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    Meta-analysis May Quell Systemic Safety Concerns

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    A new Cochrane Review of major clinical trials on the relative safety of bevacizumab (Avastin) and ranibizumab (Lucentis) concluded that the systemic safety of the two drugs appears to be similar in patients with neovascular age-related macular degeneration (AMD).1

    Some interpretations of safety findings from the earlier CATT (Comparison of AMD Treatment Trials) and IVAN (Inhibit VEGF in Age-related Choroidal Neovascularisation) studies had raised concerns that bevacizumab might elevate the risk of serious adverse events. Accordingly, certain national health systems set policies limiting the use of bevacizumab, and some ophthalmologists followed suit. Given the price difference between bevacizumab and ranibizumab, such policies came at a steep price.

    Reconsidering the concerns. The new Cochrane Review may put to rest some of those safety concerns. “Our study concludes that policies that require the use of ranibizumab to treat neovascular AMD for reasons of systemic safety are not sustained by the evidence,” said Koren H. Kwag, MSc, a lead author, at the Clinical Epidemiology Unit, IRCCS Galeazzi Orthopaedic Institute, Milan, Italy.

    “When we compared all serious systemic adverse events (SSAEs), and when we compared SSAEs by organ system class or by specific adverse events, we found no significant differences between the drugs, with the exception of gastrointestinal disorders.”

    Study details. This metaanalysis, conducted by a multinational research team, synthesized the results of nine randomized controlled trials that compared the drugs head to head. The trials selected for inclusion comprised 3,665 participants who received either bevacizumab or ranibizumab for up to two years. All studies used the approved dosage of ranibizumab (0.5 mg) or the most common bevacizumab dosage for AMD (1.25 mg), though the dosing regimen—monthly or as needed—varied among the studies. None of the trials received funding from the manufacturer.

    Safety statistics. Two primary outcomes were studied: all-cause mortality and all SSAEs. Based on the results of eight studies (n = 3,338), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95 percent confidence interval [CI], 0.78-1.57, p = .59) at maximum follow-up of one or two years. This gives a 3.4 percent risk of death with ranibizumab and a 3.7 percent risk with bevacizumab (CI, 2.7-5.3 percent).

    For all SSAEs (nine studies, n = 3,665), the estimated RR was 1.08 for bevacizumab versus ranibizumab (CI, 0.90-1.31, p = .41). This gives a risk of SSAEs of 22.2 percent with ranibizumab and 24 percent with bevacizumab (CI, 20.0-29.1 percent).

    Secondary analysis showed that the only significant difference in systemic safety between the drugs was an increased risk of gastrointestinal disorders for patients treated with bevacizumab. The difference was small (1.3 percent higher with bevacizumab) and not attributable to any specific gastrointestinal disorder.

    Limitations. The authors rated the quality of the evidence as “low to moderate” due to study limitations such as heterogeneity between study populations and dosing regimens. Although no significant safety differences were detected between the drugs, the study could not definitely rule out the possibility that either treatment is less harmful than the other. Finally, they said that the conclusions should be verified once the unpublished results of three of the included studies are available.

    —Mary Wade 

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    1 Moja L et al. Cochrane Database Syst Rev. 2014(9). doi:10.1002/14651858.CD011230.pub2.

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    Dr. Kwag reports no related financial interests.

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