included trials involving participants of all ages who had unilateral or bilateral macular oedema secondary to CRVO.

Types of interventions

We included trials in which anti-VEGF treatment was compared to placebo or no treatment, and trials that investigated dosage and duration of treatment. We excluded studies in which anti-VEGF agents were only compared to, or used in combination with, other agents.

Types of outcome measures

Primary outcomes

The primary outcome for this review was the proportion of participants with an improvement from baseline in best-corrected visual acuity (BCVA) of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart at four metres, after six months of follow-up, and any additional follow-up times. A gain of 15 letters represents a doubling of the visual angle, and whilst this binary cut-off considerably exceeds the amount of change required to have a high degree of certainty that the observed change is real, even in the presence of poor vision, it has been the standard primary outcome measure for evaluating the efficacy of treatments for retinal diseases for more than a decade (Beck 2007).

Secondary outcomes

We included the following secondary outcomes, at six months and any additional follow-up times:

  1. The proportion of participants with a loss of 15 letters or more (ETDRS) compared to baseline.

  2. Mean visual acuity change.

  3. Objective assessment of macular oedema regression measured by mean change in central retinal thickness (CRT) on ocular coherence tomography (OCT).

  4. The number and type of complications relating to CRVO.

  5. The number of anti-VEGF or sham injections administered.

  6. The number and type of additional interventions administered.

Adverse outcomes

We documented any ocular or systemic adverse outcomes reported in the trials, which were potentially related to the intervention or to intravitreal injection. We specifically aimed to report the proportion of participants experiencing potentially serious systemic or ocular adverse events including, but not limited to, retinal tears, retinal detachment, ocular inflammation, endophthalmitis, thromboembolic events, ocular hypertension, glaucoma (excluding neovascular) and cataract.

Economic data

We reported any cost-benefit data included in the primary studies.

Quality of life data

We reported any data relating to impact on health- or vision-related quality of life or daily functioning included in the primary studies.

Search methods for identification of studies

Electronic searches

We searched CENTRAL (which contains the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 10), Ovid MEDLINE (January 1950 to October 2013), EMBASE (January 1980 to October 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2013), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to October 2013), OpenGrey, OpenSIGLE (January 1950 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and Web of Science Conference Proceedings Citation Index-Science (CPCI-S). There were no language or date restrictions in the electronic search for trials. The electronic databases and clinical trials registers were last searched on 29th October 2013.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), CINAHL (Appendix 5), OpenSIGLE, mRCT (Appendix 6) and ClinicalTrials.gov (Appendix 8).

Searching other resources

We manually searched references of included studies and used the Science Citation Index to identify additional studies citing trials.

Data collection and analysis

Selection of studies

Two review authors independently screened the titles and abstracts resulting from the electronic and manual searches. We classified abstracts as relevant, potentially relevant or not relevant for this review. We obtained full-text copies of articles for those abstracts that were designated relevant or potentially relevant. Two review authors independently assessed each article and determined whether to definitely include, definitely exclude or record each trial as unclear. We documented agreement between review authors and resolved discrepancies by consensus. For any studies classified as unclear we contacted the authors in an attempt to include or exclude the study from the review. We reported any studies that were definitely excluded.

Data extraction and management

We extracted the following participant and trial characteristics and reported them in a table format.

  1. Methodology (group size, randomisation and masking).

  2. Participant characteristics (gender, age, type of CRVO and diagnostic criteria used, baseline visual acuity, OCT-determined thickness of macular oedema).

  3. Intervention (agent, dose, timing of first dose in relation to diagnosis, delivery route, frequency and treatment length).

  4. Primary and secondary outcomes (proportion with 15 letter gain in visual acuity at six months, proportion with 15 letter loss in visual acuity at six months, mean difference in visual acuity at six months compared to baseline, central retinal thickness, adverse events and outcomes at longer follow-up intervals).

  5. Additional data (economic, quality of life and visual functioning data).

  6. Treatment compliance and losses to follow-up.

Two review authors independently extracted the data using a form developed by the Cochrane Eyes and Vision Group. We contacted trial authors for more information when data were missing or difficult to interpret. We resolved any discrepancies between the two review authors by discussion and consensus. One review author entered the data into Review Manager 5 (RevMan 2011) and the second author checked the entered data for any errors or inconsistencies.

Assessment of risk of bias in included studies

Two review authors assessed the methodological quality of the selected trials according to the methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We considered the following domains:

  1. random sequence generation (selection bias);

  2. allocation concealment (selection bias);

  3. masking of participants and personnel (performance bias);

  4. masking of outcome assessment (detection bias);

  5. incomplete outcome data (attrition bias);

  6. selective reporting (reporting bias); and

  7. other sources of bias.

We documented relevant information on each domain in a 'Risk of bias' table for each study. Each assessor assigned a judgement of 'high risk', 'low risk' or 'unclear risk' relating to whether the study was adequate with regard to the risk of bias for each domain's entry. We contacted the authors of trials for additional information on domains judged to be 'unclear'. When authors did not respond within four weeks, we assigned a judgement on the domain based on the available information. We documented agreement between review authors and resolved discrepancies by consensus.

Measures of treatment effect

We reported dichotomous variables as risk ratios (RRs) with 95% confidence intervals (CIs), unless the outcome of interest occurred at very low frequency (< 1%), in which case we used the Peto odds ratio. We reported continuous variables as mean differences between treatment groups with 95% CIs. We did not check for skewness of data as both continuous outcomes of interest (mean change in visual acuity and mean change in central retinal thickness) were measured as mean changes from baseline.

Unit of analysis issues

The unit of analysis was the eye for data on visual acuity and macular oedema measurements. The unit of analysis was the individual for ocular adverse events, demographic characteristics, economic data and quality of life data. In all trials, only one eye from each patient was enrolled, and we reviewed the method for selecting the study eye to assess for potential selection bias.

Dealing with missing data

We attempted to contact authors for missing data. When authors did not respond within four weeks, we imputed data where possible using available information such as P values or confidence intervals (CIs).

Assessment of heterogeneity

We assessed clinical diversity (variability in the participants, interventions and outcomes studied), methodological diversity (variability in study design and risk of bias) and statistical heterogeneity (variability in the intervention effects being evaluated) by examining study characteristics and forest plots of the results. We used the I2 statistic to quantify inconsistency across studies and the Chi2 test to assess statistical heterogeneity for meta-analysis. We interpreted an I2 value of 50% or more to be substantial, as this suggests that more than 50% of the variability in effect estimates was due to heterogeneity rather than sampling error (chance). We considered P < 0.10 to represent significant statistical heterogeneity for the Chi2 test.

Assessment of reporting biases

We accessed the primary and secondary outcomes registered on clinicaltrials.gov for each trial to look for possible selective outcome reporting. We did not examine funnel plots for publication bias as fewer than 10 studies were included in the review. Where summary estimates of treatment effect across multiple studies (i.e. more than 10) are included in the future, we will examine funnel plots from each meta-analysis to assess publication bias.

Data synthesis

Where data from three or more trials were available, we considered performing meta-analysis using a random-effects model. We considered a fixed-effect model if synthesising data from fewer than three trials. If significant heterogeneity was found, we reported results in tabular form, rather than performing meta-analysis. The dichotomous outcome variables were the proportion of patients with at least a 15 letter gain or loss in visual acuity. Continuous outcome variables included the mean changes from baseline in visual acuity and central retinal thickness.

Additional dichotomous outcomes were the proportion of patients experiencing each ocular or systemic adverse event, and the proportion requiring additional treatments (e.g. panretinal photocoagulation), at six months and other follow-up times. We reported the total number of events at six months, in the combined treatment groups and combined control groups. Since the sample size was tailored to the primary outcome, these secondary outcomes may well lack power to detect important differences. We used the Peto odds ratio method to combine data on a given outcome across multiple studies at event rates below 1%, providing there was no substantial imbalance between the treatment and control group sizes.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses and investigate possible sources of heterogeneity based on type of anti-VEGF agent, clinical subtype (ischaemic an non-ischaemic), duration since onset and baseline BCVA. Data were not sufficient to conduct subgroup analyses for this review (only six studies were included and outcome-specific data were not always available for each study); however, we documented when individual trials noted subgroup differences. If sufficient and comparable data are reported in future updates to this review, we will conduct subgroup analyses based on the criteria listed above.

Sensitivity analysis

We considered performing sensitivity analyses to examine how strongly related our review results were to decisions and assumptions that were made during the review. If there were a sufficient number of studies to obtain an informative result, we planned to investigate the impact of studies with lower methodological quality (e.g. domains judged to be inadequate with regard to risk of bias, marked 'high risk' or 'unclear' in the 'Risk of bias' table). We also planned to perform sensitivity analyses if there were any unpublished data or if studies differed with regard to their funding source (e.g. industry-funded studies).

Summary of findings

We produced a 'Summary of findings' tables of the primary and secondary outcomes included in our review for the comparison of anti-VEGF therapy versus sham injection. We judged the quality of evidence by consensus and assessed each outcome as follows.

  • High quality: most evidence comes from RCTs at low risk of bias, consistent results with no unexplained heterogeneity, low probability of publication bias, and a large magnitude of effect or an apparent dose-response gradient.

  • Moderate quality: most evidence comes from RCTs with some limitations. For example, limitations may include an unclear risk of bias in one or several domains, few participants and wide confidence intervals suggesting imprecision of evidence.

  • Low quality: most evidence comes from studies with limitations. For example, limitations may include an unclear or high risk of bias in one or several domains, few studies reporting this outcome, few participants and wide confidence intervals suggesting imprecision of evidence.

  • Very low quality: most evidence comes from studies with major limitations. For example, limitations may include high risk of bias in one or several domains, few studies reporting this outcome and great uncertainty about the estimate.

Results

Description of studies

Results of the search

The electronic search on 10 August 2010 yielded a total of 123 non-duplicate titles with accompanying abstracts. We screened full-text articles corresponding to 34 possibly relevant titles and two definitely relevant titles (CRUISE 2010; Wroblewski 2009), which identified two RCTs comparing an anti-VEGF treatment to sham injection. There were no RCTs comparing anti-VEGF agents to observation only. We excluded one trial because it compared treatment with bevacizumab to combined treatment with bevacizumab and timolol-dorzolamide, with no group that did not receive anti-VEGF treatment (Byeon 2009). Two studies are awaiting classification as they are potentially relevant to this review, yet no results have been made available (EBOVER; Habibabadi 2008).

An updated electronic search on 29 October 2013 yielded 217 additional non-duplicate titles with accompanying abstracts. We screened full-text articles corresponding to 22 possibly relevant titles, of which 18 were pertinent to this review. From these 18 reports we identified four new RCTs comparing an anti-VEGF treatment to sham injection (Copernicus 2012; Epstein 2012; GALILEO 2013; ROCC 2010). We excluded four reports from three randomised studies which did not include a control or observation group (Campochiaro 2008; Ding 2011; Wang 2011) (See Figure 1). There were no RCTs comparing anti-VEGF agents to observation.

Figure 1.

Results from searching for studies for inclusion in the review (as of 29 October 2013).

Included studies

We found six trials that met our inclusion criteria (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; ROCC 2010; Wroblewski 2009). These investigated four anti-VEGF agents in comparison to sham injection: VEGF Trap Eye (Aflibercept), bevacizumab (Avastin), ranibizumab (Lucentis) and Pegaptanib sodium (Macugen). The study design, treatments, doses and duration of treatment are summarised in the following table. The table Characteristics of included studies details a full summary of each of these trials.

Table: Summary of included studies
StudyStudy designTreatment group 1Treatment group 2Control groupNumber of injectionsTreatment period
Copernicus 2012Phase III dmRCTVEGF Trap-Eye 2.0 mg (n = 114)-Sham injection (n = 74)66 months
CRUISE 2010Phase III dmRCTRanibizumab 0.3 mg (n = 132)Ranibizumab 0.5 mg (n = 130)Sham injection (n = 130)66 months
Epstein 2012Phase III dmRCTBevacizumab 1.25 mg (n = 30)-Sham injection (n = 30)424 weeks
GALILEO 2013Phase III dmRCTVEGF Trap-Eye 2.0 mg (n = 106)-Sham injection (n = 71)6 + PRN52 weeks
ROCC 2010Phase III dmRCTRanibizumab 0.5 mg (n = 16)-Sham injection (n = 16)3 + 3 (PRN)6 months
Wroblewski 2009Phase II dmRCTPegaptanib sodium 0.3 mg (n = 33)Pegaptanib sodium 1.0 mg (n = 33)Sham injection (n = 32)530 weeks

PRN = pro re nata (as the circumstances require)
dmRCT = double-masked randomised controlled trial

Extension studies

In an open-label, six-month extension of the bevacizumab trial (Epstein 2012), all participants (n = 60, 100%) in both the sham control and bevacizumab 1.25 mg groups were treated with bevacizumab 1.25 mg every six weeks, to 12 months.

In an open-label, six-month observation period (i.e. months 7 to 12) participants in the CRUISE 2010 trial were reviewed monthly and offered ranibizumab if they met retreatment criteria including central retinal thickness > 250 or BCVA < 6/12. Those in the original treatment groups received either 0.3 mg or 0.5 mg ranibizumab, according to their original randomisation, whilst participants in the original sham control group received 0.5 mg ranibizumab. Of 392 participants randomised at baseline, 363 (92.6%) completed the study to six months, and 349 (89.0%) completed the open-label extension study to 12 months. A further 12-month, open-label extension (i.e. months 13 onwards), the HORIZON trial, explored safety and efficacy in 304 (77.5%) of those originally recruited to the CRUISE trial. Participants were seen at least every three months and offered 0.5 mg ranibizumab if they met retreatment criteria. During the study, ranibizumab was approved by the FDA for the treatment of retinal vein occlusion and according to the protocol, all participants were discontinued from the study by 30 days after the approval date. The duration of follow-up in the HORIZON trial was therefore variable, with a mean of 14 months (standard deviation (SD) 4.7, range 1 to 24 months), and missing outcome data at 24 months were considerable, with the consequent potential for significant attrition bias in the available results.

In an open-label, six-month extension of the Copernicus 2012 trial (i.e. months 7 to 12), all participants were offered 2.0 mg aflibercept (VEGF Trap-Eye) monthly as needed, according to retreatment criteria. One hundred and sixty-four (86.8%) of the participants randomised at baseline completed 52 weeks.

Baseline characteristics

The six trials included patients with broadly similar baseline characteristics, which are summarised in the table below. There was some difference in the proportion of recruited patients who were ischaemic at baseline, with negligible ischaemia at baseline in patients recruited to CRUISE 2010 and Wroblewski 2009. The mean age and percentage of male participants was similar across the six trials. The mean time between occlusive event and study entry was also broadly similar across the groups. The baseline mean BCVA measured in ETDRS letters was broadly similar between studies, ranging from a mean of 52 letters in GALILEO 2013 (Snellen approximately 6/30 or 20/100) to 43 letters (Snellen approximately 6/42 or 20/138) in the smaller of the ranibizumab trials (ROCC 2010). The percentage of patients with a poor presenting BCVA of less than 35 letters (Snellen approximately 6/60 or 20/200) ranged from 17% (GALILEO 2013) to 32% (Epstein 2012). The mean baseline central retinal thickness (CRT) was broadly similar across the six trials, ranging between 619 μm (Wroblewski 2009) and 721 μm (Epstein 2012).

Table: Summary of baseline characteristics
StudyDuration of CRVO-MO% IschaemicMean age (years)% MaleDurationBaseline mean VA (letters)% BCVA less than 35 letters (6/60)Mean CRT (μm)
Copernicus 2012< 9 months

15.5% (29/187) ischaemic

16.6% (31/187) undetermined

6657Mean 2.40 months (SD 2.80)50.0 (SD 14.1)24.6%665.8 (SD 239.8)
CRUISE 2010< 3 months0.5% (2/392)6857

Mean 3.3 months

Median 2 months (range 0 to 27)

48.1 (14.6)30%680 (242) to 689 (253)
Epstein 2012< 6 months11.7% (7/60)*7160Mean 8.8 weeks (SD 5.7)44.1 (SD 15.5) letters32%721 (SD 269)
GALILEO 2013< 9 months

8.2% (14/171) ischaemic

8.2% (14/171) undetermined

6256Mean 82 days (SD 85)52.2 (SD 15.7)17%665.5 (SD 231.0)
ROCC 2010< 6 months15.6% (5/32)7255Mean 78 days (range 10 to 163)43 (SD 22)NR625 (SD 159)
Wroblewski 2009< 6 months0% (0/98)6353Mean 80 days48.522%619 to 675

* Personal communication
SD = standard deviation
VA = visual acuity, measured in ETDRS letters
CRT = central retinal thickness

Excluded studies

We excluded four randomised studies including an anti-VEGF intervention group because they did not include a sham control or observation arm. One non-masked trial randomised 20 patients with CRVO macular oedema to receive 0.3 mg (n = 10) or 0.5 mg (n = 10) ranibizumab given monthly for three months (Campochiaro 2008). In a subsequent extension trial to 24 months, patients were reviewed every two months and treated with the same dose of ranibizumab as their initial treatment assignment, if retreatment criteria were met (Campochiaro 2010). A second trial compared treatment with bevacizumab to combined treatment with bevacizumab and timolol-dorzolamide, without comparison to a sham injection or observation group. This trial combined patients with both BRVO and CRVO, and the small sample size precluded analysis of CRVO macular oedema specifically (Byeon 2009). A third open-label study randomised patients with CRVO macular oedema to receive intravitreal injection of either 4 mg preservative-free triamcinolone acetonide (n = 16) or 1.25 mg bevacizumab (n = 16) at baseline, with subsequent 'as required' injections from three months (Ding 2011). A fourth open-label study randomised patients with CRVO macular oedema to a single injection of either 1.25 mg bevacizumab or to combination therapy with 1.25 mg bevacizumab plus 2.0 mg triamcinolone acetonide, with follow-up over 12 weeks (Wang 2011). (See the Characteristics of excluded studies table for further details).

We did not conduct a separate electronic search for study designs less rigorous than the randomised controlled trial. We identified numerous interventional case series and case reports and summarised them in tables in the first publication of this review (Braithwaite 2010). These studies did not meet the inclusion criteria for the systematic review, and these tables were not updated or included in the current review.

Risk of bias in included studies

The six included studies had a low risk of bias in a majority of domains (see Figure 2 and Figure 3). In all studies one eye was enrolled in the study per participant. In CRUISE 2010 the authors specified that where both eyes met the inclusion criteria, the eye with the worse BCVA at screening was selected. In Copernicus 2012 and GALILEO 2013 the patient was excluded if both eyes had a retinal vein occlusion at baseline. In ROCC 2010 patients were only recruited to the study if they had unilateral CRVO macular oedema. Whilst one eye per patient was included in the remaining two trials, Wroblewski 2009 and Epstein 2012, no statement regarding the method of selection of the study eye was given to cover the uncommon event that both eyes met the eligibility criteria.

Figure 2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We judged there to be a low risk of bias in random sequence generation in three studies (Copernicus 2012 CRUISE 2010; Wroblewski 2009). These studies all reported a centralised randomisation method. We considered the risk of bias 'unclear' in the other three studies (Epstein 2012; GALILEO 2013; ROCC 2010). We gave a judgement of unclear risk of bias where the study investigators did not explicitly report the process of random sequence generation, and either did not respond to a request for further information, or did not provide sufficient additional explanation via personal communication.

We judged there to be a low risk of bias in allocation concealment in three studies (Epstein 2012; ROCC 2010; Wroblewski 2009). We considered the risk of bias to be low in studies that explicitly reported the method of protection of the allocation sequence between the time of randomisation and of treatment assignment to injection or sham injection. For example, if the medication kits were identical in appearance and identified by randomisation number only, and if the allocation was conveyed to the injecting ophthalmologist by the study co-ordinator, or another third party, in a way that did not inform the injecting ophthalmologist of the allocation until the time of the injection procedure, then we considered the risk of bias low. When sealed, opaque envelopes drawn by staff not involved in patient treatment or follow-up were used to conceal allocation until the first day of injection, we judged the risk of bias to be low, even if the envelopes were not sequentially numbered based on the randomisation code, although we note that methods utilising envelopes may be subject to manipulation. We felt the risk of bias in this domain was unclear in the remaining three studies (Copernicus 2012; CRUISE 2010; GALILEO 2013), in which the method of concealment of the allocations was not described explicitly.

Blinding

We considered all six studies to have a low risk of bias in this domain. In these studies, the participants, examining ophthalmologists and other clinical examiners were masked to the treatment allocation. In addition, in the aflibercept trial (Copernicus 2012), pegaptanib sodium trial (Wroblewski 2009) and the CRUISE 2010 trial, grading of OCT and FFA images was done by an independent grading centre. The ophthalmologists performing the intravitreal injections, who performed either a sham injection or a drug injection, were not involved in reviewing the participants at their follow-up assessments. In all studies an attempt was made to mask patients randomised to the control group by treating them similarly to those in the treatment groups, except that the hub of a syringe was placed against the injection site and the plunger depressed to mimic an injection, without globe penetration (i.e. sham injection). It is unclear whether sham injection effectively masks patients to their treatment allocation, given that patients sometimes report 'feeling' the needle despite topical anaesthesia, and that the injection can cause a subconjunctival haemorrhage which would not necessarily be expected with a sham injection. However, a majority of the outcomes in these studies are relatively objective measures, so that even if a patient suspected their assignment this would be unlikely to bias the outcome data.

Incomplete outcome data

We considered there to be a low risk of attrition bias in one study reporting no loss to follow-up (Epstein 2012). We also would have considered the risk of bias to be low if the losses to follow-up were small and balanced between the groups, with analysis by intention-to-treat, or if imputation methods that provide valid type 1 error rates under explicitly stated assumptions were used to take moderate missing data into account.

Where we considered the losses to be slightly more considerable as a proportion of the total sample (an issue with small studies), or where we felt that losses to follow-up were unbalanced between groups, but where the investigators reported reasons for losses, we considered the risk of bias 'unclear' (Copernicus 2012; CRUISE 2010; GALILEO 2013; ROCC 2010; Wroblewski 2009). Unbalanced loss of patients with potentially more severe and visually significant disease from the sham group in these trials might have introduced bias, reducing any apparent benefit associated with anti-VEGF therapy. We also considered the risk of bias 'unclear' where investigators did not account for missing data, performing only a 'per protocol' analysis (ROCC 2010), restricted to those participants who fulfilled the criteria for eligibility, received all prescribed interventions and attended all outcome assessments. Non-random loss of participants is better handled through analysis by the intention-to-treat approach, in which data are analysed according to randomisation group, regardless of whether the participants received or adhered to their allocated intervention, as this provides fair comparisons among the groups.

Where investigators accounted for losses to follow-up or unbalanced missing data using the last-observation-carried-forward (LOCF) method, without performing sensitivity analyses to assess the impact of assumptions about the method of accounting for missing data on trial outcomes, we also considered the risk 'unclear' (Copernicus 2012; CRUISE 2010; GALILEO 2013). The LOCF method limits the number of patients eliminated from the analysis. However, it assumes that patients do not change from their last follow-up (i.e. they could improve or get worse and in either case this would not be captured). Treating missing data as if there has been no change from a previous visit generally yields a conservative estimate of treatment effect. If patients who are given treatment drop out because they get worse or experience harmful side effects then the LOCF methods may over-report efficacy or under-report harmful safety problems.

Selective reporting

We accessed ClinicalTrials.gov to review the prespecified primary and secondary outcomes for the trials, where these were available. We considered there to be a low risk of selective reporting bias in all six studies (Copernicus 2012; CRUISE 2010; GALILEO 2013; ROCC 2010; Wroblewski 2009), in which the main prespecified primary and secondary outcomes were reported. In Epstein 2012, an additional secondary outcome of mean change in BCVA was added in the published report. In Copernicus 2012, two additional secondary outcomes were reported: the proportion of eyes progressing to ocular neovascularisation and the change in total score on the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) from baseline. In ROCC 2010, the investigators prespecified that they would include mean change from baseline in the NEI VFQ-25 near activities subscale as a secondary outcome, but did not include this in their published report. However, as the subscale on this instrument is not a validated outcome measure, we felt that failure to report these results had no impact on the key outcome measures of interest. The ClinicalTrials.gov entry for Wroblewski 2009 did not include prespecified outcome measures. However, all outcomes that would be expected were included, and both positive and negative results were reported without apparent bias, so although we were not able to exclude the possibility of selective reporting, we considered the study 'low risk' in this domain. Four studies did not report measures of variance for continuous variables including mean change in best-corrected visual acuity from baseline and mean change in central retinal thickness from baseline (Copernicus 2012; Epstein 2012; GALILEO 2013; Wroblewski 2009); unpublished data were provided for the bevacizumab trial (personal communication).

Other potential sources of bias

We considered the risk of bias to be low in three studies where no other threats to validity were identified, or where we considered potential sources of bias to be very small (Copernicus 2012; Epstein 2012; Wroblewski 2009). We considered the risk of bias to be 'unclear' in three studies where protocol violations were reported, resulting from recruitment of small numbers of patients who either did not meet the prespecified inclusion criteria, or who did not receive all planned treatment (CRUISE 2010; GALILEO 2013; ROCC 2010).

Effects of interventions

See: Summary of findings for the main comparison

Primary outcome

Gain of at least 15 letters best-corrected visual acuity at six months

Five studies reported this outcome (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; Wroblewski 2009), and unpublished data were provided by study investigators for the sixth study (ROCC 2010). The table below summarises and compares the data across the six randomised controlled trials (RCTs) at six months. The proportion gaining 15 letters or more of visual acuity at six months ranged from 12.3% to 28.1% in the sham groups, and from 36.4% to 60.2% in the treatment groups. Data from six trials were included in the meta-analysis. Meta-analysis indicated that patients receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment were 2.71 times more likely to gain 15 letters or more of visual acuity at six months compared to patients treated with sham injections, and the 95% confidence interval (CI) suggested a statistically significant effect (RR 2.71; 95% CI 2.10 to 3.49) (see Analysis 1.1; Figure 4). There was no significant statistical heterogeneity (I2 = 10%), and also no significant difference between the different anti-VEGF subgroups (I2 = 11.7%). This demonstrates a clinically significant gain in visual acuity at six months associated with anti-VEGF therapy.

Figure 4.

Forest plot of comparison: Anti-VEGF versus sham intravitreal injection, outcome: 1.1 Gain of 15 letters or more at 6 months.

StudyTreatment group 1% > 15 letters gain at 6 months (n)Treatment group 2% > 15 letters gain at 6 months (n)Control group% > 15 letters gain at 6 months (n)P value
Copernicus 2012VEGF Trap-Eye 2.0 mg (n = 114)56.1 (64/114)--Sham injection12.3 (9/73)< 0.001
CRUISE 2010Ranibizumab 0.3 mg (n = 132)46.2 (61/132)Ranibizumab 0.5 mg (n = 130)47.7 (62/130)Sham injection16.9 (22/130)< 0.0001
Epstein 2012Bevacizumab 1.25 mg (n = 30)60.0 (18/30)--Sham injection20.0 (6/30)0.003
GALILEO 2013VEGF Trap-Eye 2.0 mg (n = 106)60.2 (62/103)--Sham injection22.1 (15/68)< 0.0001
ROCC 2010Ranibizumab 0.5 mg (n = 16)53.3 (8/15)--Sham injection14.3 (2/14)-
Wroblewski 2009Pegaptanib sodium 0.3 mg (n = 33)36.4 (12/33)Pegaptanib sodium 1.0 mg (n = 33)39.4 (13/33)Sham injection28.1 (9/32)0.35

Only one RCT reported 12-month outcomes for 15-letter gain in visual acuity, comparing treatment with 2 mg intravitreal aflibercept versus sham control, using PRN (as needed) dosing between months 6 and 12 (GALILEO 2013). Meta-analysis was therefore not performed. The proportion receiving aflibercept who gained 15 letters or more was largely maintained between months 6 and 12, at 60.2%. A mean 2.5 injections (standard deviation (SD) 1.7) were required during the PRN phase. The proportion gaining 15 letters of visual acuity improved in those randomised to sham injection who received PRN aflibercept between 6 and 12 months, from 22.1% to 32.4% (GALILEO 2013), but remained significantly worse than those randomised to aflibercept (P = 0.0004).

In the three open-label extension studies the gain in visual acuity seen at six months in those treated with anti-VEGF agents was also largely maintained at 12 months (Copernicus 2012; CRUISE 2010; Epstein 2012). Fifteen letters or more of visual acuity was gained at 12 months by 55.3% (63/114) of those treated with aflibercept monthly for six months then PRN with monthly reassessment for a further six months (Copernicus 2012); by 60% (18/30) of those treated with bevacizumab every six weeks for 12 months (Epstein 2012); and by 47.0% (62/132) and 50.8% (66/130) of those treated with 0.3 mg and 0.5 mg ranibizumab, respectively, every month for six months then PRN with monthly reassessment for a further six months (CRUISE 2010). Patients randomised to sham injection in these three trials crossed over to treatment with anti-VEGF from months 7 to 12, and in all sham/anti-VEGF groups the proportion gaining 15 letters or more at 12 months was higher than it had been at six months prior to treatment with anti-VEGF. Specifically, 15 letters or more gain in BCVA was reported in 30.1% (22/73) receiving delayed 2.0 mg aflibercept PRN for six months (Copernicus 2012), 33.1% (43/130) receiving delayed 0.5 mg ranibizumab PRN for six months (CRUISE 2010) and 33.3% (10/30) receiving delayed 1.25 mg bevacizumab every six weeks for six months (Epstein 2012). However, in all three trials the sham/anti-VEGF cross-over groups remained significantly worse with respect to this primary outcome than the groups initially randomised to anti-VEGF treatment.

Subgroup comparison of patients with baseline ischaemic central retinal vein occlusion (CRVO) macular oedema versus non-ischaemic CRVO macular oedema, defined as over 10 disc areas of retinal non-perfusion on a seven standard field fluorescein angiogram, was reported in one trial (Copernicus 2012). The proportion of eyes with baseline ischaemia who gained 15 letters at six months was 51.4% versus 4.3% in those treated with aflibercept and sham respectively (Copernicus 2012). The proportion of eyes without ischaemia at baseline who gained 15 letters at six months was 58.4% versus 16.0% in those treated with aflibercept and sham, respectively. At 52 weeks, the proportion gaining 15 letters or more of visual acuity following anti-VEGF treatment was largely maintained in both ischaemic and non-ischaemic treatment groups, at 48.6% and 58.4%, respectively. Following cross-over PRN treatment of the sham group from months 7 to 12, the proportion gaining 15 letters or more improved in both ischaemic and non-ischaemic sham randomised patients, to 30.4% and 30.0%. This suggests a beneficial effect of anti-VEGF treatment in both patients with ischaemic CRVO and with non-ischaemic CRVO, and a lesser benefit to both ischaemic and non-ischaemic subgroups if treatment is delayed by six months.

Subgroup comparison of patients randomised to receive treatment within or beyond two months of diagnosis was performed in two trials (Copernicus 2012; GALILEO 2013). The proportion of patients treated with aflibercept who gained 15 letters or more at six months was 64.1% versus 42.9% in those receiving first aflibercept treatment within or later than two months of diagnosis, respectively (Copernicus 2012). Similarly, in the GALILEO study, a 15 letter gain was seen in 70.9% versus 50.0% treated with aflibercept within or beyond two months of diagnosis, respectively (GALILEO 2013). This suggests a more beneficial effect of anti-VEGF treatment when commenced early.

Subgroup comparison of patients with a baseline BCVA of 6/60 (20/200) or worse was performed in one trial (Copernicus 2012). The proportion gaining 15 letters or more at six months was 67.9% versus 16.7% in the aflibercept versus sham groups with a baseline visual acuity of 6/60 (20/200) or worse, and 52.3% versus 10.9% in the aflibercept versus sham treated groups with a baseline visual acuity better than 6/60. This suggests that anti-VEGF treatment is beneficial even with a very poor presenting visual acuity.

Secondary outcomes

Loss of 15 letters or more best-corrected visual acuity at six months

Four studies reported this outcome (Copernicus 2012; CRUISE 2010; Epstein 2012; Wroblewski 2009), and unpublished data were provided by study investigators for a fifth study (ROCC 2010). The table below summarises and compares the data across the five RCTs. The proportion losing 15 letters of visual acuity at six months ranged from 15.4% to 31.2% in the sham groups, and from 1.8% to 13.3% in the treatment groups. We included data from all five studies in the meta-analysis. Meta-analysis suggested that patients receiving intravitreal anti-VEGF treatment had an 80% lower risk of losing 15 letters of visual acuity at six months compared to patients receiving a sham injection (RR 0.20; 95% CI 0.12 to 0.34) and the 95% CI suggested a statistically significant effect (see Analysis 1.2; Figure 5). There was no significant statistical heterogeneity (I2 = 0%) and also no significant difference between the different anti-VEGF subgroups (I2 = 0%). This represents a clinically significant benefit of anti-VEGF therapy at six months.

Figure 5.

Forest plot of comparison: Anti-VEGF versus sham intravitreal injection, outcome: 1.2 Loss of 15 letters or more at 6 months.

StudyTreatment group 1% > 15 letters loss at 6 monthsTreatment group 2% > 15 letters loss at 6 monthsControl group% > 15 letters loss at 6 monthsP value
Copernicus 2012VEGF Trap-Eye 2.0 mg (n = 114)1.8% (2/114)--Sham injection27.4% (20/73)-
CRUISE 2010Ranibizumab 0.3 mg (n = 132)3.8% (5/132)Ranibizumab 0.5 mg (n = 130)1.5% (2/130)Sham injection15.4% (20/130)< 0.005
Epstein 2012Bevacizumab 1.25 mg (n = 30)6.7% (2/30)--Sham injection23.3% (7/30)0.15
GALILEO 2013VEGF Trap-Eye 2.0 mg (n = 106)Not reported--Sham injectionNot reported-
ROCC 2010Ranibizumab 0.5 mg (n = 16)13.3% (2/15)--Sham injection28.6% (4/14)-
Wroblewski 2009Pegaptanib sodium 0.3 mg (n = 33)9.1% (3/33)Pegaptanib sodium 1.0 mg (n = 33)6.1% (2/33)Sham injection31.2% (10/32)0.03

Only one trial reported 12-month outcomes and so we did not perform meta-analysis of this outcome at 12 months (GALILEO 2013). Loss of 15 letters or more visual acuity at 12 months developed in 1% (n = 1) of the treatment group versus 14.7% (n = 10) of the sham group (GALILEO 2013).

In the three open-label extension trials the number of patients treated with anti-VEGF therapy who lost 15 letters or more of visual acuity remained stable (CRUISE 2010; Epstein 2012), or worsened slightly (Copernicus 2012), between months 6 and 12. Specifically, 6.7% (2/30) treated with an additional six months of bevacizumab six-weekly (Epstein 2012), 5.3% (6/114) treated with an additional six months of aflibercept PRN Copernicus 2012, 3.8% (5/132) treated with an extra six months of 0.3 mg ranibizumab PRN, and 2.3% (3/130) treated with an extra six months of 0.5 mg ranibizumab PRN (CRUISE 2010) had > 15 letters loss at 12 months. With six-month delayed anti-VEGF treatment, fewer patients in the sham cross-over groups had > 15 L vision loss at 12 months compared to their six-month outcomes. Specifically, 6.7% (2/30) (Epstein 2012), 10.0% (13/130) (CRUISE 2010) and 15.1% (11/73) (Copernicus 2012) of sham/anti-VEGF cross-over patients had more than 15 letters vision loss at 12 months, suggesting a beneficial effect of delayed anti-VEGF therapy.

Mean change in best-corrected visual acuity at six months

All six studies reported this outcome, but only three reported measures of dispersion (standard deviation or 95% CI) (Copernicus 2012; CRUISE 2010; ROCC 2010). Unpublished data from a fourth study were provided by the investigators (Epstein 2012). The table below summarises and compares the data across the six RCTs. The mean change in best-corrected visual acuity letter score at six months ranged from a gain of 3.3 letters to a loss of 4.0 letters in the sham groups, and from a gain of 7.1 letters to a gain of 18.0 letters in the treatment groups. In all studies, the greatest gain in BCVA was seen within one to two months of treatment with the anti-VEGF agents, with maintenance or more gradual improvement thereafter to six months. The mean difference (MD) between anti-VEGF and sham was 15.23 letters (95% CI 11.57 to 18.89) at six months. Although the statistical heterogeneity was considerable (I2 = 63%), we combined data in meta-analysis because the direction of effect was the same for all trials (Analysis 1.3).

StudyTreatment group 1Mean change in BCVA (letters)Treatment group 2Mean change in BCVA (letters)Control groupMean change in BCVA (letters)P value
Copernicus 2012VEGF Trap-Eye 2.0 mg (n = 114)+17.3--Sham injection-4.0< 0.001
CRUISE 2010Ranibizumab 0.3 mg (n = 132)+12.7Ranibizumab 0.5 mg (n = 130)+14.9Sham injection+0.8< 0.0001
Epstein 2012Bevacizumab 1.25 mg (n = 30)+14.1--Sham injection-2.0-
GALILEO 2013VEGF Trap-Eye 2.0 mg (n = 106)+18.0--Sham injection+3.3< 0.0001
ROCC 2010Ranibizumab 0.5 mg (n = 16)+12.0--Sham injection-1.0< 0.01
Wroblewski 2009Pegaptanib sodium 0.3 mg (n = 33)+7.1Pegaptanib sodium 1.0 mg (n = 33)+9.9 LSham injection-3.20.02 and 0.09

Only one trial reported change in mean BCVA at 12 months and so meta-analysis was not performed (GALILEO 2013). The significant difference between treatment and sham groups seen at 24 weeks was maintained to 52 weeks, with a respective gain from baseline in BCVA of 16.9 letters and 3.8 letters (P < 0.0001).

In the three open-label PRN extension studies the mean gain in BCVA from baseline seen at six months in those treated with anti-VEGF agents was also largely maintained at 12 months (Copernicus 2012; CRUISE 2010; Epstein 2012). The mean gain in the treatment groups was 16.2 letters (Copernicus 2012), 16.1 letters (Epstein 2012) and 13.9 letters in those treated with both 0.3 mg and 0.5 mg ranibizumab (CRUISE 2010). Patients randomised to sham injection in these three trials crossed over to treatment with anti-VEGF from months 7 to 12, and in all sham/anti-VEGF groups the mean gain in BCVA at 12 months was higher than it had been at six months prior to treatment with anti-VEGF. Specifically, a BCVA gain of 3.8 letters from baseline was reported in those receiving six-month delayed 2.0 mg aflibercept PRN for six months (Copernicus 2012), a gain of 7.3 letters was reported in those receiving delayed 0.5 mg ranibizumab PRN for six months (CRUISE 2010), and a gain of 4.6 letters was reported in those receiving delayed 1.25 mg bevacizumab every six weeks for six months (Epstein 2012). However, in all three trials the sham/anti-VEGF cross-over groups remained significantly worse with respect to this outcome than the groups initially randomised to anti-VEGF treatment, with P values for comparison between groups at 12 months of P < 0.001 (Copernicus 2012), P < 0.001 (CRUISE 2010) and P < 0.05 (Epstein 2012). Only one study, the HORIZON trial, considered longer-term acuity outcomes, in 304 patients (87%) who completed the 12-month CRUISE trial (CRUISE 2010). Patients originally randomised to sham (n = 98), 0.3 mg ranibizumab (n = 107) and 0.5 mg ranibizumab (n = 99) were eligible for PRN treatment with 0.5 mg ranibizumab during months 12 to 24, were typically reviewed every three months and received a mean of 2.9, 3.8 and 3.5 injections, respectively. At the end of 24 months of treatment in total, the mean BCVA gain from baseline was 7.6 letters, 8.2 letters and 12.0 letters in the sham/0.5 mg, 0.3 mg/0.5 mg and 0.5 mg groups, respectively.

Subgroup analysis in anti-VEGF treatment groups, based on disease duration, was performed in three studies (Copernicus 2012; Epstein 2012; GALILEO 2013). Patients treated with bevacizumab within 90 days improved by 18.7 letters at six months, compared to 9.8 letters in patients with a longer disease duration (Epstein 2012). Patients treated with aflibercept within two months improved by 20.2 letters (versus a -5.5 loss in the sham group) at six months, compared to 13.4 letters (versus -0.5 letters loss in the sham group) in patients with a longer disease duration (Copernicus 2012). A similar difference was seen at 12 months in those treated with aflibercept within two months of diagnosis who gained 19.5 letters (versus 2.1 letters in the sham group), compared to a gain of 13.7 letters (versus 5.5 letters in the sham group) seen in those with a longer disease duration (GALILEO 2013).

Subgroup analysis according to baseline perfusion status was reported in two trials (Copernicus 2012; GALILEO 2013). Eyes with ischaemic CRVO macular oedema at baseline gained +17.8 letters by six months when treated with aflibercept, compared to -2.3 letters in the sham group (Copernicus 2012). Eyes with non-ischaemic CRVO macular oedema at baseline gained +17.1 letters by six months when treated with aflibercept, compared to -4.8 letters in the sham group (Copernicus 2012). Similarly, the GALILEO 2013 trial demonstrated that patients stratified by baseline perfusion status and treated with aflibercept for six months plus six months PRN had a similar gain from baseline in BCVA at 12 months, of +16.8 (SD 14.7 letters) and 17.4 (SD 16.1 letters) in the non-ischaemic and ischaemic groups, respectively (GALILEO 2013). In contrast, eyes with no baseline retinal ischaemia in the sham group gained a mean 6.8 letters (SD 17.5) compared to a loss of 8.0 letters (SD 15.8 letters) in those with baseline ischaemia (GALILEO 2013). Importantly, this suggests a benefit of anti-VEGF treatment with aflibercept in eyes with both ischaemic and non-ischaemic CRVO macular oedema, and possibly a relatively greater gain in those with ischaemic CRVO macular oedema at baseline, whose visual outcome without treatment is worse.

Subgroup analysis of patients according to baseline mean BCVA of better than or worse than 6/60 (20/200) was performed in two trials (Copernicus 2012; GALILEO 2013). In patients with a baseline BCVA of 6/60 or worse, the mean change in Early Treatment of Diabetic Retinopathy Study (ETDRS) letter score was +21.9 versus 0 in the anti-VEGF versus sham groups; in patients with a baseline BCVA of better than 6/60 the mean change was +15.9 versus -5.4 letters in the anti-VEGF and sham groups, respectively (Copernicus 2012). In the second trial, at 12 months, patients with a baseline BCVA of 6/60 or worse also had a greater BCVA gain than those with a baseline BCVA of better than 6/60 (9.4 versus 2.4 letters for sham and 21.1 versus 16.0 letters for aflibercept monthly for six months then PRN for six months, respectively) (GALILEO 2013). This suggests a benefit of anti-VEGF treatment compared to sham, especially for patients with a worse presenting baseline BCVA.

Mean change in central retinal thickness (CRT) from baseline

All six studies measured this outcome but only two reported measures of dispersion (standard deviation or 95% CI) (CRUISE 2010; ROCC 2010); unpublished data were supplied for a third study (Epstein 2012, personal communication). The table below summarises and compares the data across the six RCTs. The mean change in CRT from baseline to six months ranged from a reduction of 102 µm to 169.3 µm in the sham groups, to a reduction of 243 µm to 457.2 µm in the treatment groups. Meta-analysis of the data from three studies suggests that patients treated with anti-VEGF agents have a mean reduction in CRT from baseline of 267.4 µm more than patients treated with sham, with 95% confidence that the true difference in the reduction lies between 211.4 µm and 323.4 µm. There was no significant statistical heterogeneity (I2 = 8%) and also no significant difference between the different anti-VEGF subgroups (I2 = 0%) (see Analysis 1.4; Figure 6). This represents a clinically significant benefit of anti-VEGF treatment over sham treatment at six months.

Figure 6.

Forest plot of comparison: Anti-VEGF versus sham intravitreal injection, outcome: 1.4 Mean change from baseline in central retinal thickness at 6 months.

StudyTreatment group 1Mean change in CRT (µm)Treatment group 2Mean change in CRT (µm)Control groupMean change in CRT
Copernicus 2012VEGF Trap-Eye 2.0 mg (n = 114)-457.2--Sham injection-144.8
CRUISE 2010Ranibizumab 0.3 mg (n = 132)-433.7Ranibizumab 0.5 mg (n = 130)-452.3Sham injection-167
Epstein 2012Bevacizumab 1.25 mg (n = 30)-426--Sham injection-102
GALILEO 2013VEGF Trap-Eye 2.0 mg (n = 106)-448.6--Sham injection-169.3
ROCC 2010Ranibizumab 0.5 mg (n = 16)-304--Sham injection-151
Wroblewski 2009Pegaptanib sodium 0.3 mg (n = 33)-243Pegaptanib sodium 1.0 mg (n = 33)-179Sham injection-148

In all six trials, graphs of the mean change in CRT over time convincingly illustrated the rapid and beneficial effect of all the anti-VEGF agents on resolution of macular oedema. The greatest reduction is seen within a month of the first injection in all trials, and the CRT reduction benefit is maintained throughout the treatment period. This is in marked contrast to the trajectory of change in CRT from baseline of the control patients, who demonstrate a more gentle, linear reduction in CRT over time.

Three open-label extension trials investigated the impact of immediate versus six-month delayed treatment with anti-VEGF on central retinal thickness (CRT) at 12 months. In these trials, patients initially randomised to sham injection for six months crossed over to receive treatment with anti-VEGF agents from months 7 to 12, either every six weeks (Epstein 2012), or monthly as required, and according to retreatment criteria (Copernicus 2012; CRUISE 2010). In all three trials, the mean reduction in CRT was largely maintained from months 6 to 12 in the anti-VEGF treatment groups (Copernicus 2012; CRUISE 2010; Epstein 2012). No significant difference in CRT, or the proportion of patients with residual macular oedema, was found between the anti-VEGF and sham/anti-VEGF groups at 12 months (Copernicus 2012; CRUISE 2010; Epstein 2012). These trials suggest that patients not receiving anti-VEGF therapy for an initial six months catch up, in terms of improvement in CRT, following six months of anti-VEGF therapy (CRUISE 2010; Epstein 2012). It should be noted, however, that resolution towards normal CRT does not necessarily indicate restoration of normal structural integrity or neuroretinal function.

One trial reported subgroup analysis for 12-month outcomes by baseline retinal perfusion status (GALILEO 2013). Patients treated with six months of monthly aflibercept followed by six months of PRN aflibercept, versus sham, had a greater reduction from baseline in mean CRT, regardless of baseline non-ischaemia or ischaemia (412.4 (SD 238.1) versus 201.2 (SD 226.4) for the non-ischaemic treatment and sham groups, and 494.6 (SD 318.4) versus 294.3 (SD 258.6) for the ischaemic treatment and sham groups) (GALILEO 2013).

Complications and ocular adverse events

Certain complications may develop in the natural history of untreated CRVO macular oedema, in particular neovascularisation of the iris and retina, associated neovascular glaucoma and vitreous haemorrhage. Objective differentiation of complications versus adverse events associated with intravitreal injection is not always possible, and so we considered these outcomes together without a priori assumption in this review, at six months of follow-up. In addition, one study reported safety data at 12 months (GALILEO 2013). Three studies included open-label extension to 12 months (Copernicus 2012; CRUISE 2010; Epstein 2012). One study included open-label extension to 24 months (CRUISE 2010). However, since patients initially randomised to sham injection received PRN anti-VEGF therapy beyond six months in these three trials, there was no untreated control group for inclusion in meta-analysis to compare outcomes at 12 months. Where the outcome developed with greater frequency in the sham group, we suggest that anti-VEGF reduced progression to this complication. Where the outcome occurred with greater frequency in the anti-VEGF group, we suggest it to be an adverse event associated with intravitreal injection or with anti-VEGF therapy. The six trials did not all report all potential adverse events or complications at six months. Where data on a specific outcome are incomplete, we do not know whether no outcomes occurred, whether outcomes that occurred were not documented or reported, or whether there was selective reporting bias (Analysis 1.5).

The development of iris or retinal neovascularisation was reported in all six studies. Across all studies, there were a total of 26/346 patients with this complication in the sham injection groups compared to 8/590 in the anti-VEGF treatment groups at six months. The Peto odds ratio was 0.18 (95% CI 0.09 to 0.36), with no significant statistical heterogeneity (I2 = 0%). This suggests that treatment with anti-VEGF therapy reduced the odds of progression to this recognised complication of CRVO to about 18% of what it would have been without treatment. Four studies specifically reported that many of these patients received panretinal photocoagulation treatment for this (Copernicus 2012; GALILEO 2013; ROCC 2010; Wroblewski 2009). Cases of neovascular glaucoma at six months were reported in three trials (Copernicus 2012; CRUISE 2010; GALILEO 2013) in a total of 1/479 patients treated with anti-VEGF and 5/271 patients in the sham groups. The Peto odds ratio was 0.14 (95% CI 0.03 to 0.72), with no significant statistical heterogeneity (I2 = 0%), suggesting a beneficial effect of anti-VEGF therapy in reducing progression to about 14% of what it would have been without anti-VEGF treatment. Additional non-neovascular glaucoma cases were reported in two trials, in 0/170 patients in the anti-VEGF groups and 1/100 patients in the control groups (GALILEO 2013; Wroblewski 2009). Considering longer durations of follow-up, new iris neovascularisation developing between 6 and 12 months did not occur in the sham or treatment groups of the aflibercept or bevacizumab trials (Copernicus 2012; Epstein 2012; GALILEO 2013), but did develop in an additional two people in the sham/0.5 mg ranibizumab PRN group, and in an additional four persons in the 0.5 mg/0.5 mg PRN treatment groups of the CRUISE 2010 trial.

Vitreous haemorrhage was specifically reported in three studies (Copernicus 2012; CRUISE 2010; ROCC 2010), in a total of 14/390 patients treated with anti-VEGF and 13/217 patients in the sham groups. The Peto odds ratio was 0.55 (95% CI 0.24 to 1.23) suggesting that treatment with anti-VEGF reduced the odds of vitreous haemorrhage to about 55% of what it would have been without treatment. However, there was significant statistical heterogeneity (I2 = 72%), perhaps reflecting that vitreous haemorrhage may result from intravitreal injection (i.e. an adverse event) or develop as a complication of CRVO and neovascularisation. Considering longer durations of follow-up, vitreous haemorrhage developed in an additional one person in each of the treatment and sham/PRN treatment (Copernicus 2012) or sham (GALILEO 2013) groups in both the Copernicus 2012 and GALILEO 2013 trials between 6 and 12 months, and in two persons in the original 0.3 mg ranibizumab group, treated with PRN ranibizumab between months 6 and 12 (CRUISE 2010).

All six studies specifically reported on endophthalmitis, with 1/590 cases occurring in the anti-VEGF groups (following intravital infection of aflibercept) (Copernicus 2012) and 0/347 occurring in the sham groups (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; ROCC 2010; Wroblewski 2009). The Peto odds ratio was 5.20 (95% CI 0.09 to 287.41), reflecting that the odds of this outcome are best estimated at over five times higher in those treated with intravitreal injection or with anti-VEGF therapy compared to no injection or anti-VEGF treatment, although the CI reflects considerable uncertainty. This one case was culture-positive for coagulase negative Staphylococcus and was considered to be associated with intravitreal injection. There were no additional cases of endophthalmitis at 12 months (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013). However, two cases of endophthalmitis were reported after 12 months in the HORIZON extension to the CRUISE trial, in patients in the 0.3 mg/0.5 mg group (CRUISE 2010).

Five trials reported no retinal detachments at six months (CRUISE 2010; Epstein 2012; GALILEO 2013; ROCC 2010; Wroblewski 2009). One retinal detachment developed between months 6 and 12 in the group treated with PRN aflibercept (GALILEO 2013), but there were no additional detachments in three open-label extension trials (Copernicus 2012; CRUISE 2010; Epstein 2012).

Three studies reported retinal artery occlusion in 3/391 patients in the anti-VEGF groups and 0/217 patients in the sham groups (Copernicus 2012; CRUISE 2010; ROCC 2010). The Peto odds ratio was 5.37 (95% CI 0.51 to 55.03), with no significant statistical heterogeneity (I2 = 0%), reflecting that the odds of this outcome are over five times higher in those treated with intravitreal injection or with anti-VEGF therapy compared to no injection or anti-VEGF treatment. No additional events were reported between 6 and 12 months (Copernicus 2012).

Cataract was reported in four out of 390 patients treated with anti-VEGF at six months versus 0 out of 217 receiving sham (Copernicus 2012; CRUISE 2010; ROCC 2010). All patients developing cataract received ranibizumab. The Peto odds ratio was 4.51 (95% CI 0.56 to 36.48) reflecting that the odds of developing cataract may be more than four times higher in those treated with anti-VEGF compared to sham. In the 12-month open-label extension trial, cataract was reported in a total of two patients treated with sham then PRN ranibizumab for six months, and an additional 10 patients in the treatment groups (CRUISE 2010). At 12 months one person in each group receiving PRN aflibercept between 6 and 12 months developed cataract (Copernicus 2012).

There was variable reporting of other more minor adverse events and complications in the studies, including subconjunctival haemorrhage, eye pain, elevation in intraocular pressure and ocular inflammation.

Non-ocular adverse events potentially associated with anti-VEGF therapy or intravitreal injection

Five trials reported two cases of myocardial infarction in 575 patients treated with anti-VEGF and two cases out of 333 treated with sham (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; Wroblewski 2009). The Peto odds ratio was 0.57 (95% CI 0.08 to 3.88), indicating that anti-VEGF treatment may be associated with lower odds of myocardial infarction compared to sham (Analysis 1.6). Four trials reported one case of transient ischaemic attack (TIA) out of 575 patients, which occurred in the 0.5 mg treatment group of the CRUISE 2010 trial, compared to no cases in 333 control patients (CRUISE 2010; Epstein 2012; GALILEO 2013; Wroblewski 2009). The Peto odds ratio was 1.49 (95% CI 0.06 to 36.29) suggesting that anti-VEGF treatment may be associated with higher odds of TIA, as compared to sham treatment. Hypertension was reported in 14 out of 479 patients receiving anti-VEGF, compared to 4 out 271 receiving sham (Copernicus 2012; CRUISE 2010; GALILEO 2013). The Peto odds ratio was 1.27 (95% CI 0.13 to 12.29) suggesting that anti-VEGF treatment may be associated with higher odds of hypertension compared to sham. Upper respiratory tract infections were reported more frequently in association with aflibercept treatment, in 14 out of 218 as compared to 6 out of 142 with sham treatment (Copernicus 2012; GALILEO 2013). The Peto odds ratio was 1.89 (95% CI 0.20 to 17.94) suggesting that aflibercept treatment may be associated with higher odds of nasopharyngitis than sham injection. No other significant systemic adverse events were reported in the six trials.

The number of anti-VEGF or sham injections administered

The number of anti-VEGF or sham injections was prespecified in the protocol of all trials for a fixed period, which ranged from three months (ROCC 2010) to six months (GALILEO 2013, Copernicus 2012, CRUISE 2010, Epstein 2012, Wroblewski 2009). Numerous trials included a pro re nata (PRN) treatment period ranging from a further three months (ROCC 2010) to a further six months (Copernicus 2012) or more (CRUISE 2010), in which the anti-VEGF agent was given to all groups according to protocol-specified retreatment criteria. One trial included a PRN treatment period of a further six months in which randomisation to sham or anti-VEGF agent was maintained (GALILEO 2013). The following table summarises the mean injections given in each of the trials.

TrialMean number of injections months 0 to 5Mean number of injections months 6 to 12Notes
Copernicus 20126 (sham or ranibizumab)3.9 (SE 0.3) in sham + PRN ranibizumab; 2.7 (SE 0.2) in ranibizumab + PRN ranibizumabPRN ranibizumab 6 to 12 m
CRUISE 20106 (sham or 0.3 mg or 0.5 mg ranibizumab)

3.8 in 0.3 mg group;

3.3 in 0.5 mg group;

3.7 in sham/0.5 mg group

PRN ranibizumab 6 to 12m
Epstein 20125 (sham or bevacizumab)4 (bevacizumab for both groups)Fixed injection schedule
GALILEO 20136 (sham or aflibercept)From 0 to 52 weeks: 11.8 (SD 2.8) aflbercept; 10.5 (SD 4.2) shamPRN ranibizumab or sham from 6 to 12 m
ROCC 20104.3 (SD 0.9) ranibizumab; 5.5 (SD 1.1) sham-PRN ranibizumab or sham from 3 to 6 m
Wroblewski 20095 (sham or pegaptanib sodium)-Fixed injection schedule

The number and type of additional interventions administered

No additional interventions to treat CRVO-MO were reported in any of the trials.

Economic data

No trials included economic data. Aside from these six RCTs, the remainder of the literature identified through this review's electronic search was based on open-label, prospective studies, retrospective chart reviews, case reports and case series with relatively short follow-up periods.

Quality of life

Three trials included the mean change in total score from baseline to six months on the National Eye Institute 25-item Visual Function Questionnaire, NEI VFQ-25 (Copernicus 2012; CRUISE 2010; GALILEO 2013); however, only one study reported data sufficient for analysis (Analysis 1.7). Specifically, in the CRUISE 2010 trial, patients in the 0.3 mg and 0.5 mg ranibizumab groups had a mean gain of 7.1 (95% CI 5.2 to 9.0) and 6.2 (95% 4.3 to 8.0) points, respectively, compared to 2.8 (95% CI 0.8 to 4.7) in the sham group (P < 0.05 for each ranibizumab group versus sham), even though the study eye was the worse seeing eye in most cases. Similarly, in the Copernicus 2012 and GALILEO 2013 trials, patients in the 2.0 mg aflibercept groups gained an average of 7.2 points and 7.5 points, respectively, compared to 0.8 points and 3.5 points, in the sham groups. At 52 weeks, further slight gains were reported from baseline in the treatment (7.8 points) and sham (4.5 points) groups in the GALILEO 2013 trial.

Discussion

Summary of main results

All six trials demonstrated that repeated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment was associated with (predominantly) significant improvements in the primary and secondary outcomes at six months compared to sham, and no significant safety concerns relating to the drug were identified in this time. Specifically, the proportion of treated patients gaining 15 letters or more of visual acuity ranged from 36.4% for 0.3 mg pegaptanib sodium (Wroblewski 2009), to 60.2% for 2.0 mg aflibercept (GALILEO 2013). The mean gain in visual acuity ranged from 7.1 letters in those treated with 0.3 mg pegaptanib sodium (Wroblewski 2009) to 18.0 letters in those treated with 2.0 mg aflibercept (GALILEO 2013). The proportion of treated patients losing 15 letters or more of visual acuity ranged from 1.5% (CRUISE 2010) to 13.3% (ROCC 2010), in patients receiving 0.5 mg ranibizumab. Participants receiving anti-VEGF treatment had a greater reduction in mean central retinal thickness (CRT) from baseline than patients receiving sham, indicating enhanced resolution of macular oedema. The reduction ranged from -179 to -243 μm in patients receiving pegaptanib sodium (Wroblewski 2009), to between -426 and -457 μm in participants receiving ranibizumab, bevacizumab and aflibercept (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013). Participants in the treatment groups of the CRUISE 2010, Copernicus 2012 and GALILEO 2013 trials reported an improvement in quality of life, with a gain of approximately seven points on the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) instrument at six months. The three open-label extension trials demonstrated that in the anti-VEGF treatment groups, the visual acuity and CRT gains seen at six months were maintained at 12 months, and no new safety concerns were identified in the treated groups (Copernicus 2012; CRUISE 2010; Epstein 2012).

In contrast, the outcomes in the sham groups were significantly worse and were similar across the six trials. Specifically, a gain of 15 or more letters at six months was reported in between 12% (Copernicus 2012) and 28% (Wroblewski 2009), whilst a loss of 15 letters or more was reported in between 15% (CRUISE 2010) and 31% (Wroblewski 2009). In general, after six months of sham injection there was a negligible mean change from baseline visual acuity, ranging from -4 letters (Copernicus 2012) to +3.3 letters (GALILEO 2013). There was some reduction in mean central retinal thickness from baseline, ranging from 102 μm (Epstein 2012) to 169 μm (GALILEO 2013). These outcomes are summarised in Summary of findings for the main comparison. Participants in the sham groups reported minimal functional gain in quality of life from baseline to six months on the NEI VFQ-25 instrument, with an average change of 0.8 points (Copernicus 2012), 2.8 points (CRUISE 2010) and 3.5 points (GALILEO 2013).

Allowing for variability resulting from the relatively small sample sizes, the six randomised controlled trials (RCTs) included participants with broadly similar baseline characteristics in both the sham and treatment groups (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; ROCC 2010; Wroblewski 2009). The mean duration from diagnosis to first treatment ranged from 61 days (Epstein 2012) to 80 days (Wroblewski 2009). The mean age ranged from 62 years (GALILEO 2013) to 72 years (ROCC 2010). The proportion of male patients ranged from 53% (Wroblewski 2009) to 60% (Epstein 2012). The mean baseline BCVA ranged from 52 letters (GALILEO 2013) to 43 letters (ROCC 2010), and the percentage of patients with a baseline visual acuity worse than 35 letters (6/60) ranged from 17% (GALILEO 2013) to 32% (Epstein 2012). The mean baseline central retinal thickness ranged from 619 µm (Wroblewski 2009) to 721 µm (Epstein 2012). Two trials included only patients with non-ischaemic central retinal vein occlusion (CRVO) macular oedema (CRUISE 2010; Wroblewski 2009), and four trials included a mixed cohort of ischaemic and non-ischaemic patients. The proportion of patients with baseline ischaemic CRVO macular oedema was 8.2% (plus 8.2% undetermined) in the GALILEO 2013 trial of aflibercept; 11.7% in the bevacizumab trial (Epstein 2012); 15.6% in the smaller ranibizumab trial (ROCC 2010) and 15.5% (plus 16.6% undetermined) in the other trial of aflibercept (Copernicus 2012).

Subgroup analyses to investigate the impact of treatment delay were performed in a few studies (Copernicus 2012; Epstein 2012; GALILEO 2013). This suggested that the greatest benefit of anti-VEGF treatment occurs in patients with a shorter duration between diagnosis and treatment (analysis was based on before and after two months or 90 days). Three open-label extension trials, in which patients randomised to sham injection for six months crossed over to receive PRN (as needed) anti-VEGF between months 7 and 12, further corroborated this. Six-month delayed anti-VEGF therapy resulted in resolution of macular oedema, with no significant differences between groups at 12 months in mean CRT. However, whilst visual outcomes improved in groups treated with anti-VEGF on a PRN basis after six months, the visual outcomes remained significantly worse at 12 months in these groups compared to the groups initially randomised to anti-VEGF therapy (Copernicus 2012; CRUISE 2010; Epstein 2012). Only one open-label extension trial, the HORIZON trial, considered longer-term outcomes at 24 months (CRUISE 2010). It is difficult to determine whether the lack of sustained benefit of anti-VEGF treatment at 24 months, with worsening of functional (but not anatomical) outcomes compared to 12 months, reflected reduced efficacy of anti-VEGF over time, or whether it was related to the lower assessment and treatment frequency in months 12 to 24, or to the high probability of attrition bias in the outcome data resulting from early termination of the trial.

Subgroup analyses to investigate the impact of retinal perfusion status on visual outcomes were performed in a few studies (Copernicus 2012; GALILEO 2013). These demonstrated that without anti-VEGF treatment, eyes with baseline ischaemic CRVO macular oedema have a worse visual prognosis than eyes with non-ischaemic CRVO macular oedema, but that both groups experience similar gains in visual acuity and anatomical resolution of macular oedema with anti-VEGF therapy. Subgroup analyses with stratification by baseline visual acuity (better or worse than 6/60) indicated that greater absolute gains in visual acuity are seen in patients with a baseline BCVA worse than 6/60 than with a baseline acuity better than 6/60, in both sham and treatment groups (Copernicus 2012; GALILEO 2013).

Anti-VEGF therapy was associated with significant reduction in the odds of developing iris or retinal neovascularisation or neovascular glaucoma at six months compared to sham treatment (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; ROCC 2010; Wroblewski 2009). Recognised complications of intravitreal injection therapy, including endophthalmitis, rhegmatogenous retinal detachment and retinal artery occlusion, were reported at very low frequency in some of the treatment groups. No significant association between anti-VEGF therapy and serious systemic adverse events was identified at six months.

In summary, despite some variability in baseline characteristics between the trials, all four anti-VEGF agents were demonstrated to enhance the anatomical resolution of macular oedema, to stabilise the visual acuity in some participants and to significantly improve the visual acuity in approximately half of those treated, with associated gains in quality of life in the trials which included this outcome, with no significant safety concerns up to 12 months. The 12-month GALILEO 2013 trial and the three open-label extension trials demonstrated a benefit to sham patients commenced on anti-VEGF treatment following a delay of six months (Copernicus 2012; CRUISE 2010; Epstein 2012). Subgroup analyses indicated benefit of anti-VEGF treatment to both ischaemic and non-ischaemic CRVO macular oedema patients. The results of this systematic review and meta-analysis demonstrate that treatment with anti-VEGF agents confers significant clinical gains in all outcomes of interest compared to no treatment.

Overall completeness and applicability of evidence

One limitation of some of the trials was their relatively small sample sizes; these ranged from 14 participants per group (ROCC 2010) to 132 participants per group (CRUISE 2010). Whilst this may have reduced the power to identify a significant difference between the treatment and sham groups in the main and secondary outcomes of interest (Wroblewski 2009), the treatment effect associated with anti-VEGF therapy in most studies was sufficiently large to yield significant differences from the control groups (Copernicus 2012; CRUISE 2010; Epstein 2012; GALILEO 2013; ROCC 2010). Two different treatment doses were investigated in comparison to sham in the CRUISE 2010 and Wroblewski 2009 trials, but neither trial had sufficient power to investigate outcome differences between these doses.

A second limitation in five out of six of the trials was the relatively short follow-up period of approximately six months, which did not permit assessment of how long the apparent benefits of treatment with anti-VEGF are sustained. One trial reported 12-month outcomes compared to sham (GALILEO 2013), and three open-label extension trials yielded safety data to 12 months (Copernicus 2012; Epstein 2012) and 24 months (CRUISE 2010), for the treatment and cross-over groups. Ocular or systemic adverse events occurring at a longer latency from treatment may have been missed.

Whilst the treatment of CRVO macular oedema with these four anti-VEGF agents appears very promising, the applicability of the available trial data to important subgroups of patients in clinical practice is not known. For example, since patients who had persisting CRVO macular oedema for more than one year were excluded from recruitment into the trials, the efficacy and safety of anti-VEGF therapy in these patients is not known. Patients with previous retinal vein occlusion, or other co-morbid eye disease including diabetic retinopathy and age-related macular degeneration, were also excluded, even though age and diabetes are among the established risk factors for CRVO (Shahsuvaryan 2003). It is not uncommon for patients in clinical practice to have multiple ocular and systemic pathologies. Furthermore, the CVOS Study reported that 29% of patients with CRVO present with a visual acuity of 6/12 or better (CVOS Group 1997), but as these participants were mostly excluded it is not possible to determine whether treatment with anti-VEGF might confer sufficient benefit in this group to outweigh the risks associated with intravitreal injection.

Quality of the evidence

The six included RCTs were small to moderate in size but were well designed with a low risk of bias in the majority of domains. They can therefore be considered to provide reasonably high-quality evidence on 6- to 12-month outcomes for the specific cohort of participants studied.

Data from numerous non-randomised studies were reviewed in the previous publication of this review (Braithwaite 2010). A comprehensive search for such data was not performed, and these tables were not included or updated in the current review.

Agreements and disagreements with other studies or reviews

We are not aware of any other systematic reviews on the use of anti-VEGF agents for the treatment of CRVO macular oedema. However, these agents have been administered intravitreally in numerous other ophthalmological contexts, and a good short-term safety profile is emerging, with a low incidence of serious ocular and systemic adverse events. A systematic review including 278 studies on 9061 participants who received 49,584 intravitreal anti-VEGF injections, specifically, ranibizumab (19,908 injections given over a mean of 16 months), bevacizumab (11,018 injections given over a mean of five months) and pegaptanib sodium (18,658 injections given over a mean of 11 months) reported a low incidence of all serious ocular adverse events with all three agents (van der Reis 2011). Specifically, there was a low cumulative incidence (per 100 injections) of endophthalmitis (0.04% to 0.11%), retinal detachment (0.01% to 0.08%), intraocular inflammation (0.25% to 1.06%), elevated intraocular pressure (IOP) (0.15% to 3.60%), intraocular haemorrhage (0.03% to 0.18%) and cataract progression (0.05% to 0.64%) (van der Reis 2011). Similarly, five cases of retinal detachment were reported over three years out of 35,942 anti-VEGF intravitreal injections performed at six high-volume centres in Germany (Meyer 2011). All retinal detachments occurred within two to six days of injection, and were more frequent in myopic patients (Meyer 2011). Other less serious side effects associated with intravitreal injections have included lid irritation, ocular discomfort and foreign body sensation, transient vision blurring, subconjunctival haemorrhage, mild anterior chamber inflammation and mild vitreitis, uveitis and raised IOP (Lynch 2007). Systemic adverse events including stroke, myocardial infarction and blood pressure elevation have been reported following intravenous administration of bevacizumab at doses more than 300 times higher than are used for ophthalmic indications (Lynch 2007). Wu et al reported systemic adverse events at one year in 1.5% of patients following intravitreal administration of 4303 bevacizumab injections into 1310 eyes. These adverse events included acute systolic blood pressure elevation (0.59%), cerebrovascular accident (0.5%), myocardial infarction (0.4%), iliac artery aneurysm (0.17%), toe amputation (0.17%) and death (0.4%) (Wu 2008). In the systematic review of three anti-VEGF agents, systemic adverse events were similarly infrequent, with a low cumulative incidence (per 100 injections) of heart disease (0.05% to 0.34%), vascular disease (0.01% to 0.05%), hypertension (0.15% to 0.55%), cerebrovascular accident (CVA) or transient ischaemic attack (TIA) (0.01% to 0.07%) and thromboembolic events (0.07% to 0.19%) (van der Reis 2011). The available evidence for the short-term safety profile of these agents is reassuring, but the follow-up periods are still too short, and the total number of treated patients too small to detect serious adverse events that occur at very low incidence, or at long latency from the treatment period.

It will be important to determine the relative effectiveness and safety of anti-VEGF agents versus other interventions for the treatment of CRVO macular oedema, but no head-to-head trial data are available yet. Comparison with RCT data on intravitreal corticosteroids will be particularly important, as both anti-VEGF agents and steroid implants have now been approved for the treatment of CRVO macular oedema in various countries, and are being used extensively off-label in others. Differences in baseline characteristics of participants recruited to the existing trials, comparing either anti-VEGF agents or steroid treatments to sham, render outcome comparison challenging at present. For example, the average duration of disease was less than two months in 62% patients recruited to the Copernicus 2012 trial, and less than three months in 69% participants in the CRUISE 2010 trial, but in only 39% participants recruited to the SCORE 2009 trial and 17% recruited to the Ozurdex GENEVA 2010 trial. Numerous head-to-head RCTs comparing different anti-VEGF agents and steroid treatments are currently underway and will begin to address this.

Authors' conclusions

Implications for practice

The randomised controlled trial (RCT) evidence from six trials clearly demonstrates that repeated intravitreal injection therapy for central retinal vein occlusion (CRVO) macular oedema with the anti-vascular endothelial growth factor (anti-VEGF) agents ranibizumab, pegaptanib sodium, aflibercept and bevacizumab, improves visual and anatomical outcomes at six and 12 months, compared to sham treatment. Smaller subgroup analyses suggest that early initiation of treatment (within two months or 90 days of diagnosis) is probably more beneficial than delayed treatment. Clinical benefit has been demonstrated by a few trials in subgroups of patients with both ischaemic and non-ischaemic CRVO macular oedema at baseline, and with baseline best-corrected visual acuity (BCVA) both better than and worse than 6/60. The efficacy and safety of anti-VEGF therapy, and of repeat intravitreal injections, over longer periods of follow-up has yet to be determined.

The relative effectiveness and safety profile of anti-VEGF agents versus steroid therapies for the treatment of different subgroups of CRVO macular oedema was not explored in this review and has yet to be determined. The impact of prior or combined treatment with intravitreal corticosteroid, or other treatments, was also not explored in this review.

In summary, anti-VEGF therapy is a relatively safe and effective treatment for CRVO macular oedema in the short term, and this represents an important therapeutic advance for the treatment of this visually disabling disease. It is not yet possible to determine the potential economic impact of the use of anti-VEGF agents in this clinical context, but we will be reassess this if data become available.

Implications for research

That anti-VEGF therapy confers clear clinical benefit for the treatment of CRVO macular oedema over no treatment (sham) in patients with certain baseline characteristics has been demonstrated, and marketing licenses have been granted to several agents accordingly. Future research should explore the relative efficacy and safety of different anti-VEGF agents in head-to-head trials, and other treatments (including corticosteroid injections and implants) and combination therapies. Further research into the efficacy and safety of anti-VEGF treatment for patients excluded from the trials reviewed here is needed. In particular, there is a clinical need to determine whether anti-VEGF therapy is also beneficial to patients with a duration from diagnosis exceeding a year, to those with ocular comorbidity and to those with a baseline visual acuity of 6/12 or better. Trials including larger patient samples would be needed to ensure sufficient statistical power for important subgroup analyses to be performed. Longer-term outcomes data on anti-VEGF treatment groups would also be valuable, to investigate whether the apparently low incidence of ocular and systemic adverse events is maintained in the longer term, or if there are any ocular or systemic harms associated with chronic VEGF inhibition.

The burden placed on patients and healthcare systems of monthly reassessment and repeat injection is very considerable, and the relative efficacy of different treatment intervals and approaches to reassessment and retreatment needs to be investigated further. The length of treatment to achieve a stable visual outcome has also yet to be determined. Recent trials have demonstrated that patients with both ischaemic and non-ischaemic CRVO macular oedema, with baseline BCVA worse than and better than 6/60, and with shorter and longer duration of disease at baseline all benefit, to a greater or lesser extent, from anti-VEGF therapy. Comprehensive baseline assessment to permit stratification and subgroup analysis would facilitate exploration of the prognostic significance of these important baseline factors. The inclusion of patients with a baseline BCVA better than 6/12 in future trials would also provide valuable clinical management information for this important subset of patients to whom the existing trial data do not necessarily apply. Further epidemiological data from different populations on the risk factors for developing CRVO macular oedema would also be beneficial.

Acknowledgements

We are especially grateful to Anupa Shah, Ann Ervin and Richard Wormald for their guidance on this review and to Iris Gordon for performing the electronic searches. We wish to thank Catey Bunce, Jenny Evans and Mariacristina Parravano for their peer review comments. We would also like to thank Barbara Hawkins, Michele Melia and Quan Dong Nguyen who made valuable comments on the protocol and first review manuscript.

Richard Wormald (Co-ordinating Editor for Cochrane Eyes and Vision Group) acknowledges financial support for his CEVG research sessions¬from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.

Data and analyses

Download statistical data

Comparison 1. Anti-VEGF versus sham intravitreal injection
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Gain of 15 letters or more at 6 months6937Risk Ratio (M-H, Random, 95% CI)2.71 [2.10, 3.49]
1.1 Pegaptanib sodium 0.3 mg149Risk Ratio (M-H, Random, 95% CI)1.45 [0.56, 3.80]
1.2 Pegaptanib sodium 1.0 mg149Risk Ratio (M-H, Random, 95% CI)1.26 [0.54, 2.92]
1.3 Ranibizumab 0.3 mg1197Risk Ratio (M-H, Random, 95% CI)2.73 [1.55, 4.82]
1.4 Ranibizumab 0.5 mg2224Risk Ratio (M-H, Random, 95% CI)2.94 [1.74, 4.96]
1.5 Bevacizumab 1.25 mg160Risk Ratio (M-H, Random, 95% CI)3.0 [1.38, 6.50]
1.6 Aflibercept 2.0 mg2358Risk Ratio (M-H, Random, 95% CI)3.37 [2.04, 5.57]
2 Loss of 15 letters or more at 6 months5766Risk Ratio (M-H, Random, 95% CI)0.20 [0.12, 0.34]
2.1 Pegaptanib sodium 0.3 mg149Risk Ratio (M-H, Random, 95% CI)0.29 [0.08, 1.07]
2.2 Pegaptanib sodium 1.0 mg149Risk Ratio (M-H, Random, 95% CI)0.19 [0.04, 0.89]
2.3 Ranibizumab 0.3 mg1197Risk Ratio (M-H, Random, 95% CI)0.25 [0.09, 0.69]
2.4 Ranibizumab 0.5 mg2224Risk Ratio (M-H, Random, 95% CI)0.21 [0.05, 0.99]
2.5 Bevacizumab 1.25 mg160Risk Ratio (M-H, Random, 95% CI)0.29 [0.06, 1.26]
2.6 Aflibercept 2.0 mg1187Risk Ratio (M-H, Random, 95% CI)0.06 [0.02, 0.27]
3 Mean change in BCVA from baseline at 6 months6937Mean Difference (IV, Random, 95% CI)15.23 [11.57, 18.89]
3.1 Pegaptanib sodium 0.3 mg149Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Pegaptanib sodium 1.0 mg149Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Ranibizumab 0.3 mg1197Mean Difference (IV, Random, 95% CI)11.90 [8.80, 15.00]
3.4 Ranibizumab 0.5 mg2224Mean Difference (IV, Random, 95% CI)14.06 [11.39, 16.73]
3.5 Bevacizumab 1.25 mg160Mean Difference (IV, Random, 95% CI)16.1 [5.63, 26.57]
3.6 Aflibercept 2.0 mg2358Mean Difference (IV, Random, 95% CI)21.3 [16.55, 26.05]
4 Mean change from baseline in central retinal thickness at 6 months6935Mean Difference (IV, Random, 95% CI)-267.39 [-323.36, -211.43]
4.1 Pegaptanib sodium 0.3 mg149Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
4.2 Pegaptanib sodium 1.0 mg149Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Ranibizumab 0.3 mg1197Mean Difference (IV, Random, 95% CI)-266.7 [-358.12, -175.28]
4.4 Ranibizumab 0.5 mg2223Mean Difference (IV, Random, 95% CI)-232.26 [-359.34, -105.18]
4.5 Bevacizumab 1.25 mg160Mean Difference (IV, Random, 95% CI)-324.0 [-452.64, -195.36]
4.6 Aflibercept 2.0 mg2357Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
5 Adverse events and complications at 6 months (ocular)6 Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only
5.1 Neovascularisation (iris or retina)6936Peto Odds Ratio (Peto, Fixed, 95% CI)0.18 [0.09, 0.36]
5.2 Neovascular glaucoma3750Peto Odds Ratio (Peto, Fixed, 95% CI)0.14 [0.03, 0.72]
5.3 Glaucoma (excluding neovascular)2270Peto Odds Ratio (Peto, Fixed, 95% CI)0.08 [0.00, 4.39]
5.4 Vitreous haemorrhage3607Peto Odds Ratio (Peto, Fixed, 95% CI)0.55 [0.24, 1.23]
5.5 Endophthalmitis6937Peto Odds Ratio (Peto, Fixed, 95% CI)5.20 [0.09, 287.41]
5.6 Retinal artery occlusion3608Peto Odds Ratio (Peto, Fixed, 95% CI)5.37 [0.52, 55.03]
5.7 Retinal tear5839Peto Odds Ratio (Peto, Fixed, 95% CI)0.37 [0.04, 3.66]
5.8 Retinal detachment5747Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
5.9 Ocular inflammation2562Peto Odds Ratio (Peto, Fixed, 95% CI)0.58 [0.16, 2.06]
5.10 Cataract3607Peto Odds Ratio (Peto, Fixed, 95% CI)4.51 [0.56, 36.48]
5.11 Subconjunctival haemorrhage2360Peto Odds Ratio (Peto, Fixed, 95% CI)1.07 [0.55, 2.07]
5.12 Elevation in intraocular pressure1172Peto Odds Ratio (Peto, Fixed, 95% CI)1.64 [0.54, 5.01]
5.13 Eye pain1172Peto Odds Ratio (Peto, Fixed, 95% CI)2.44 [0.83, 7.17]
6 Adverse events (systemic) at 6 months5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Myocardial infarction5908Risk Ratio (M-H, Random, 95% CI)0.57 [0.08, 3.88]
6.2 CVA or TIA5908Risk Ratio (M-H, Random, 95% CI)1.49 [0.06, 36.29]
6.3 Hypertension3750Risk Ratio (M-H, Random, 95% CI)1.27 [0.13, 12.29]
6.4 Nasopharyngitis2360Risk Ratio (M-H, Random, 95% CI)1.89 [0.20, 17.94]
7 Mean change in NEI VFQ 25 score (a vision-related quality of life instrument)3743Mean Difference (IV, Fixed, 95% CI)3.84 [1.49, 6.20]
7.1 Ranibizumab 0.3 mg1193Mean Difference (IV, Fixed, 95% CI)4.3 [0.94, 7.66]
7.2 Ranibizumab 0.5 mg1192Mean Difference (IV, Fixed, 95% CI)3.4 [0.09, 6.71]
7.3 Aflibercept 2.0 mg2358Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 1 Gain of 15 letters or more at 6 months.

Analysis 1.2.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 2 Loss of 15 letters or more at 6 months.

Analysis 1.3.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 3 Mean change in BCVA from baseline at 6 months.

Analysis 1.4.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 4 Mean change from baseline in central retinal thickness at 6 months.

Analysis 1.5.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 5 Adverse events and complications at 6 months (ocular).

Analysis 1.6.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 6 Adverse events (systemic) at 6 months.

Analysis 1.7.

Comparison 1 Anti-VEGF versus sham intravitreal injection, Outcome 7 Mean change in NEI VFQ 25 score (a vision-related quality of life instrument).

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Macular Edema, Cystoid
#2 MeSH descriptor Edema
#3 MeSH descriptor Macula Lutea
#4 macula* near/3 oedema
#5 macula* near/3 edema
#6 CME or CMO
#7 (#1 OR #2 OR #3 OR #4 OR #5 OR #6)
#8 MeSH descriptor Retinal Vein Occlusion
#9 MeSH descriptor Retinal Vein
#10 retina* near/3 (vein* or occlu* or obstruct* or clos* or stricture* or steno* or block* or embolism*)
#11 CRVO or CVO or RVO
#12 (#8 OR #9 OR #10 OR #11)
#13 MeSH descriptor Angiogenesis Inhibitors
#14 MeSH descriptor Angiogenesis Inducing Agents
#15 MeSH descriptor Endothelial Growth Factors
#16 MeSH descriptor Vascular Endothelial Growth Factors
#17 macugen* or pegaptanib* or lucentis* or rhufab* or ranibizumab* or bevacizumab* or avastin
#18 anti near/2 VEGF*
#19 endothelial near/2 growth near/2 factor*
#20 (#13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19)
#21 (#7 AND #12 AND #20)

Appendix 2. MEDLINE search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp macular edema cystoid/
14. exp edema/
15. exp macula lutea/
16. (macula$ adj3 oedema).tw.
17. (macula$ adj3 edema).tw.
18. (CME or CMO).tw.
19. or/13-18
20. exp retinal vein occlusion/
21. exp retinal vein/
22. ((vein$ or occlu$ or obstruct$ or clos$ or stricture$ or steno$ or block$ or embolism$) adj3 retina$).tw.
23. (CRVO or CVO or RVO).tw.
24. or/20-23
25. exp angiogenesis inhibitors/
26. exp angiogenesis inducing agents/
27. exp endothelial growth factors/
28. exp vascular endothelial growth factors/
29. (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin).tw.
30. (anti adj2 VEGF$).tw.
31. (endothelial adj2 growth adj2 factor$).tw.
32. or/25-31
33. 19 and 24 and 32

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (Glanville 2006).

Appendix 3. EMBASE search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or propspectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp retina macula cystoid edema/
34. exp eye edema/
35. exp retina macula lutea/
36. (macula$ adj3 oedema).tw.
37. (macula$ adj3 edema).tw.
38. (CME or CMO).tw.
39. or/33-38
40. exp retinal vein occlusion/
41. exp retina vein/
42. ((vein$ or occlu$ or obstruct$ or clos$ or stricture$ or steno$ or block$ or embolism$) adj3 retina$).tw.
43. (CRVO or CVO or RVO).tw.
44. or/40-43
45. exp angiogenesis/
46. exp angiogenesis inhibitors/
47. exp angiogenic factor/
48. exp endothelial cell growth factor/
49. exp vasculotropin/
50. (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin).tw.
51. (anti adj2 VEGF$).tw.
52. (endothelial adj2 growth adj2 factor$).tw.
53. or/45-52
54. 39 and 44 and 53
55. 32 and 54

Appendix 4. LILACS search strategy

macula$ oedema or macula$ edema or CME or CMO
AND vein$ or occlu$ or obstruct$ or CRVO or CVO or RVO
AND angiogenesis or endothelial growth factor or macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin

Appendix 5. CINAHL search strategy

macula$ oedema or macula$ edema or CME or CMO
AND vein$ or occlu$ or obstruct$ or CRVO or CVO or RVO
AND angiogenesis or endothelial growth factor or macugen$ or pegaptanib$ or lucentis or
rhufab$ or ranibizumab$ or bevacizumab$ or avastin

Appendix 6. OpenSIGLE search strategy

macula* oedema or macula* edema or CME or CMO
AND vein* or occlu* or obstruct* or CRVO or CVO or RVO
AND angiogenesis or endothelial growth factor or macugen* or pegaptanib* or lucentis or
rhufab* or ranibizumab* or bevacizumab* or avastin

Appendix 7. metaRegister of Controlled Trials search strategy

(angiogenesis or endothelial growth factor) AND macula oedema

Appendix 8. ClinicalTrials.gov search strategy

(Angiogenesis or Endothelial Growth Factor) AND (Macula Oedema)

What's new

DateEventDescription
14 January 2014New citation required and conclusions have changedIssue 5, 2014: Four new RCTs identified, meta-analysis performed and conclusions amended
14 January 2014New search has been performedIssue 5, 2014: Electronic searches updated

Contributions of authors

Conceiving the review: PG, TB
Designing the review: TB, AN
Co-ordinating the review: TB
Data collection for the review
- Designing electronic search strategies: TB, AN, CEVG Trials Search Co-ordinator
- Undertaking manual searches: TB, AN
- Screening search results: TB, AN
- Organising retrieval of papers: TB, AN
- Screening retrieved papers against inclusion criteria: TB, AN
- Appraising quality of papers: TB, AN
- Extracting data from papers: TB, AN
- Writing to authors of papers for additional information: TB
- Providing additional data about papers: TB, AN
- Obtaining and screening data on unpublished studies: TB, AN
Data management for the review
- Entering data into RevMan: TB, AN
- Analysis of data: TB, AN
Interpretation of data
- Providing a methodological perspective: TB, KL, AN
- Providing a clinical perspective: TB, PG, AN
- Providing a policy perspective: TB, PG
- Providing a consumer perspective: TB, AN, PG
Writing the review: TB
Providing general advice on the review: KL, PG, TB, AN
Performing previous work that was the foundation of the current study: TB, AN, PG

Updating the review
- Screening search results: TB, AN, KL
- Extracting data from and appraising quality of papers: TB, AN, KL
- Analysis of data: TB, KL
- Writing the review: TB
- Providing feedback on the review: TB, AN, KL, PG

Declarations of interest

All authors have no known conflicts of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Grant 1 U01 EY020522, National Eye Institute, National Institutes of Health, USA.

Differences between protocol and review

We decided to limit the scope of this review to RCTs comparing anti-VEGF agents to placebo (sham injection) or observation groups. RCTs in which anti-VEGF agents are compared only to other interventions such as corticosteroids (i.e. head-to-head RCTs) were not included in the review, nor will they be included in future updates of this review, in order to maintain the review's focus amidst a rapidly expanding literature.

The primary outcome was changed from a greater than or equal to 10 letter (ETDRS) improvement in visual acuity in the study protocol, to greater than or equal to 15 letter (ETDRS) improvement in visual acuity in the first publication of this review (Braithwaite 2010), as the latter corresponds to a doubling of the visual angle and is the standard binary outcome measure in clinical trials of treatments in retinal disease (Beck 2007). The follow-up interval is unchanged, at six months.

A secondary binary outcome, of a 15 letter or more (ETDRS) reduction in visual acuity at six months, was added to the first publication of this review to report more clearly the proportion of patients experiencing a significant deterioration in visual acuity.

In the present update of the review, we have tried to differentiate between adverse events which are potentially related to the intervention (the therapeutic agent and its mode of administration), and complications more probably arising from the disease process.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Copernicus 2012

Methods

Study design: double-masked, randomised, sham injection-controlled, phase III trial
Unit of randomisation and analysis: one study eye per participant

Loss to follow-up: 14 (18.9%) in control group, 5 (4.3%) in aflibercept (VEGF Trap-Eye) 2.0 mg group

Study duration: 6 months (2-year follow-up planned)

Participants

Countries: United States, Canada, India, Israel, Argentina and Columbia (70 sites)

Enrolment: 189 eyes (74 control group, 115 in VEGF Trap-Eye group) with CRVO-MO of < 9 months duration. Non-ischaemic* (67.9%), ischaemic (15.5%) and indeterminate (16.6%) included

Baseline characteristics:

  • Age: 18 and over (mean 66.3 years)

  • Gender: male (57%) and female (43%)

  • Mean duration from diagnosis: 2.4 months

  • Mean baseline BCVA: 50.0 ETDRS letters

  • Mean baseline CRT 665.8 μm

  • Mean NEI-VFQ 25 score: 77.1

Inclusion criteria:

  • Adults at least 18 years of age with centre-involving CRVO-MO diagnosed within 9 months of study initiation

  • Mean central retinal thickness > 250 μm on OCT

  • ETDRS best corrected visual acuity of 20/40 to 20/320 (73 to 24 letters) in study eye.

Exclusion criteria:

  • History of vitreoretinal surgery in the study eye, including radial optic neurotomy or sheathotomy

  • Current bilateral retinal vein occlusion

  • Previous panretinal or macular laser photocoagulation

  • Other causes for decreased visual acuity

  • Ocular conditions with poorer prognosis in the fellow eye

  • History or presence of AMD, diabetic macular oedema or diabetic retinopathy

  • Any use of intraocular or periocular corticosteroids or anti-angiogenic treatment in the study eye at any time or in the fellow eye in the preceding 3 months

  • Iris neovascularisation, vitreous haemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula

  • Vitreomacular traction or epiretinal membrane that significantly affected central vision

  • Ocular inflammation or uveitis

  • Any intraocular surgery in the preceding 3 months

  • Aphakia

  • Uncontrolled glaucoma, hypertension or diabetes

  • Spherical equivalent of a refractive error of more than -8 diopters myopia

  • Infectious blepharitis, keratitis, scleritis or conjunctivitis

  • Cerebral vascular accident or myocardial infarction in the preceding 6 months

  • Other conditions that may interfere with interpretation of the results or increase the risk of complications

*Non-ischaemic CRVO defined as < 10 disc areas of non-perfusion on FFA

Interventions

Intervention #1 (n = 74): sham injection

Intervention #2 (n = 114): aflibercept (VEGF Trap-Eye) 2.0 mg

 

Intravitreal injection (or sham injection) given every 4 weeks for 24 weeks, followed by an open-label extension from weeks 24 to 52, in which all patients were offered 2 mg aflibercept as required, according to retreatment criteria

Other treatments: All patients were eligible to receive panretinal photocoagulation at any time during the study at the discretion of the investigator if they progressed to neovascularisation of the anterior segment, disc or elsewhere

Outcomes

Primary outcome: proportion of eyes with a gain of 15 ETDRS letters or more in BCVA from baseline to week 24

Secondary outcomes: change from baseline to week 24 and 52 in the following variables: BCVA, CRT, proportion of eyes progressing to ocular neovascularisation, and NEI-VFQ 25 total score

Safety assessments included ocular adverse events (AEs) in the study and fellow eye, non-ocular AEs, ocular and non-ocular serious AE (SAEs), AEs of interest, laboratory assessments, vital signs and measurement of anti-drug antibody in serum.

Measurements: full ocular exam including visual acuity testing, slit-lamp biomicroscopy, indirect ophthalmoscopy, intraocular pressure measurement (preinjection and 30 minutes after injection) and OCT: day 1, week 4 and every 4 weeks thereafter to week 24. Adverse events and concomitant medications were recorded, and vital signs were obtained at each visit

Fundus photography and FFA: baseline, week 12 and week 24. NEI-VFQ 25: baseline and week 24. Laboratory assessments, including anti-VEGF Trap-Eye antibodies: baseline and weeks 12 and 24

Unit of analysis: eye

Notes

Study dates: July 2009 to October 2010 (for 24-week data)

Funding source: Regeneron Pharmaceuticals, Inc, Tarrytown, New York, and Bayer Healthcare, Berlin, Germany

Publication language: English

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Randomization was stratified using a centralized interactive voice randomization system, by geographic region and by baseline BCVA score."

1 eye per patient was selected as the study eye; patients with bilateral retinal vein occlusion at baseline were excluded

Allocation concealment (selection bias)Unclear risk

The method of allocation concealment was not described

Comment: Probably done

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Sham injections were performed by pressing an empty, needleless syringe barrel to the conjunctival surface to simulate an injection"; "examiners masked to treatment arm… NEI-VFQ25 administered by masked site personnel before intravitreal injection"; "OCT scans read at a masked independent central reading center…angiographic images ..transmitted to an independent reading centre for review by masked graders."
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Missing outcome data not balanced in distribution across groups; 14/74 (18.9%) in sham group versus 5/115 (4.3%) in the aflibercept group discontinued before week 24. 4 patients in the sham group, and none in the treatment group, discontinued as a result of adverse events associated with possible complications of CRVO, which included 1 patient with elevated IOP associated with rubeosis and vitreous haemorrhage, 1 with neovascular glaucoma, 1 with vitreous haemorrhage and rubeosis, and 1 with a 29 letter reduction in BCVA and rubeosis. 2 patients in the sham group died and 4 withdrew on account of treatment failure. 1 patient in the treatment group discontinued after developing a retinal tear after the first injection

Comment: The unbalanced loss of patients with potentially more severe and visually significant disease from the sham group might have introduced bias, reducing any apparent benefit associated with anti-VEGF therapy. To account for the missing data, the study investigators imputed missing data using the last-observation-carried-forward method. This may have introduced bias by not taking into account changes in outcomes over time

Selective reporting (reporting bias)Low riskPrimary and secondary outcomes reported as per the pre-specification on ClinicalTrials.gov. However, no measure of variance was reported for the mean change in central retinal thickness from baseline
Other biasLow riskNone identified

CRUISE 2010

Methods

Study design: double-masked, randomised, sham injection-controlled phase III trial
Unit of randomisation and analysis: one study eye per participant

Loss to follow-up: 2.3% in 0.3 mg group, 8.5% in 0.5 mg group, 11.5% in sham group

Study duration: 6 months, with subsequent 6-month open-label PRN treatment with ranibizumab 0.3 mg in the initial 0.3 mg group, 0.5 mg in the initial 0.5 mg group, and 0.5 mg in the initial sham group

Randomisation was stratified by study centre and baseline BCVA letter score < 34, 35 to 54, and > 55

Patients completing 12 months were eligible for a further 12-month open-label extension trial in which they were seen at least every 3 months and offered 0.5 mg ranibizumab if they met retreatment criteria and no exclusion criteria. This study was discontinued 30 days after FDA approval of ranibizumab for RVO in June 2010, resulting in incomplete follow-up data (Heier 2012)

Participants

Country: USA (95 centres)

Enrolment: n = 392 patients with non-ischaemic* (except n = 2 with ischaemic in the 0.5 mg group) CRVO-ME

Baseline characteristics:

  • Age: 18 and older (mean 68 years)

  • Gender: female and male (female 43%, 57% male)

  • Mean time from diagnosis to screening: 3.3 months

  • Mean study eye baseline BCVA: 48.3 letters (approximately 20/100 Snellen equivalent)

  • Mean baseline CFT: 685.2 μm

  • Mean baseline NEI VFQ-25 score: 76.8

Inclusion criteria:

  • 18 years or older

  • Diagnosis of CRVO-MO within 12 months of study initiation

  • BCVA 20/40 to 20/320 Snellen equivalent in study eye using ETDRS chart

  • Mean CRT on 2 OCT scans of 250 μm or greater at baseline screening and on day of first treatment

Exclusion criteria:

  • Prior treatment with radial optic neurotomy or sheathotomy

  • Intraocular corticosteroid use in study eye within 3 months of day 0

  • Intraocular anti-VEGF in study or fellow eye within 3 months before day 0 or systemic anti-VEGF or pro-VEGF treatment within 6 months of day 0

  • Prior panretinal or sectoral scatter photocoagulation within 3 months before day 0 or anticipated within 4 months after day 0

  • Laser photocoagulation for macular oedema within 4 months before day 0

  • Prior episode of RVO

  • Wet or dry AMD or any diabetic retinopathy

  • Presence of a brisk relative afferent pupillary defect

  • CVA or MI within 3 months of day 0

  • More than 10 letter improvement in BCVA between screening and treatment day 0

Exclusion criteria for HORIZON open-label extension trial (months 13 to 24):

  • Intraocular surgery within 1 month of study entry

  • Use of intravitreal bevacizumab in either eye

  • Concurrent use of any systemic anti-VEGF therapy

  • Use of any non-FDA approved treatments for RVO in the study eye

  • Macular oedema in the study eye due to causes other than RVO

*Non-ischaemic CRVO defined as < 10 disc areas of capillary non-perfusion on FFA

Interventions

Intervention #1 (n = 130): 0.5 mg ranibizumab every month for 6 months (6 injections) then PRN (open-label) for 6 months

Intervention #2 (n = 132): 0.3 mg ranibizumab every month for 6 months (6 injections) then PRN (open-label) for 6 months

Intervention #3 (Control) (n = 130): sham injection every month for 6 months (6 injections) then PRN 0.5 mg ranibizumab (open-label) for 6 months

General instructions/treatments: all participants received topical then subconjunctival anaesthetic. Sham participants did not have scleral penetration; blunt pressure was applied to the globe without a needle

Extension studies

In months 6 to 12 (the observation period), ranibizumab injection was given if study eye Snellen equivalent BCVA was < 20/40 or mean central subfield thickness on OCT, assessed by the investigator, was > 250 μm

In months 13 to 24 (open-label HORIZON extension trial), ranibizumab 0.5 mg injection was given if mean central subfield thickness was > 250 μm or if there was evidence of persisting/recurrent MO deemed to be affecting the BCVA

Outcomes

Primary outcome: mean change from baseline BCVA at month 6

Secondary outcomes: 1) Mean change from baseline BCVA over time to month 6; 2) Percentage of patients who gained 15 letters or more from baseline BCVA at month 6; 3) Percentage of patients who lost 15 letters or more from baseline BCVA at month 6; 4) Percentage of patients with CFT < 250 μm at month 6; 5) Mean change from baseline CFT over time to month 6; 6) Mean change in NEI VFQ-25 scores at month 6

Additional efficacy outcomes included the percentage of patients with Snellen equivalent BCVA 20/200 or worse at month 6, mean change from baseline excess foveal thickness over time to month 6 (CFT minus 212 μm). Additional outcomes included the percentage of patients with Snellen equivalent BCVA > 20/40 at month 6 (an outcome generally considered sufficient to support reading and driving). Safety outcomes included the incidence and severity of ocular and non-ocular adverse events and serious adverse events

Measurements: examination and OCT - day 0 and day 7, months 1 to 12. Patient-reported visual function assessed with the NEI VFQ-25 at day 0 and months 1, 3, 6 and 12

FFA - at screening visit, prior to day 0, months 6, 9, 12 (and 24 if included in HORIZON trial)

Unit of analysis: eye

No economic data included

Notes

Study dates: July 2007 to December 2008

Funding source: Genentech, Inc., South San Francisco, California

Publication language: English

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "patients were randomized 1:1:1".. "using a dynamic randomization method." "Randomization was stratified by baseline BCVA letter score" .. "and study center." 1 eye per patient was selected as the study eye; if both eyes were eligible, the eye with the worst BCVA at screening was selected
Allocation concealment (selection bias)Unclear risk

The method of allocation concealment was not described

Comment: probably done

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Patients, certified BCVA examiners, and evaluating physicians were masked to treatment and dose."

Quote: "Injecting physicians, who did not perform examination or outcome assessments, were masked to dose but not treatment."

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote: "the intent-to-treat approach was used for efficacy analyses and included all patients as randomized. Missing values for efficacy outcomes were imputed using the last-observation-carried-forward method"

The percentage of patients completing 6 months follow-up was 97.7% (n = 129) in the 0.3 mg group, 91.5% (n = 119) in the 0.5 mg treatment group and 88.5% (n = 115) in the sham group. The most common reason for withdrawal from the study was, "a decision made by the physician or patient to do so." Furthermore, not all participants completing the study to 6 months received all 6 monthly injections. Specifically, n = 4 (3.0%) in the 0.3 mg group, n = 10 (7.7%) in the 0.5 mg group and 16 (n = 12.3%) in the sham group discontinued treatment at or before month 5. This unbalanced loss to follow-up may have introduced bias in the reported outcomes

Selective reporting (reporting bias)Low riskPrimary and secondary outcomes reported as per the pre-specification on ClinicalTrials.gov
Other biasUnclear risk

4 patients, 1 in the sham group and 3 in the 0.5 mg group, were included whose time from diagnosis to screening exceeded the specified inclusion criteria of up to 12 months (protocol violation). The greatest duration included was 27 months, for a participant in the 0.5 mg group

Comment: the inclusion of outliers with a longer duration of CRVO-ME before treatment initiation is likely to reduce the apparent benefit of treatment, thus introducing a low risk of bias in the reported outcomes

3 patients (2%) in the 0.5 mg group had more than 10 disc areas of capillary non-perfusion, specifically 112, 113 and 109 disc areas, compared to no patients in either the sham or 0.3 mg groups

Comment: since these 3 patients were not excluded we assume that they did not have a brisk afferent pupillary defect. However, they may have had more ischaemic CRVO-ME than the other participants in the trial and since all 3 were in the 0.5 mg treatment group this may have introduced a bias in the outcomes, toward a reduced apparent benefit of treatment in the 0.5 mg group

Patients with a baseline BCVA falling outside the specified inclusion range of 20/40 (˜70 letters (Gregori 2010) to 20/320 (˜25 letters) were included. The number of patients with BCVA better than 20/40 or worse than 20/320, by group, cannot be determined from the data presented, although the range in BCVA (letters) was reported to be 16 to 71 letters in the sham group, 9 to 72 letters in the 0.3 mg group and 21 to 73 letters in the 0.5 mg group. The participants were stratified according to BCVA (in letters) of < 34 (˜20/200), 35 to 54 and > 55 (˜20/80), with similar proportions of each strata in each group

Comment: there is no reason why the range of baseline BCVAs should not be broader than that specified in the protocol, and the inclusion of participants with a poorer baseline BCVA than that prespecified should not introduce bias, providing a similar proportion of such participants were distributed across the 3 groups

Epstein 2012

Methods

Study design: double-masked, randomised, sham injection-controlled trial
Unit of randomisation and analysis: one study eye per participant

Loss to follow-up: no losses reported in 6-month RCT. Loss to follow-up in the open-label extension between 6 and 12 months was reported in 4 patients: 3 patients in the original treatment group discontinued on account of metastatic lung cancer, metastatic prostate cancer and old age; 1 in the original sham group discontinued on account of a TIA

Study duration: 6 months, with subsequent 6-month open-label extension

Participants

Country: Sweden

Enrolment: n = 60 with CRVO-MO (of whom 3 in the treatment group and 4 in the treatment group were ischaemic at baseline*)

Baseline characteristics

  • Age: 70.5 (SD 12.6)

  • Gender: 36 male (60%), 24 (40%) female

  • Mean duration from diagnosis: 8.8 (SD 5.7) weeks

  • Mean baseline BCVA: 44.1(SD 15.5) letters

  • Mean baseline CRT: 721 (SD 269)

Inclusion criteria:

  • Duration of 6 months or less

  • BCVA 15 to 65 ETDRS letters

  • mean central subfield thickness > 300 on OCT

Exclusion criteria:

  • CRVO with neovascularisation

  • Any previous treatment for CRVO

  • Intraocular surgery during the previous 3 months

  • Vascular retinopathy of other causes

  • Glaucoma with advanced visual field defect or uncontrolled ocular hypertension > 25 mmHg despite full therapy

  • Myocardial infarction or stroke during the last 12 months

Interventions

Intervention #1: sham injection (n = 30)

Intervention #2: 1.25 mg (0.05 ml) bevacizumab (Avastin) (n = 30)

Injections every 6 weeks for 24 weeks/6 months (total 4 injections)

Open-label extension for 6 months: all patients in both groups received bevacizumab 1.25 mg every 6 weeks (4 injections). N = 3 in original Avastin group discontinued and n = 1 in original sham group discontinued during extension phase

General instructions/treatments: all eyes treated with topical fucidinic acid 1% 30 minutes prior to injection

Outcomes

Primary outcomes: proportion of patients gaining at least 15 ETDRS letters at 6 months

Secondary outcomes: mean change from baseline BCVA, foveal thickness and number of cases of neovascular glaucoma (increased intraocular pressure caused by new vessels forming in the angle as diagnosed by gonioscopy)

Measurements: BCVA, gonioscopy, IOP, full dilated slit-lamp examination, OCT at baseline and every 6 weeks. FFA, colour and red-free photographs: baseline and 24 weeks

Unit of analysis: eye

Notes

Study dates: April 2009 to December 2010

Funding source: none

Publication language: English

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Each study participant was randomly assigned with equal probability."

Comment: method of generation of randomisation sequence not specified

1 eye per patient was selected but the method of selection of the study eye, in the event of both eyes meeting the inclusion criteria, was not explicitly stated

Allocation concealment (selection bias)Low risk

Quote: "Randomisation was done at the day of the first injection by sealed, opaque envelopes drawn by staff not involved in patient treatment or follow-up."

Comment: methods using envelopes may be susceptible to manipulation.

Personal communication with study investigator: Envelopes were blank and were not sequentially numbered based on the randomisation code

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Study patients were masked to the treatment given"; "Patients in the control group received a sham injection by pressing a syringe without a needle to the globe"; "Staff performing VA testing, OCT, fundus photographs, and follow-up investigators were masked to treatment group."
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up reported (100% completion). Missing outcome data for n = 1 in bevacizumab group (VA and OCT thickness) and n = 2 in sham group (OCT thickness) was imputed using last-observation-carried-forward, and analysis was by intention-to-treat
Selective reporting (reporting bias)Low riskPrimary and secondary outcomes reported as per the pre-specification on ClinicalTrials.gov. The standard error of the mean for continuous variables was not reported numerically in the published report, but this unpublished data provided (personal communication)
Other biasLow riskQuote: "The present study included patients with risk factors for developing..neovascular glaucoma…for example…severe ischaemic changes"; "The presence of a relative afferent pupillary defect was not an exclusion criteria." Whilst no information on relative afferent pupil defect (RAPD) or baseline FFA (e.g. disc areas of non-perfusion) was provided in the published study, unpublished data confirmed 7 patients had ischaemia at baseline, balanced between the groups (3 in the treatment group, 4 in the control group). (Personal communication with study investigators)

GALILEO 2013

Methods

Study design: multicentre, double-masked, randomised, sham-controlled phase III clinical trial
Unit of randomisation and analysis: one study eye per participant

Loss to follow-up: 25 out of 177 (14.1%) lost to follow-up at 24 weeks

Study duration: 76 weeks

Participants

Country: 63 centres in Europe (Austria 3; France 5; Germany 21; Hungary 5; Italy 7; Latvia 2) and the Asian/Pacific region (Australia 6; Japan 6; Singapore 2; South Korea 6)

Enrolment: 177 patients with CRVO-MO and no prior treatment for CRVO in the study eye

Baseline characteristics

  • Age: 18 years and older (mean 61.5 years)

  • Gender: female (44.4%) and male (55.6%)

  • Time from diagnosis: mean 81.8 days; 90% < 2 months  

  • Baseline BCVA: mean 52.2 ETDRS letters

  • Baseline CRT: men 665.5 μm

  • Retinal perfusion status: non-ischaemic (83.6%); ischaemic (8.2%), indeterminate (8.2%)*

Inclusion criteria:

  • Age: > 18 years

  • < 9 months mean duration from diagnosis

  • Baseline BCVA 20/40 to 20/320 (73 to 24 letters) in the study eye

  • Baseline CRT > 250 microns

Exclusion criteria:

  • Pregnant

  • Uncontrolled glaucoma (IOP ≥ 25 mm Hg)

  • Previous filtration surgery

  • Bilateral manifestation of RVO; iris neovascularisation

  • Previous treatment with anti-VEGF agents, panretinal or macular laser photocoagulation, or intraocular corticosteroids

*Baseline retinal perfusion status was determined by fluorescein angiography using the central vein occlusion study (CVOS) classification. Patients were considered ischaemic if they had ≥10 disc areas of capillary non-perfusion

Interventions

Randomised 2:3 ratio

Intervention #1: sham injection group n = 71. Weeks 0 to 20 sham injection every 4 weeks for 24 weeks; weeks 24 to 48 sham injection every 4 weeks; week 52 VEGF Trap-Eye (unless investigator declines for medical reasons), plus additional reassessment on weeks 60 and 68 and either PRN injection of VEGF Trap-Eye or sham injection

Intervention #2: 2 mg VEGF Trap-Eye Q4 (aflibercept) group n = 106. Weeks 0 to 20 injection every 4 weeks for 24 weeks; weeks 24 to 52 injection every 4 weeks plus additional reassessment on weeks 60 and 68 and either PRN injection of VEGF Trap-Eye or sham injection

 

General instructions/treatments: panretinal photocoagulation was allowed at any time for all patients if they progressed to neovascularisation of the anterior segment, optic disc or fundus

Outcomes

Primary outcomes: the proportion gaining at least 15 letters in BCVA compared with baseline at week 24 endpoint

Secondary outcomes:

1. Change from baseline in BCVA score at 24 weeks

2. Absolute change from baseline in CRT, assessed by OCT at week 24

3. Proportion of patients progressing to anterior segment neovascularisation, neovascularisation of the optic disc, or neovascularisation of the retina elsewhere requiring panretinal photocoagulation at week 24

4. Change in NEI-VFQ-25 total score from baseline to week 24

5. Change in EQ-5D score from baseline to week 24

Analyses at 24 weeks (published), 52 weeks (unpublished)

 

Unit of analysis: eye

Notes

Study dates: total study duration 76 weeks (masked), with 68 weeks of treatment

Funding source: Bayer and Regeneron Pharmaceuticals

Publication language: English

Clinicaltrials.gov ID: NCT01012973

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Randomisation was stratified by region (Europe vs Asia/Pacific) and baseline BCVA (≤20/200 vs >20/200)."

Method of generation of randomisation sequence not detailed in published report

Comment: probably centralised (i.e. low risk of bias)

1 eye per patient was selected as the study eye; patients with bilateral retinal vein occlusion at baseline were excluded

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not detailed in published report
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Sham procedure was performed by pressing an empty syringe with no needle to the conjunctival surface."

Masking not described in detail in published report

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

10/106 (9.4%) in treatment group were lost to follow-up of whom n = 5 had a protocol violation, n = 3 withdrew consent, n = 1 were lost to follow-up and 1 had another reason for withdrawal; 15/71 (21.1%) in the sham group were lost to follow-up of whom 4 had an adverse event, 2 had protocol violation, 3 withdrew consent, 5 reported lack of efficacy and 1 'other'

Comment: moderate loss to follow-up, unbalanced between groups

Sensitivity analysis compared the 'full analysis set' of n = 171/177, 25 of whom had imputation of missing data using the last observation carried forward method, to the 'per protocol' set of n = 138/177

Quote: "The sham group had a higher percentage of patients discontinuing study primarily due to adverse events and lack of efficacy this had no major impact on the primary endpoint as similar results were obtained after imputing the missing values with the LOCF approach using observed cases, or excluding patients who discontinued prior to week 24 and received fewer than five injections"

Selective reporting (reporting bias)Low riskPrimary and secondary outcomes reported as per the pre-specification on ClinicalTrials.gov except change in EQ-5D score from baseline to 24 weeks, which was not reported specifically for each group. No measure of variance was reported for the continuous variables including mean change in BCVA from baseline and mean change in CRT from baseline
Other biasUnclear risk

7 patients out of 177 (4.0%) had protocol violation; 5 in the treatment group and 2 in the control group. No detail of the nature of the protocol violation is given

Comment: this represents a small proportion of the patients and the resulting risk of bias is probably low

ROCC 2010

Methods

Study design: double-masked, randomised, sham injection-controlled trial
Unit of randomisation and analysis: one study eye per participant

Loss to follow-up: n = 3 of 32 (1 withdrew from ranibizumab group, after developing CRAO; 2 withdrew from sham group - 1 required planned surgery after developing cholecystitis and 1 developed AMD)

Study duration: 6 months

Participants

Country: Norway (4 centres)

Enrolment: n = 32 with CRVO-MO of whom 1/15 (6.7%) in the ranibizumab group and 4/14 (28.6%) in the sham group completing 6 months follow-up had ischaemic CRVO-MO*

Baseline characteristics

  • Age: 72 years

  • Gender: 16 male and 13 female

  • Mean duration from diagnosis: 78 days (range 10 to 163 days)

  • Mean baseline BCVA: 43 (SD 22) letters

  • Mean baseline CRT: 625 (SD 159)

Inclusion criteria

  • Symptom duration < 6 months

  • Age > 50 years

  • BCVA > 6 and < 73 ETDRS letters

Exclusion criteria:

  • Any concomitant ocular disease that could compromise the assessments in the study eye or induce complications such as active extraocular or intraocular infection or inflammation

  • Prior treatments of macular disease

  • History of uncontrolled glaucoma

  • Filtration surgery or corneal transplantation

  • Cataract surgery 3 months prior to baseline

  • Aphakia

  • Cataract or diabetic retinopathy in rapid progression

  • Vitreous haemorrhage

  • Previous rhegmatogenous retinal detachment

  • If any risk of pregnancy

  • Previous treatment with investigational drugs or drugs known to be toxic to the eye

  • Known contraindication to the use of an investigational drug

  • Current treatment for active systemic infection

  • History of hypersensitivity or allergy to fluorescein

*Ischaemic CRVO defined as > 5 disc areas of non-perfusion on FFA

Interventions

Intervention #1 (n = 14): sham injection (plastic syringe pressed against the eyeball)

Intervention #2 (n = 15): 0.5 mg/0.05 mL ranibizumab (Lucentis)

Injection every month for 3 months, then as required (at the discretion of the physician) for persisting macular oedema

Outcomes

Primary outcomes: mean change from baseline in BCVA score and CRT at 6 months

Secondary outcomes: number of treatments needed, safety and tolerability, development of neovascularisation

Measurements: full ophthalmic examination including OCT, and blood pressure and pulse: monthly for 6 month. Fundus photography and FFA: baseline, 3 and 6 months

Unit of analysis: eye

Notes

Study dates: March 2007 to October 2008 (from ClinicalTrials.gov protocol)

Funding source: Novartis Ophthalmic Inc

Publication language: English

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

The investigators do not detail their sequence generation process in the published study

1 eye per patient was included as the study eye and patients were only recruited to the trial if they had unilateral CRVO-MO

Allocation concealment (selection bias)Low risk

Personal communication with study investigator: sealed, opaque envelopes were used to conceal allocation. These were not sequentially numbered based on a randomisation code. They were opened after being assigned to individual patients

Comment: methods using envelopes may be susceptible to manipulation

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The investigating physician and nurse were masked toward the injecting physician and nurse and vice versa"; "All treatments were administered after subconjunctival anaesthesia...and sham treatment was conducted by pressing a plastic syringe against the eyeball."
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Small sample size with n = 16 per group of whom 15/16 (93.8%) completed 6 months follow-up in the ranibizumab group and 14/16 completed 6 months follow-up in the sham group (87.5%). The efficacy analysis was based on the per protocol treated participants, rather than on intention-to-treat, with no imputation of missing values

Reasons for missing outcomes are reported explicitly, however: 1 patient in ranibizumab group and 2 in sham group withdrew, with reason directly related to the treatment (CRAO following first injection) in the ranibizumab group, and not related to the treatment or outcomes in the sham group

Selective reporting (reporting bias)Low riskPrimary and secondary outcomes reported as per the pre-specification on ClinicalTrials.gov except the NEI VFQ-25 near activities subscale, which was not reported. Two outcomes of interest (proportion gaining and proportion losing 15 letters from baseline at 6 months) were not reported (these were not prespecified in the protocol), but were available as unpublished data (personal communication with study investigator)
Other biasUnclear risk

The protocol prespecified definition of ischaemic CRVO was > 10 disc areas of non-perfusion but in the final report a more conservative definition of > 5 disc areas of non-perfusion was used. There was an imbalance in the baseline proportion of patients with ischaemic CRVO between groups, of 1/15 (6.7%) in the ranibizumab group and 4/14 (28.6%) in the sham group. This imbalance in the proportion with ischaemic CRVO was reflected in the slightly worse baseline BCVA in the sham group of 41 (SD 22) letters compared to 45 (SD 23) letters in the Lucentis group. Ischaemic CRVO has a worse visual prognosis, and given the small sample size, this imbalance might have introduced bias in the outcome measures, enhancing the apparent difference between groups in primary and secondary outcomes

The authors also report that, "the accuracy of the OCT measurement was reduced in cases of severe macular oedema. This introduces the possibility of measuring bias," which may have increased estimate uncertainty. Comment: given that severe MO results in significant central retinal thickening, some imprecision in measurement would be unlikely to introduce bias in the results

Wroblewski 2009

  1. a

    AE: adverse event
    AMD: age-related macular degeneration
    BCVA: best-corrected visual acuity
    BRVO: branch retinal vein occlusion
    CFT: central foveal thickness
    CRT: central retinal thickness
    CRUISE: Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety
    CRAO: central retinal artery occlusion
    CRVO: central retinal vein occlusion
    CVA: cerebrovascular accident
    ETDRS: Early Treatment Diabetic Retinopathy Study
    FDA: US Food and Drug Administration
    FFA: fluorescein fundus angiography
    IOP: intraocular pressure
    µm: micrometres
    MO: macular oedema
    mg: milligram
    MI: myocardial infarction
    NEI-VFQ 25: National Eye Institute Visual Functioning Questionnaire 25 question instrument
    OCT: ocular coherence tomography
    PRN: pro re nata (as needed)
    PRP: panretinal photocoagulation
    QALY: quality of life
    RCT: randomised controlled trial
    RVO: retinal vein occlusion
    SAE: serious adverse event
    SD: standard deviation
    TIA: transient ischaemic attack
    VA: visual acuity
    VEGF: vascular endothelial growth factor

    * Personal communication with study investigator

Methods

Study design: double-masked, randomised controlled trial
Unit of randomisation and analysis: one study eye per participant

Loss to follow-up: 7 withdrawals (7%)

Study duration: 30 weeks

Participants

Country: Australia, France, Germany, Israel, Spain, United States

Enrolment: 98 eyes with non-ischaemic CRVO-MO

Baseline characteristics

  • Age: 18 and older (mean 62.6 years)

  • Gender: female and male (46 female, 52 male)

  • Mean time from diagnosis to screening: 77 to 82 days

  • Mean study eye baseline BCVA: 47.6 to 48.5 letters (Snellen equivalent 20/100)

  • Mean baseline CFT μm: 632 to 688 μm

Inclusion criteria:

  • 18 years or older

  • Onset of symptoms 6 months or less before baseline measurement

  • BCVA of 65 to 20 ETDRS letters inclusive (˜20/50 to 20/400 Snellen equivalent) in study eye

  • BCVA of better than or equal to 35 letters (˜20/200) in fellow eye

  • Central retinal thickness of 250 μm or greater at baseline and on day of first treatment

Exclusion criteria:

  • History of subtenon corticosteroid injection

  • Prior panretinal or sectoral scatter photocoagulation

  • Signs of old BRVO or CRVO in study eye

  • Other retinal vascular disease

  • Presence of a brisk relative afferent pupillary defect (an indicator for ischaemic CRVO)

  • Evidence of any neovascularisation involving the iris, disc or retina

  • Vitreous haemorrhage except from breakthrough intraretinal haemorrhage

  • Clinically significant concomitant ocular disease

Interventions

Intervention #1: 0.3 mg pegaptanib sodium every 6 weeks for 24 weeks (5 injections)

Intervention #2: 1.0 mg pegaptanib sodium every 6 weeks for 24 weeks (5 injections)

Intervention #3 (Control): sham injections every 6 weeks for 24 weeks (5 injections)

General instructions/treatments: all participants received injected subconjunctival anaesthetic. Sham participants did not have scleral penetration; blunt pressure was applied to the globe without a needle

Outcomes

Primary outcome: percentage of eyes in each group gaining 15 letters or more of visual acuity at 30 weeks compared to baseline

Secondary outcomes: 1) Mean change in BCVA from baseline to week 30; 2) Percentage of eyes losing 15 or more letters of BCVA from baseline to week 30; 3) Percentage of eyes with BCVA of 35 letters or more (20/200 or better) at week 30; 4) Mean change in centre point and central subfield retinal thickness measured by OCT at week 30 compared to baseline, and at interval assessments; 5) Percentage of eyes developing retinal or iris neovascularisation; 6) Incidence of ocular and systemic adverse events

Measurements: examination - baseline (week 0) and weeks 6, 12, 18, 24, 30

FFA - baseline and week 30

Colour photography - baseline, week 12, week 30

OCT - baseline, weeks 1, 3, 6, 12, 18, 24, 30

Unit of analysis: eye

No economic or QALY data included

Notes

Study dates: August 2004 to September 2006

Funding source: EyeTech Inc and Pfizer Inc

Publication language: English

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "subjects were allocated equally (1:1:1)...with randomization stratified by center and baseline visual acuity."

Quote: "Treatment assignment was based on a dynamic minimization procedure that used a stochastic treatment allocation algorithm based on the variance method"

1 eye per patient was selected but the method of selection of the study eye, in the event of both eyes meeting the inclusion criteria, was not explicitly stated

Allocation concealment (selection bias)Low risk

Quote: "Medication kits were identified by randomization number. All kits were similar in appearance, regardless of dose."

Quote: "The study coordinator conveyed the treatment assignment to the study ophthalmologist administering the injection in a way that did not inform the treating ophthalmologist or the subject"

Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants, personnel and outcome assessors were masked. Antisepsis and anaesthetic procedures were the same for all participants including those receiving sham. The latter group did not have scleral penetration, but blunt pressure was applied to the globe without a needle to mimic penetration

Quote: "The injection was not administered by the study ophthalmologist responsible for patient care and assessments."

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote: "Efficacy analyses were conducted on the intent to treat population, which included all randomized subjects. Missing data were imputed using the last-observation-carried-forward method, except for repeated-measures analyses of variance in which no imputation of missing data was performed"

7 patients withdrew from the trial (3 in the 0.3 mg group, 1 in the 1.0 mg group and 3 in the sham group). The percentage of patients receiving all 5 planned injections was 81% in the 0.3 mg group, 90% in the 1 mg treatment group, and 88% in the sham group

Comment: given the small sample size in this study, this unbalanced loss to follow-up may have introduced bias in the reported outcomes

Selective reporting (reporting bias)Low riskPrimary and secondary outcomes were not prespecified on ClinicalTrials.gov, however both positive and negative, significant and non-significant, outcomes were reported for all 3 groups. No measure of variance was reported for the continuous variables including mean change in BCVA from baseline and mean change in CRT from baseline
Other biasLow risk

The mean time between occlusive event and study entry was similar between groups, at 81, 82 and 77 days in the 0.3 mg, 1 mg and sham groups, respectively

Comment: we assume that all participants had a duration of less than 6 months, but the range of durations since onset was not reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    BCVA: best-corrected visual acuity
    BRVO: branch retinal vein occlusion
    CRT: central retinal thickness
    CRVO: central retinal vein occlusion
    FFA: fluorescein fundus angiography
    MO: macular oedema
    mg: milligrams
    OCT: ocular coherence tomography
    SD: standard deviation

Byeon 2009This randomised controlled trial compared adjuvant topical treatment with an aqueous depressant (timolol-dorzolamide) twice daily for 9 weeks, to no adjuvant treatment (control), in patients receiving a single injection of 1.25 mg bevacizumab for MO resulting from retinal vein occlusion, with a 9-week follow-up. Of 19 patients in each arm, only 5 in the adjuvant treatment group and 4 in the control group had CRVO-MO, with the remainder having BRVO-MO. Subgroup analysis of outcomes in the CRVO-MO group was not reported and the small CRVO-MO subgroup alone had insufficient power to address the null hypothesis of no difference between groups in the elimination of bevacizumab, as estimated by a change in central retinal thickness on OCT, at 1, 5 and 9 weeks follow-up
Campochiaro 2008This non-masked trial randomised 20 patients with CRVO-MO to receive 0.3 mg (n = 10) or 0.5 mg (n = 10) ranibizumab given monthly for 3 months, but did not include a sham or observation group, and was therefore excluded. At 3 months, the median BCVA gain was 17 letters in the 0.3 mg group, and 14 letters in 0.5 mg group, with 93% and 89% reduction in excess macular oedema. In a subsequent extension trial to 24 months, patients were reviewed every 2 months and treated with the same dose of ranibizumab as their initial treatment assignment, if retreatment criteria were met (Campochiaro 2010). The investigators aimed to 'wean off' treatment between 3 and 12 months, and reported that a mean of 3.4 injections were required during year 2. At 24 months, 14/20 completed final follow-up, with a mean change in BCVA from baseline of +8.5 (SD 14.8) letters; 29% (n = 4) gained 15 letters or more, 21% (n = 3) had no change from baseline, and 14% (n = 2) lost vision (-7 and -20 letters each). The mean change from baseline CRT was -195 microns, and only 3 participants had no persisting MO at 24 months. The authors concluded that 2 monthly review for 2 years was probably insufficient, in the majority of patients, to maintain the visual acuity gains seen after 3 months of monthly injections (Campochiaro 2010)
Ding 2011This open-label study randomised patients with CRVO-MO to receive intravitreal injection of either 4 mg preservative-free triamcinolone acetonide (n = 16) or 1.25 mg bevacizumab (n = 16) at baseline, with subsequent 'as required' injections from 3 months (Ding 2011), and final follow-up at 9 months. Approximately one-third of the patients in each group had ischaemic CRVO-MO at baseline, defined as > 10 disc areas of non-perfusion on FFA. No observation or sham injection control group was included
Wang 2011This open-label study randomised treatment-naive patients with CRVO-MO to receive intravitreal injection with either 1.25 mg bevacizumab (n = 36) or 1.25 mg bevacizumab plus 2.0 mg triamcinolone acetonide (n = 39), with no control group. At 3 months there was no significant difference between groups in mean CRT or BCVA (Wang 2011)

Characteristics of studies awaiting assessment [ordered by study ID]

EBOVER

MethodsRandomised, double blind, sham-controlled phase III clinical trial
Participants1 eye per adult subject with CRVO-MO or BRVO-MO and CRT > 250 microns, BCVA 20/40 to 20/400 in the study eye, reduction in BCVA within 6 months, and no prior treatment for RVO
Interventions

Experimental: 1.25 mg Avastin monthly for 3 months then PRN as per protocol

Control: Sham injection monthly for 3 months then PRN as per protocol

Outcomes

Primary outcome: BCVA (1 month)

Secondary outcome: CRT (1 month)

NotesRecruitment complete and active follow-up in progress (correspondence with investigator, October 2012)

Habibabadi 2008

  1. a

    BCVA: best-corrected visual acuity
    BRVO: branch retinal vein occlusion
    CRT: central retinal thickness
    CRVO: central retinal vein occlusion
    ETDRS: Early Treatment Diabetic Retinopathy Study
    IVTA: intravitreal triamcinolone
    µm: micrometres
    m: metre
    ME: macular oedema
    mg: milligram
    NEI-VFQ: National Eye Institute Visual Functioning Questionnaire
    OCT: ocular coherence tomography
    PRN: pro re nata (as needed)
    PRP: panretinal photocoagulation
    VA: visual acuity
    VEGF: vascular endothelial growth factor

MethodsRandomised controlled trial
Participants94 eyes with CRVO-MO
InterventionsIntravitreal bevacizumab versus combined intravitreal bevacizumab and triamcinolone versus sham injection
OutcomesBest-corrected visual acuity and central macular thickness at 18 weeks
Notes

Conference abstracts presented in 2007 and 2008. No published report found

Significant loss to follow-up (63 patients completed 18-week follow-up)

Ancillary