PhD Christine Schmucker
email: schmucker@cochrane.de

Yoon K Loke

Christoph Ehlken

Hansjuergen T Agostini

L Lutz

Gerd Hansen

Monika Antes

Lelgemann

‡ Lutz

L Hansen

Gerd Antes

Monika Lelgemann

Intravitreal bevacizumab (Avastin®) versus ranibizumab (Lucentis®) for the treatment of age-related macular degeneration: a safety review

Keywords: systematic review, bevacizumab, ranibizumab, safety

HAL is

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people over the age of 50 in the developed world. [START_REF] Bressler | Age-related macular degeneration is the leading cause of blindness[END_REF] Although an estimated 80% of patients with AMD have the non-neovascular form, [START_REF] Kahn | The Framingham Eye Study: I. Outline and major prevalence findings[END_REF] the neovascular (wet or exudative) form is responsible for almost 90% of severe visual loss resulting from AMD. [START_REF] Ferris | Age-related macular degeneration and blindness due to neovascular maculopathy[END_REF] Anti-angiogenic therapy, e.g., anti-vascular endothelial growth factors (anti-VEGF), which aims to prevent further neovascularization rather than only destroy it, is the latest approach to the treatment of exudative AMD. Currently, the most commonly used VEGF antagonists are ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA) and bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA). Ranibizumab, which is an antibody fragment from the bevacizumab molecule with an increased binding affinity for all forms of VEGF, has been approved for the treatment of patients with neovascular AMD by the Food and Drug Administration and by the European Medicines Agency since 2006 and 2007, respectively. The approval was based on three randomised controlled trials (RCTs). [START_REF] Bla | BL125156) Ranibizumab injection, Genentech, Inc. LUCENTIS™ (ranibizumab injection)[END_REF] Two of these studies showed that approximately 95% of the patients treated with monthly ranibizumab injections lost fewer than 15 letters in 12 months, compared to 64% of patients receiving PDT [START_REF] Brown | Ranibizumab versus verteporfin for neovascular age-related macular degeneration[END_REF] and 62% receiving sham treatment. [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF] In addition, approximately every third patient showed improvements in visual acuity under ranibizumab treatment. The costs of ranibizumab, however, are immense. Using monthly injections with a dose of 0.5 mg, the annual costs come to more than US$ 23,000 per patient. [START_REF] Steinbrook | The price of sight -ranibizumab, bevacizumab, and the treatment of macular degeneration[END_REF] In contrast to ranibizumab, bevacizumab was not developed for the treatment of AMD and consequently has no approval for this use. Bevacizumab is approved for the treatment of specific cancers, e.g., metastatic colon and rectum cancer. Even before ranibizumab was licensed, bevacizumab had been used as an off-label treatment for AMD. The first report of intravitreal bevacizumab administration for neovascular AMD was published in 2005. [START_REF] Rosenfeld | Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration[END_REF] After this initial report, numerous case series which (apparently) support the efficacy and safety of bevacizumab were published. The costs of intravitreal bevacizumab are much less than for ranibizumab. Small aliquots in syringes for intraocular injections can be prepared for about US$ 17-50 a month (≤ US$ 600 annually). [START_REF] Steinbrook | The price of sight -ranibizumab, bevacizumab, and the treatment of macular degeneration[END_REF] Despite lacking evidence, most published reviews agree that bevacizumab seems to be, similar to ranibizumab, effective in maintaining visual acuity. However, the safety and tolerability of bevacizumab in comparison to ranibizumab have not been adequately assessed and hence, the crucial question whether the existing safety data justify the widespread intravitreal off-label use of bevacizumab has not yet been answered. Moreover, it is essential to assess differences in reporting of harm between well-controlled phase III studies, RCTs which do not fulfil phase III study requirements, and non-RCTs. In particular, a critical assessment of the large number of published case series evaluating bevacizumab will

show to what extent they can be used as a substitute for high quality trials.

MATERIALS AND METHODS

Systematic

Study selection

Included were RCTs and non-RCTs which compared intravitreal bevacizumab or ranibizumab as monotherapy with any other treatment in patients with neovascular AMD.

Case series were included if they enrolled a minimum of ten patients and met predefined quality standards; that is, the publication had to provide adequate information regarding patient selection criteria or the selection of patients had to be consecutive. Studies which included patients with other indications than exudative AMD, patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy were excluded.

Data extraction and quality assessment

Titles and abstracts were reviewed using the above mentioned selection criteria. Full papers of appropriate studies were obtained for detailed evaluation. Data extraction and quality assessment was carried out after a modified evaluation tool of the Center for Reviews and Dissemination (Chapter 4, Systematic reviews of adverse effects). [START_REF]Undertaking systematic reviews of research on effectiveness: CRD's guidance for those carrying out or commissioning reviews[END_REF] Information on the number of participants, ascertainment of exposure (e.g., dosage and frequency of drug administered), follow-up time, definition of expected adverse effects, method used to collect adverse effects data, ascertainment of outcomes (ocular and systemic adverse effects) and transparency of patient flow were abstracted. All stages of study selection, data extraction and quality assessment were done independently by two reviewers (CS and CE or CS and ML). Any disagreement was resolved by discussion and consensus.

Statistical analysis

Ranibizumab data were analysed using the R software. [START_REF]R: A language and environment for statistical computing[END_REF] This programme was used to compute statistics and generate forest plots to compare safety outcomes in different treatment arms. A chi-square test (p-value < 0.05) and an I² test were used to test for statistical heterogeneity between studies. We used the fixed effects model (Mantel-Haeszel method) in the meta-analysis of rare events as it has been shown to be the more appropriate and less biased approach compared to the random effects model. [START_REF] Bradburn | Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events[END_REF] A narrative summary was provided for data that were unsuitable for pooling (studies evaluating bevacizumab).

RESULTS

Results of the search and selection process

The numbers of studies identified at each stage of the systematic review are shown in fig 1 .   After removing duplicate references, the searches identified 3628 citations. The inclusion criteria were met by four RCTs [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF][START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF][START_REF] Regillo | Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degnereation: PIER Study Year 1[END_REF][START_REF] Heier | Ranibizumab for treatment of neovascular agerelated macular degeneration: a phase I/II multicenter, controlled, multidose study[END_REF] (11 publications [START_REF] Brown | Ranibizumab versus verteporfin for neovascular age-related macular degeneration[END_REF][START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF][START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF][START_REF] Kaiser | Ranibizumab for predominantly Classic Neovascular Age-related Macular Degneration: Subgroup Analysis of First-year ANCHOR Results[END_REF][START_REF] Bressler | Improved vision-related function after ranibizumab vs photodynamic therapy: a randomized clinical trial[END_REF][15][START_REF] Boyer | Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration[END_REF][17][START_REF] Chang | Improved Vision-Related Function After Ranibizumab Treatment of Neovascular Age-Related Macular Degeneration[END_REF][START_REF] Regillo | Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degnereation: PIER Study Year 1[END_REF][START_REF] Heier | Ranibizumab for treatment of neovascular agerelated macular degeneration: a phase I/II multicenter, controlled, multidose study[END_REF]) evaluating ranibizumab vs PDT, sham or usual care with a total of 1392 patients and four RCTs [START_REF] Bashshur | Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration[END_REF][START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF][23][24] (five publications [START_REF] Bashshur | Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration[END_REF][START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF][23][24][START_REF] Weigert | Intravitreal bevacizumab (Avastin) therapy versus photodynamic therapy plus intravitreal triamcinolone for neovascular age-related macular degeneration: 6-month results of a prospective, randomised, controlled clinical study[END_REF]) evaluating bevacizumab vs PDT ± triamcinolone with a total of 287 patients. In addition, 17 case series [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF][START_REF] Aisenbrey | Intravitreal bevaizumab (Avastin) for occult choroidal neovascularization in age-related macular degnereation[END_REF][START_REF] Bashshur | Intravitreal Bevacizumab for the Management of Choroidal Neovascularization in Age-related Macular Degeneration[END_REF][START_REF] Bashshur | Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study[END_REF][START_REF] Chen | Intravitreal Bevacizumab (Avastin) for Neovascular Agerelated Macular Degeneration: A Short-term Study[END_REF][START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF][START_REF] Falkenstein | Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin) treatment for choroidal neovascularization in age-related macular degeneration[END_REF][START_REF] Geitzenauer | Early effects of systemic and intravitreal bevacizumab (Avastin) therapy for neovascular age-related macular degeneration[END_REF][START_REF] Giansanti | Intravitreal bevacizumab therapy for choroidal neovascularization secondary to age-related macular degeneration: 6-month results of an open-label uncontrolled clinical study[END_REF][35][START_REF] Lazic | Intravitreal bevacizumab (Avastin) in treatment of neovascular age-related macular degeneration[END_REF][START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF][START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF][START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] examining bevacizumab including a total of 1790 patients were analysed.

Study characteristics

Ranibizumab (RCTs)

Characteristics of the RCTs evaluating intravitreal ranibizumab are presented in table 1a.

The ANCHOR study which compared monthly ranibizumab injections with PDT enrolled 423 patients with predominantly classic subfoveal CNV. [START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF] Follow-up time was 24 months. The MARINA study enrolled 716 patients with minimally classic and occult subfoveal CNV and compared monthly intravitreal ranibizumab with sham injections over 24 months. [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF] The PIER study also used sham as a comparator and enrolled 184 patients with occult or classic subfoveal CNV. [START_REF] Regillo | Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degnereation: PIER Study Year 1[END_REF] In contrast to the MARINA study, treated patients received ranibizumab injections once monthly for three consecutive months, followed by a dose administered once every three months (follow-up time: 12 months). Heier 2006 randomised 64 patients to monthly intravitreal ranibizumab with varying doses for three months or usual care (i.e., PDT in predominantly classic lesions and observation in all other lesions). [START_REF] Heier | Ranibizumab for treatment of neovascular agerelated macular degeneration: a phase I/II multicenter, controlled, multidose study[END_REF] In the second part of the study, patients could continue their regimen for three additional months or cross over to the alternative treatment. All RCTs evaluating ranibizumab were multicenter trials. The ANCHOR, [START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF] MARINA [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF] and PIER [START_REF] Regillo | Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degnereation: PIER Study Year 1[END_REF] study were sponsored by pharmaceutical companies. The source of funding was not reported in the study of Heier 2006. [START_REF] Heier | Ranibizumab for treatment of neovascular agerelated macular degeneration: a phase I/II multicenter, controlled, multidose study[END_REF] Bevacizumab (RCTs) Table 1a shows study characteristics of RCTs evaluating intravitreal bevacizumab. Bashshur 2007 randomised 64 patients with predominantly classic CNV to PDT or intravitreal bevacizumab injections pro re nata. [START_REF] Bashshur | Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration[END_REF] The patients were followed-up for six months. The three months study of Lazic 2007 enrolled 165 patients with minimally classic or occult CNV and compared a single bevacizumab injection with a single PDT session or a combination therapy. [START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF] Hahn 2007 used PDT in combination with triamcinolone as comparator and enrolled 30 patients with occult or (minimally) classic subfoveal CNV. [23] The patients in this study received monthly bevacizumab injections for three consecutive months. Saccu 2009 also used PDT in combination with triamcinolone and enrolled 28 patients with occult or (minimally) classic subfoveal CNV. [24] Treated patients received bevacizumab injections once monthly for three consecutive months, followed by a dose administered pro re nata. Follow-up time was 12 months. All trials evaluating bevacizumab were monocenter studies.

Two studies reported that no pharmaceutical sponsor was involved, [START_REF] Bashshur | Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration[END_REF]23] and two did not provide data on the source of funding. [START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF]24] Bevacizumab (case series)

In total 11 prospective [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF][START_REF] Aisenbrey | Intravitreal bevaizumab (Avastin) for occult choroidal neovascularization in age-related macular degnereation[END_REF][START_REF] Bashshur | Intravitreal Bevacizumab for the Management of Choroidal Neovascularization in Age-related Macular Degeneration[END_REF][START_REF] Bashshur | Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study[END_REF][START_REF] Chen | Intravitreal Bevacizumab (Avastin) for Neovascular Agerelated Macular Degeneration: A Short-term Study[END_REF][START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF][START_REF] Falkenstein | Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin) treatment for choroidal neovascularization in age-related macular degeneration[END_REF][START_REF] Geitzenauer | Early effects of systemic and intravitreal bevacizumab (Avastin) therapy for neovascular age-related macular degeneration[END_REF][START_REF] Giansanti | Intravitreal bevacizumab therapy for choroidal neovascularization secondary to age-related macular degeneration: 6-month results of an open-label uncontrolled clinical study[END_REF][35][START_REF] Lazic | Intravitreal bevacizumab (Avastin) in treatment of neovascular age-related macular degeneration[END_REF] and six retrospective [START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF][START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF][START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] case series evaluating bevacizumab were analysed (table 1b). The number of included patients ranged between 13 and 625 (median: 48). Minimum follow-up time was one month and maximum follow-up 12 months. The Patients received between one and four injections and the applied dosage of bevacizumab varied between 1.0 mg and 2.5 mg. In ten case series [START_REF] Aisenbrey | Intravitreal bevaizumab (Avastin) for occult choroidal neovascularization in age-related macular degnereation[END_REF][START_REF] Chen | Intravitreal Bevacizumab (Avastin) for Neovascular Agerelated Macular Degeneration: A Short-term Study[END_REF][START_REF] Geitzenauer | Early effects of systemic and intravitreal bevacizumab (Avastin) therapy for neovascular age-related macular degeneration[END_REF]35,[START_REF] Lazic | Intravitreal bevacizumab (Avastin) in treatment of neovascular age-related macular degeneration[END_REF][START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF][START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] patients were injected pro re nata, in three case series [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF][START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF][START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF] a single injection of bevacizumab was given and in four case series [START_REF] Bashshur | Intravitreal Bevacizumab for the Management of Choroidal Neovascularization in Age-related Macular Degeneration[END_REF][START_REF] Bashshur | Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study[END_REF][START_REF] Falkenstein | Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin) treatment for choroidal neovascularization in age-related macular degeneration[END_REF][START_REF] Giansanti | Intravitreal bevacizumab therapy for choroidal neovascularization secondary to age-related macular degeneration: 6-month results of an open-label uncontrolled clinical study[END_REF] injections at intervals of four or six weeks were administered. Funding sources were specified in nine publications. [29-31, 33-35, 38, 39, 41] A pharmaceutical sponsor was, however, not reported. 2a). Any transient increase in intraocular pressure after the injections was also not reported. However, an increased rate of pigment epithelial tears (5.5% vs 0.0%), posterior vitreous detachment (14.6% vs 0.0%) and cataract progression (7.3% vs 0.0%) was reported in one RCT evaluating bevacizumab. [START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF] Bevacizumab (case series)

Four publications reported an increased rate of endophthalmitis (range between 0.2% and 0.9%, table 2b). [START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF][START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] An increased rate of retinal pigment epithelial tears (rips) was observed in five reports (range between 0.9% and 7.5%). [START_REF] Giansanti | Intravitreal bevacizumab therapy for choroidal neovascularization secondary to age-related macular degeneration: 6-month results of an open-label uncontrolled clinical study[END_REF]35,[START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF][START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF] Vitreous detachment was reported in 9.8% of patients in one publication [35] and an increased rate of submacular haemorrhage was observed in two case series (2.7% [START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF], 7.5% [START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF]). Moreover, in the retrospective case series of Wu 2008 an increased rate of uveitis (0.3%), retinal detachment (0.6%) and vitreous haemorrhage (0.08%) was reported. [START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] Six case series reported minor ocular adverse effects, such as pain, [START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF] conjunctival hyperemia, [START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF] subconjunctival haemorrhage, [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF][START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF][START_REF] Falkenstein | Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin) treatment for choroidal neovascularization in age-related macular degeneration[END_REF][START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] mild intraocular inflammation, [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF] transient corneal epitheliopathy [START_REF] Giansanti | Intravitreal bevacizumab therapy for choroidal neovascularization secondary to age-related macular degeneration: 6-month results of an open-label uncontrolled clinical study[END_REF] and transient blurred vision. [35] Table 2a Rates of ocular adverse effects under ranibizumab and bevacizumab / RCTs

Nonocular adverse effects

Ranibizumab (RCTs)

The rate of nonocular adverse effects of single RCTs are displayed in table 3a and pooled analysis for different systemic outcomes in fig 2b, 2c and 2d. The rate of key arterial nonfatal thromboembolic effects (myocardial infarction and stroke) during the first and second year of the ANCHOR [START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF] and MARINA [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF] trials was numerically, but not statistically significantly higher in the 0.5 mg arm than in the control arm (3.6% [START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF] and 2.5%, [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF] respectively vs 1.4% and 0.8%, respectively). However, a pooled analysis indicated that there may be a safety signal (RR 1.35, 95%-CI 0.66-2.77). In the ANCHOR, [START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF] MARINA [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF] and PIER [START_REF] Regillo | Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degnereation: PIER Study Year 1[END_REF] specified. [START_REF] Heier | Ranibizumab for treatment of neovascular agerelated macular degeneration: a phase I/II multicenter, controlled, multidose study[END_REF] However, it was reported that the only nonocular adverse event judged by an investigator to be a possible effect of ranibizumab was a case of metallic taste in the mouth.

Bevacizumab (RCTs)

Intravitreal bevacizumab injections were apparently not associated with any systemic adverse effects in the existing RCTs (table 3a). This assumption is based on the following limited details concerning the harms reported within the articles: Two trials mentioned generically that no systemic effects were observed. [START_REF] Bashshur | Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration[END_REF]24] One study did not mention systemic complications in the results. [23] Another study reported that no thromboembolic events were observed. [START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF] Other nonocular complications were not mentioned in this study.

Bevacizumab (case series)

Nonocular adverse effects were observed in one retrospective case series (table 3b). [START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] The incidence of cerebrovascular accidents and myocardial infarct was 0.3% and the incidence of acute hypertension was 1.5%. In addition, 0.6% of patients with exudative AMD showed an iliac artery aneurysm. Overall, eight case series mentioned -by using numerical data -that no thromboembolic events occurred. [28-30, 34-36, 38, 41] Six publications stated briefly that no systemic adverse effects were observed (except blood pressure was reported in more detail) [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF][START_REF] Aisenbrey | Intravitreal bevaizumab (Avastin) for occult choroidal neovascularization in age-related macular degnereation[END_REF][START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF][START_REF] Falkenstein | Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin) treatment for choroidal neovascularization in age-related macular degeneration[END_REF][START_REF] Geitzenauer | Early effects of systemic and intravitreal bevacizumab (Avastin) therapy for neovascular age-related macular degeneration[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF] and two publications did not mention systemic complications. [START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF] However, the primary study goal of these two case series were ocular complications.

Methodological limitations

RCTs

The methodological quality of RCTs evaluating ranibizumab and bevacizumab is presented in table 4a. In contrast to the pharmaceutical industry sponsored RCTs evaluating ranibizumab, the results of the RCTs evaluating bevacizumab are of limited value. The main limitations stemmed from the lack of any description as to how adverse effects were rigorously monitored, as well as the inadequate reporting of actual events. For example, none of the RCTs evaluating bevacizumab defined the method used to collect adverse effects data sufficiently or provided an adequate definition of expected adverse effects. In addition, in two of four RCTs evaluating bevacizumab the follow-up time was not sufficient to assess potential negative systemic effects, such as death or thromboembolic events (less than six months). [START_REF] Lazic | Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration[END_REF]23] In contrast, RCTs evaluating ranibizumab showed follow-up times of up to 24 months. [START_REF] Rosenfeld | Ranibizumab for neovascular age-related macular degeneration[END_REF][START_REF] Brown | Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degneration: Two-Year Results of the ANCHOR Study[END_REF] Beside the above mentioned shortcomings, the sample size for bevacizumab treated patients was much lower than for ranibizumab treated patients (112 vs 941) and the number of received injections differed greatly (bevacizumab: between one and seven intravitreal injections per patient, ranibizumab: up to 24 injections per patient).

Case series

A critical assessment of the large number of published case series showed that no reliable conclusions on safety can be drawn using this study design (table 4b). For example, of 11 prospective case series including 501 patients, only two evaluated more than 100 patients. [START_REF] Chen | Intravitreal Bevacizumab (Avastin) for Neovascular Agerelated Macular Degeneration: A Short-term Study[END_REF]35] However, the lost to follow-up was between 60% and 70% and reasons for drop-outs were not given in these publications. In addition, more than half of the evaluated case series did not describe if all of the originally included patients were considered in the results (transparency of patient flow not given). [START_REF] Abraham-Marin | Intravitreal bevacizumab therapy for neovascular age-related macular degneration: a pilot study[END_REF][START_REF] Bashshur | Intravitreal Bevacizumab for the Management of Choroidal Neovascularization in Age-related Macular Degeneration[END_REF][START_REF] Chen | Intravitreal Bevacizumab (Avastin) for Neovascular Agerelated Macular Degeneration: A Short-term Study[END_REF][START_REF] Giansanti | Intravitreal bevacizumab therapy for choroidal neovascularization secondary to age-related macular degeneration: 6-month results of an open-label uncontrolled clinical study[END_REF]35,[START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF][START_REF] Cleary | Intravitreal bevacizumab in the treatment of neovascular age-related macular degeneration, 6-and 9-month results[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF] Similar to RCTs evaluating bevacizumab, only four [START_REF] Costa | Intravitreal Bevacizumab for Choroidal Neovascularization Caused by AMD (IBeNA Study): Results of a Phase 1 Dose-Escalation Study[END_REF][START_REF] Arias | Retinal pigment epithelial tears after intravitreal bevacizumab injection for predominantly classic choroidal neovascularization[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF][START_REF] Jonas | Infectious and Noninfectious Endophthalmitis After Intravitreal Bevacizumab[END_REF] of 17 case series provided a definition of expected adverse effects and three [START_REF] Aisenbrey | Intravitreal bevaizumab (Avastin) for occult choroidal neovascularization in age-related macular degnereation[END_REF][START_REF] Goverdhan | Submacular haemorrhages after intravitreal bevacizumab for large occult choroidal neovascularisation in age-related macular degeneration[END_REF][START_REF] Madhusudhana | Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: reults from 118 cases[END_REF] (partly) defined the method used to collect adverse effects data. The currently available safety data from case series are -similar to the data from RCTs -further limited by the low number of received bevacizumab injections and short follow-up times. *This parameter addresses "long-term" harm, such as fatal or nonfatal systemic complications (e.g., stroke or myocardial infarction). We considered follow-up times of <6 months as not sufficient to assess these complications. †For serious ocular AE and grading scales for intraocular inflammation see tables 2, 3 and 6 of the supplementary study appendix. ‡Safety assessments included: intraocular pressure measurement (before and 60±10 min after each study treatment), indirect ophthalmoscopy, slit lamp examination, assessment of the incidence and severity of ocular and nonocular AE, changes and abnormalities in clinical laboratory parameters and vital signs, immunoreactivity to ranibizumab. Independent data monitoring committee met regularly one or more times a year during the study to review unmasked safety summaries prepared by an external statistical coordinating center. §For serious ocular AE and grading scales see tables 3-5 of the supplementary study appendix. ║After injection, patients remained in the clinic at least 60 minutes for safety monitoring and measurement of intraocular pressure. Site personnel contacted patients 2±1 days postinjection to elicit reports of any new ocular symptoms. Patients were evaluated 7 days after their first ranibizumab or sham injection, but they did not return 7 days after subsequent injections. Indirect ophthalmoscopy, intraocular pressure measurement, VA testing, and slit lamp examination were performed by the evaluating physician before every monthly study treatment. Safety outcomes included: incidence and severity of ocular and nonocular AE changes, abnormalities in clinical laboratory parameters and vital signs, assessment of immunoreactivity to ranibizumab. During the study, an independent data monitoring committee met twice per year to review unmasked safety summaries prepared by an external statistical coordinating center. #Grading scales for flare/cells and vitreous hemorrhage density were used to grade intraocular inflammation or vitreous hemorrhage, assessed by slit-lamp examination, see supplemental study tables B1 to B3. **Key safety assessments: incidence and severity of ocular and nonocular AE, changes in vital signs and the incidence of positive serum antibodies to ranibizumab. Slit-lamp examination and indirect ophthalmoscopy were performed before each study injection. IOP was measured using applanation tonometry before and 60±10 minutes after each study treatment. † †Verbatim descriptions of all AE were converted to medical dictionary for regulatory activities terms for statistical analysis. Inflammation was evaluated by grading flare and cells from 0-4+. ‡ ‡Patients were observed for any systemic thromboembolic events or ocular complications. § §All patients in the bevacizumab group had blood pressure measurements at every visit. Complete blood count and urinary analysis were taken at baseline and 1 week after any injection. *This parameter addresses "long-term" harm, such as fatal or nonfatal systemic complications (e.g., stroke or myocardial infarction). We considered follow-up times of <6 months as not sufficient to assess these complications.

DISCUSSION

Principal findings

Our review indicates that funding may not be a major cause of bias in the reporting of safety data. [START_REF] Golder | Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies?[END_REF] For example, most RCTs evaluating ranibizumab have been sponsored by the pharmaceutical industry, but they fulfil most of the criteria of reporting adverse effects. The study results of ranibizumab show a potential risk of serious adverse effects related to the injection procedure. In addition, the pooled RR indicates a possible risk of arterial thromboembolic and nonocular haemorrhagic events following intravitreal use of ranibizumab. Since the trials were not powered to detect small differences in adverse event rates, no conclusion can be drawn regarding whether these differences were drug-related or due to chance alone. Therefore, these signals should be investigated in larger epidemiological studies. Despite adequate reporting of adverse effects in RCTs evaluating ranibizumab, uncertainties remain in pharmaceutical industry sponsored trials about the interpretation and conclusions of these effects by the authors. [START_REF] Golder | Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies?[END_REF] In addition, very rarely adverse effects could not be evaluated in the ranibizumab trials because the number of patients was still too small.

In contrast to the RCTs evaluating ranibizumab, the trials evaluating bevacizumab were not sponsored by the pharmaceutical industry. However, they show -as described abovecommon methodological weaknesses (e.g., short follow-up times, small sample sizes, and an inadequate reporting of adverse effects). Thus, the findings that intravitreal bevacizumab injections are not associated with major ocular or systemic adverse effects are not supported by reliable data from RCTs.

Beside RCTs, numerous case series evaluating bevacizumab have been published. Not surprisingly, they show major methodological weaknesses and are of limited validity. For example, the often cited retrospective multicenter PACORES study, [START_REF] Wu | Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES)[END_REF] which is the only publication that provides information on the rates of systemic adverse effects of intravitreal bevacizumab, reports "self-reported" harm data. This can lead, as also discussed by the study authors, to an underestimation of adverse effects. Some case series showed a high lost to follow-up without giving reasons for drop-outs.[e.g., 30, 35] However, a complete follow-up is necessary in order to determine if those patients who withdrew due to adverse effects are different from those who did not adhere. Taking also into account that intravenous bevacizumab for the management of colorectal cancer is associated with major systemic adverse effects, the low (or zero) rates for intravitreal bevacizumab are questionable -even though the dose of intravitreal bevacizumab is about 0.25% of that used for intravenous treatment.

Strengths and weaknesses of this review

Both RCTs and non-RCTs (in particularly case series) were considered for the current review. We were interested in data from non-RCTs, because it is assumed that safety data from this study type are more reliable than data from RCTs. [START_REF] Gartlehner | Assessment of adverse effects and applicability -two areas not (yet) covered adequately in Cochrane reports[END_REF] For example, in RCTs, data on adverse effects could be underestimated mainly due to the inclusion of highly selected (non-representative) patients and/or publication bias. [START_REF] Chou | Assessing harms when comparing medical interventions: AHRQ and the Effective Health-Care Program[END_REF] In addition, small sample sizes limit the ability to detect rare but serious adverse effects. [START_REF] Chou | Assessing harms when comparing medical interventions: AHRQ and the Effective Health-Care Program[END_REF] In contrast, non-RCTs often utilize large database, therefore, it is more likely that rare adverse effects for a wide range of patients can be detected with this study type. [START_REF] Chou | Assessing harms when comparing medical interventions: AHRQ and the Effective Health-Care Program[END_REF] However, the current literature shows that in the case of bevacizumab in AMD, no well-conducted non-RCTs with large sample sizes are published.

Other reviews

Up to now, ranibizumab and bevacizumab has been evaluated in several systematic reviews.

However, the published reviews focused on the beneficial effect or clinical effectiveness of VEGF inhibitors without adequately addressing adverse effects. [START_REF] Vedula | Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration[END_REF][START_REF] Schouten | A systematic review on the effect of bevacizumab in exudative age-related macular degeneration[END_REF][START_REF] Ip | Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology[END_REF] The reason behind is that due to an ongoing methodological debate about the assessment of adverse effects the conclusions on safety are more complicated and need a very thoroughly and often timeconsuming evaluation. However, it is obvious that the inadequacies of the bevacizumab safety data may potentially lead to situations where bevacizumab is used inappropriately or where patients are not fully informed of possible harm and potentially avoidable adverse consequences [START_REF] Loke | Systematic reviews of adverse effects: framework for a structured approach[END_REF] -in contrast to the clear safety information that is available with the licensed substance which has been evaluated in Phase III trials.

Implications for clinical practice

This review highlights that the perceived low rates of adverse effects for bevacizumab are not supported by reliable data. The published RCTs and case series evaluating bevacizumab are of limited value and, therefore, they can not be used as substitutes for high-quality trials.

In addition, higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and haemorrhagic risk which warrants further investigation.

  literature search We searched Medline (Ovid), Embase and the Cochrane library from inception until March 2008. An update search focusing on RCTs was carried out in August 2009. The search strategy was based on combinations of medical subject headings (MeSH) and keywords and was not restricted to specific languages or years of publication. The search strategy used in Medline is presented in appendix A. Search strategies for other databases were modified to meet the requirements of each database. The searches were supplemented by handsearching the bibliographies of included studies and reviews and by contacting the pharmaceutical manufacturer (Genentech) of ranibizumab and bevacizumab. Currently conducted RCTs comparing Avastin® versus Lucentis® were searched both in the register for clinical trials (http://clinicaltrials.gov/) and in the WHO International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/).

FullFigure 1 Figure 2

 12 Figure 1 Flow diagram

Table 1a

 1a Characteristics of RCTs evaluating ranibizumab and bevacizumab

		No included	No anti-	Follow-up	Dosage	No injections/	Sponsor
		patients	VEGF treated			patient
			patients	[months]	[mg]	[mean]
	Ranibizumab ANCHOR 2009 [12]	423	280	24	0.3 / 0.5 monthly	24	pharmaceutical industry
	Ranibizumab MARINA 2006 [6]	716	478	24	0.3 / 0.5 monthly	21	pharmaceutical industry
	Ranibizumab PIER 2008 [19]	184	121	12	0.3 / 0.5 3 monthly, then every 3 mos	10	pharmaceutical industry
	Ranibizumab Heier 2006 [20]	69	53	7	0.3 / 0.5*	8	not specified
	Bevacizumab Bashshur 2007 [21]	64	32	6	2.5 pro re nata	2.4	no
	Bevacizumab Lazic 2007 [22]	165	55	3	1.25 single injection	1	not specified
	Bevacizumab Hahn 2007 [23]	30	10	3	1.0 monthly	3	no
	Bevacizumab Sacu 2009 [24]	28	14	12	1.0 pro re nata 3 monthly, then	6.8	not specified

*Four monthly injections or 1 injection of 0.3 mg followed by 3 monthly injections of 0.5 mg; after 3 months: cross over design.

Table 1b

 1b Characteristics of case series evaluating bevacizumab

	Ocular adverse effects
	Ranibizumab (RCTs)	No included patients	Follow-up	Dosage	No injections/ patient	Sponsor
	[months] Intravitreal ranibizumab injections have been associated with endophthalmitis (≤2.1%), [mg] [mean]
	Prospective case series uveitis (≤1.3%), retinal detachment (≤1.5%), retinal tear (≤1.9%), vitreous haemorrhage
	Abraham-Marin 2007 [26] (≤8.0%) and traumatic lens damage (≤0.4%) (table 2a).[6, 12, 20] A pooled analysis on 39 1 2.5 single injection 1 not specified
	Aisenbrey 2007 [27] serious ocular adverse effects indicated some major safety issues (Risk ratio [RR] 3.13, 30 3 1.25 1.6 not specified pro re nata p=0.03, fig 2a). In addition, all trials reported a transient increase in intraocular pressure in
	Bashshur 2006 [28] the study eye after intravitreal injections. 17	3	2.5 monthly	3	not specified
					2.5		yes, but no
	Bashshur 2008 [29]	60		12	3 monthly, then pro	3.4	pharmaceutical
	Bevacizumab (RCTs)				re nata		industry
	Chen 2007 [30] Most RCTs evaluating bevacizumab stated generically that ocular adverse effects were not 102 1.5-6.5 1.25 pro re nata 0.5 per months no
	Costa 2006 [31]	45		3	1.0, 1.5, 2.0* single injection	1	no
	Falkenstein 2007 [32]	18 †		6	1.25 every 6 weeks	3.6	not specified
	Geitzenauer 2006 [33]	13		3	1.0 pro re nata	3	yes, but no pharmaceutical sponsor
	Giansanti 2007 [34]	27		6	1.25 3 monthly	3	yes, but no pharmaceutical sponsor
	Lazic 2007a [35]	102		1.5-6	1.25 pro re nata	1-4	no
	Lazic 2007b [36]	48		1.5-6	1.25 pro re nata	nr	not specified
	Retrospective case series
	Arias 2007 [37]	40		≥6	1.25 single injection	1	not specified
	Cleary 2008 [38]	111 ‡		1-12	1.25 pro re nata	1.7	no
	Goverdhan 2008 [39]	53		2-12	1.25 pro re nata	1.4	no
	Jonas 2007 [40]	625		≥1	1.5 pro re nata	1.1	not specified
	Madhusudhana 2007 [41]	115		4.6	1.25 pro re nata	1.9	no
	Wu 2008 [42]	345 §		12	1.25 or 2.5║ pro re nata	3.3	not specified
	*Approximately 33% of patients received 1.0 mg, 33% received 1.5 mg and 33% received 2.5 mg intravitreal bevacizumab. †The study evaluated a 2 nd cohort including 20 patients receiving bevacizumab+pegaptanib. This cohort is not considered in the review.
	‡Data of 111 patients presented, therefrom 72 with exudative AMD.
	§Data of 1173 patients presented, therefrom 345 with exudative AMD.
	║Approximately 16% of patients received 1.25 mg and 84% of patients received 2.5 mg intravitreal bevacizumab.

noted. As the studies did not provide a detailed breakdown on the presence or absence of specific adverse effects, we are left to make the assumption that intravitreal bevacizumab injections were not associated with major problems, such as endophthalmitis, uveitis, retinal detachment, lens damage and vitreous haemorrhage (table

Table 2b

 2b Rates of ocular adverse effects under bevacizumab / case series

		Endoph-	Uveitis	Retinal	Retinal	Lens	Vitreous	Other ocular adverse effects
		thalmitis		detachment	tear	damage	haemorrhage
		(%)	(%)	(%)	(%)	(%)	(%)
	Prospective case series
	Abraham-Marin 2007 [26]	nr	nr	nr	nr	nr	nr	Subconjunctival haemorrhage 7.7%, mild inflammation 20.5%
	Aisenbrey 2007 [27]	0.0	0.0	nr	nr	nr	nr
	Bashshur 2006 [28]	nr	nr	nr	nr	nr	nr
	Bashshur 2008 [29]	nr	nr	nr	nr	nr	nr
	Chen 2007 [30]	0.0	0.0	nr	nr	nr	nr
	Costa 2006 [31]	0.0	0.0	nr	nr	0.0	nr	Pain 18%, conjunctival hyperemia 38%, subconjunctival haemorrhage 38%
	Falkenstein 2007 [32]	0.0	0.0	0.0	0.0	nr	nr	Subconjunctival haemorrhage (rare)
	Geitzenauer 2006 [33]	nr	nr	nr	nr	nr	nr
	Giansanti 2007 [34]	0.0	nr	0.0	7.4	nr	0.0	Transient corneal epitheliopathy 7.4%
	Lazic 2007a [35]	nr	nr	present*	2.0	0.0	nr	Vitreous detachment 9.8%, transient blurred vision
	Lazic 2007b [36]	nr	nr	nr	nr	0.0	nr
	Retrospective case series
	Arias 2007 [37]	nr	nr	nr	7.5 (study goal)	nr	nr
	Cleary 2008 [38]	0.9	0.0	nr	2.7	nr	nr	Submacular haemorrhage 2.7%
	Goverdhan 2008 [39]	nr	nr	nr	nr	nr	nr	Submacular haemorrhage 7.5% (study goal)
	Jonas 2007 [40]	0.2 (study goal)	nr	nr	nr	nr	nr
	Madhusudhana 2007 [41]	0.9	nr	nr	0.9	nr	nr
	Wu 2008 † [42]	0.60	0.3	0.6 (tractional)	nr	nr	0.08	Subconjunctival haemorrhage 71.4%, IOP increase 0.6%, transient hypotony 0.08%
	Nr, not reported; RPE, retinale pigment epithelium.
	*Number not given.
	†1265 patients injected, 92 lost to follow-up, data of 1173 patients presented , therefrom 345 with exudative AMD. The given percentage rates refer to 1173 patients.

Table 3a

 3a Rates of systemic adverse effects under ranibizumab and bevacizumab / RCTs

		Death		Myocardial infarction	Cerebrovascular	Nonocular		(Treatment-emergent)
					(nonfatal)		accident (nonfatal)	haemorrhage	hypertension
		(%)			(%)			(%)			(%)			(%)
		0.3mg	0.5mg PDT	0.3mg	0.5mg PDT	0.3mg	0.5mg PDT	0.3mg	0.5mg	PDT	0.3mg	0.5mg	PDT
	Ranibizumab
	ANCHOR 2009 [12]	3.7	2.1	3.5	0.7	3.6	1.4	2.2	0.0	1.4	8.8*	9.3*	4.9*	9.5	12.1	16.1
											2.9 †	2.1 †	0.7 †
				Sham			Sham			Sham			Sham			Sham
	Ranibizumab
	MARINA 2006 [6]	2.1	2.5	2.5	2.5	1.3	1.7	1.3	2.5	0.8	9.2*	8.8*	5.5*	17.2 ‡	16.3 ‡	16.1 ‡
											1.3 †	2.1 †	0.8 †
	Ranibizumab	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	3.4*	6.6*	4.8*	6.8	9.8	8.1
	PIER 2008 [19]										0.0 †	0.6 †	0.0 †
				UC			UC			UC			UC			UC
	Ranibizumab
	Heier 2006 [20]	nr	nr	nr	nr	nr	nr	nr	nr	nr	nr	nr	nr	nr	nr	nr
		2.5mg		PDT	2.5mg		PDT	2.5mg		PDT	2.5mg		PDT	2.5mg		PDT
	Bevacizumab
	Bashshur 2007 [21]	nr		nr	nr		nr	nr		nr	nr		nr	0.0		0.0
		1.25mg		PDT	1.25mg		PDT	1.25mg		PDT	1.25mg		PDT	1.25mg		PDT
	Bevacizumab
	Lazic 2007 [22]	nr		nr	0		0	0		0	nr		nr	nr		nr
		1.0mg	PDT+ivTC	1.0mg	PDT+ivTC	1.0mg	PDT+ivTC	1.0mg	PDT+ivTC	1.0mg	PDT+ivTC
	Bevacizumab
	Hahn 2007 [23]	nr		nr	nr		nr	nr		nr	nr		nr	nr		nr
		1.0mg	PDT+ivTC	1.0mg	PDT+ivTC	1.0mg	PDT+ivTC	1.0mg	PDT+ivTC	1.0mg	PDT+ivTC
	Bevacizumab
	Sacu 2009 [24]	nr		nr	nr		nr	nr		nr	nr		nr	nr		nr
	Nr, not reported; IvTC, intravitreal triamcinolone.
	*Refers to serious or nonserious nonocular haemorrhage.
	†Refers to serious nonocular haemorrhage.
	‡ Investigator defined hypertension.

Table 3b

 3b Rates of systemic adverse effects under bevacizumab / case series

		Death	Myocardial	Cerebrovascular	Nonocular	(Treatment-emergent)	Other systemic adverse
			infarction	accident	haemorrhage	hypertension	effects
		(%)	(%)	(%)	(%)	(%)
	Prospective case series
	Abraham-Marin 2007 [26]	nr	nr	nr	nr	nr	nr
	Aisenbrey 2007 [27]	nr	nr	nr	nr	0.0	nr
	Bashshur 2006 [28]	0.0	0.0	0.0	nr	0.0	nr
	Bashshur 2008 [29]	0.0	0.0	0.0	nr	0.0	nr
	Chen 2007 [30]	nr	0.0	nr	nr	nr	nr
	Costa 2006 [31]	nr	nr	nr	nr	0.0	nr
	Falkenstein 2007 [32]	nr	nr	nr	nr	nr	nr
	Geitzenauer 2006 [33]	nr	nr	nr	nr	0.0	nr
	Giansanti 2007 [34]	0.0	0.0	0.0	nr	0.0	nr
	Lazic 2007a [35]	nr	0	0	nr	nr	nr
	Lazic 2007b [36]	nr	0	0	nr	nr	nr
	Retrospective case series
	Arias 2007 [37]	nr	nr	nr	nr	nr	nr
	Cleary 2008 [38]	0.0	0.0	0.0	nr	0.0	nr
	Goverdhan 2008 [39]	nr	nr	nr	nr	nr	nr
	Jonas 2007 [40]	nr	nr	nr	nr	nr	nr
	Madhusudhana 2007 [41]	0.0	0.0	0.0	0.0	0.0	nr
	Wu 2008* [42]	0	0.29	0.29	nr	1.45	Iliac artery aneurysm 0.58%
	Nr, not reported.
	*1265 patients injected, 92 lost to follow-up, data of 1173 patients presented, therefrom 345 with exudative AMD. The given percentage rates refer to 345 patients with AMD.

Table 4a

 4a Methodological quality of RCTs evaluating ranibizumab and bevacizumab

		Follow-up time	Definition of	Definition of	Transparency of	Validity
		sufficient to	expected AE	method used to	patient flow	safety
		assess safety*		collect AE data
	Ranibizumab ANCHOR 2009 [12]	yes	yes †	yes ‡	yes	high
	Ranibizumab MARINA 2006 [6]	yes	yes §	yes║	yes	high
	Ranibizumab PIER 2008 [19]	yes	yes#	yes**	yes	high
	Ranibizumab Heier 2006 [20]	yes	in part † †	no	yes	moderate
	Bevacizumab Bashshur 2007 [21]	yes	in part ‡ ‡	in part § §	yes	low
	Bevacizumab Lazic 2007 [22]	no	no	no	yes	low
	Bevacizumab Hahn 2007 [23]	no	no	no	unclear	low
	Bevacizumab Sacu 2009 [24]	yes	no	no	yes	low
	AE, adverse effects.

Table 4b

 4b Methodological quality of case series evaluating bevacizumab

	Follow-up time
	sufficient to
	assess safety*

Definition of expected AE Definition of method used to collect AE data Transparency of patient flow Validity safety Prospective case series

	Abraham-Marin 2007 [26]	no	no	no	unclear	low
	Aisenbrey 2007 [27]	no	no	in part	yes	low
	Bashshur 2006 [28]	no	no	no	unclear	low
	Bashshur 2008 [29]	yes	no	no	yes	low
	Chen 2007 [30]	yes	no	no	no	low
	Costa 2006 [31]	no	yes	no	yes	low
	Falkenstein 2007 [32]	yes	no	no	yes	low
	Geitzenauer 2006 [33]	no	no	no	yes	low
	Giansanti 2007 [34]	yes	no	no	unclear	low
	Lazic 2007a [35]	yes	no	no	no	low
	Lazic 2007b [36]	no	no	no	yes	low
	Retrospective case series
	Arias 2007 [37]	yes	yes	no	unclear	low
	Cleary 2008 [38]	yes	no	no	no	low
	Goverdhan 2008 [39]	not applicable	yes	yes	unclear	moderate
	Jonas 2007 [40]	not applicable	yes	no	unclear	low
	Madhusudhana 2007 [41]	no	no	in part	unclear	low
	Wu 2008 [42]	yes	no	no	yes	low

Acknowledgments:

We are grateful to Dr Gerta Ruecker for providing us with statistical support.

Funding:

The review was commissioned and funded by the German health insurance fund (Verband der Ersatzkassen e. V. (vdek), Askanischer Platz 1, D-10963 Berlin, Germany).

Competing Interests:

None.

Licence for Publication:

The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BJO