A Safety Review and Meta-Analyses of Bevacizumab and Ranibizumab: Off-Label versus Goldstandard

Abstract

BackgroundWe 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 FindingsMedline, 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.ConclusionsEvidence 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.

Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature

“…49 A recent meta-analyses reported higher proportion of patients with serious systemic infections and gastrointestinal disorders with bevacizumab than with ranibizumab (RR ¼ 1.3; 95% CI 1.0-1.7); the arterial thromboembolic events were similar between the two groups. 47 Contrary to these studies, other reports could not find significant differences between ranibizumab and bevacizumab safety profile. Van der Reis et al 50 systematically assessed and compared the incidences of adverse effects of ranibizumab, bevacizumab, and pegaptanib, and concluded that there is no sufficient evidence to show a difference between the safety profiles of different VEGF inhibitors.…”

“…In comparison with the ranibizumab clinical trials, intravitreal bevacizumab injections may or may not be associated with an increased risk of nonocular hemorrhage. 47 In a retrospective study of 1173 patients receiving bevacizumab injections, the reported systemic events included acute blood pressure elevations (0.59%), cerebrovascular accidents (0.5%), myocardial infarctions (0.4%), iliac artery aneurysms (0.17%), and five deaths. 48 Different results were reported in the recent head-tohead trials and meta-analyses comparing intravitreal injections of bevacizumab and ranibizumab.…”

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

“…Activities involve generic medicines (46)(47)(48), including ways to obtain low prices for good quality generics as well as increase their utilisation versus originators and patented (single-sourced) products in a class (48)(49)(50)(51)(52) They also involve appraising medicines and other technologies that should be discontinued (53)(54)(55)(56) as well as potentially reviewing funding for the off-label use of medicines where there is robust evidence that they can act as alternatives to patented medicines, e.g. replacing the use of ranibizumab with bevacizumab to treat age-related macular degeneration (57)(58)(59). However, these activities are outside the scope of this paper.…”

Incidence of Myocardial Infarction, Stroke, and Death in Patients With Age-Related Macular Degeneration Treated With Intravitreal Anti–Vascular Endothelial Growth Factor Therapy

“…Other studies, however, have not found bevacizumab to confer an increased risk of systemic side effects. [14][15][16] In this study, we report the incidence of myocardial infarction (MI), stroke, and death from any cause among individuals who have been treated with intravitreal anti-VEGF therapy for AMD at a major tertiary eye hospital in Singapore. We compared the rates of these events with the national population data.…”