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Christine Schmucker, Yoon K. Loke, Hansjuergen T. Agostini, Lutz L. Hansen, Monika Lelgemann, Gerd Antes, Christoph Ehlken; A Safety Review Of Bevacizumab And Ranibizumab: Off-label Versus Goldstandard. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3806.
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We set out a systematic review to assess whether adverse effects (AE) differ between off-label bevacizumab and goldstandard ranibizumab in the treatment of age-related macular degeneration (AMD).
Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. We included randomised trials (RCTs) with a minimum follow-up of 1 year which investigated bevacizumab or ranibizumab in direct comparison or against any other control group (indirect comparison).
Of 1185 citations retrieved, 12 RCTs met the inclusion criteria (for direct comparison: 3 RCTs with a total of 1356 patients, for indirect comparison: 6 RCTs evaluating ranibizumab with a total of 4072 patients and 3 RCTs evaluating bevacizumab with a total of 244 patients). Direct comparison: The 1 year data show a significantly higher rate of serious ocular AE with bevacizumab compared to ranibizumab (RR 4.90, 95% CI 1.67 to 14.35). The proportion of patients with serious systemic AE (infections e.g.,pneumonia; gastrointestinal disorders e.g., haemorrhage) was also higher with bevacizumab than with ranibizumab (24.1% vs 19.0%, RR 1.29 95% CI 1.01 to 1.66). Arteriothrombotic events were equally distributed among the groups, at 2 to 3%. Socioeconomic differences and unmasked patients which could have impact on the safety outcomes have not been adequately considered in the head-to-head trials. Indirect comparison: The 2 year results of phase III trials evaluating ranibizumab against PDT or sham showed that while absolute rates of serious ocular AE were low (≤2.1%), relative harm was significantly raised (RR 3.13, 95% CI 1.10 to 8.92). A significant increase in non-ocular haemorrhage was also observed with ranibizumab (RR 1.62, 95% CI 1.03 to 2.55). We were unable to judge the safety of bevacizumab due to the poor quality of AE monitoring and reporting in the trials.
Bevacizumab studies for indirect comparison show too many methodological limitations to rule out any major safety concerns. Evidence from head-to-head trials raises concerns about an increased risk of ocular and systemic (infections and gastrointestinal disorders) AEs with bevacizumab which warrants further investigation.
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