A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus goldstandard

PLoS One. 2012;7(8):e42701. doi: 10.1371/journal.pone.0042701. Epub 2012 Aug 3.


Background: We set out a systemic review to evaluate whether off-label bevacizumab is as safe as licensed ranibizumab, and whether bevacizumab can be justifiably offered to patients as a treatment for age-related macular degeneration with robust evidence of no differential risk.

Methods and findings: Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. We included RCTs with a minimum follow-up of one year which investigated bevacizumab or ranibizumab in direct comparison or against any other control group (indirect comparison). Direct comparison (3 trials, 1333 patients): The one year data show a significantly higher rate of ocular adverse effects (AE) with bevacizumab compared to ranibizumab (RR = 2.8; 95% CI 1.2-6.5). The proportion of patients with serious infections and gastrointestinal disorders was also higher with bevacizumab than with ranibizumab (RR = 1.3; 95% CI 1.0-1.7). Arterial thromboembolic events were equally distributed among the groups. Indirect comparison: Ranibizumab versus any control (5 trials, 4054 patients): The two year results of three landmark trials showed that while absolute rates of serious ocular AE were low (≤ 2.1%), relative harm was significantly raised (RR = 3.1; 95% CI 1.1-8.9). A significant increase in nonocular haemorrhage was also observed with ranibizumab (RR = 1.7; 95% CI 1.1-2.7). Bevacizumab versus any control (3 trials, 244 patients): We were unable to judge the safety profile of bevacizumab due to the poor quality of AE monitoring and reporting in the trials.

Conclusions: Evidence from head-to-head trials raises concern about an increased risk of ocular and multiple systemic AE with bevacizumab. Therefore, clinicians and patients should continue to carefully weight up the benefits and harms when choosing between the two treatment options. We also emphasize the need for studies that are powered not just for efficacy, but for defined safety outcomes based on the signals detected in this systematic review.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Bevacizumab
  • Bias
  • Dose-Response Relationship, Drug
  • Eye / drug effects
  • Eye / pathology
  • Humans
  • Off-Label Use / standards*
  • Randomized Controlled Trials as Topic
  • Ranibizumab
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • Bevacizumab
  • Ranibizumab

Grant support

This research was supported by a grant from the German Federal Ministry of Education and Research (Grant number: 01KG1020, http://www.gesundheitsforschung-bmbf.de/de/4312.php). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.