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Meta-Analysis
. 2014 Sep 15;9(9):CD011230.
doi: 10.1002/14651858.CD011230.pub2.

Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration

Lorenzo Moja  1 , Ersilia Lucenteforte, Koren H Kwag, Vittorio Bertele, Annalisa Campomori, Usha Chakravarthy, Roberto D'Amico, Kay Dickersin, Laurent Kodjikian, Kristina Lindsley, Yoon Loke, Maureen Maguire, Daniel F Martin, Alessandro Mugelli, Bernd Mühlbauer, Isabel Püntmann, Barnaby Reeves, Chris Rogers, Christine Schmucker, Manju L Subramanian, Gianni Virgili
Affiliations
Meta-Analysis

Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration

Lorenzo Moja et al. Cochrane Database Syst Rev. .

Abstract

Background: Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD.

Objectives: To assess the systemic safety of intravitreal bevacizumab (brand name Avastin®; Genentech/Roche) compared with intravitreal ranibizumab (brand name Lucentis®; Novartis/Genentech) in people with neovascular AMD. Primary outcomes were death and All serious systemic adverse events (All SSAEs), the latter as a composite outcome in accordance with the International Conference on Harmonisation Good Clinical Practice. Secondary outcomes examined specific SSAEs: fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections, and events grouped in some Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC). We assessed the safety at the longest available follow-up to a maximum of two years.

Search methods: We searched CENTRAL, MEDLINE, EMBASE and other online databases up to 27 March 2014. We also searched abstracts and clinical study presentations at meetings, trial registries, and contacted authors of included studies when we had questions.

Selection criteria: Randomised controlled trials (RCTs) directly comparing intravitreal bevacizumab (1.25 mg) and ranibizumab (0.5 mg) in people with neovascular AMD, regardless of publication status, drug dose, treatment regimen, or follow-up length, and whether the SSAEs of interest were reported in the trial report.

Data collection and analysis: Two authors independently selected studies and assessed the risk of bias for each study. Three authors independently extracted data.We conducted random-effects meta-analyses for the primary and secondary outcomes. We planned a pre-specified analysis to explore deaths and All SSAEs at the one-year follow-up.

Main results: We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision.At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%).For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%).For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants).Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review.Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%).The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab.

Authors' conclusions: This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.

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Conflict of interest statement

DECLARATIONS OF INTEREST

Some of the review authors are trial investigators on the studies included in this review.

Figures

Analysis 1.1
Analysis 1.1
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 1 All-cause death.
Analysis 1.2
Analysis 1.2
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 2 All serious systemic adverse events.
Analysis 1.3
Analysis 1.3
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 3 Arterial thromboembolic event.
Analysis 1.4
Analysis 1.4
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 4 Gastrointestinal perforation.
Analysis 1.5
Analysis 1.5
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 5 Infection.
Analysis 1.6
Analysis 1.6
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 6 Myocardial infarction.
Analysis 1.7
Analysis 1.7
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 7 Neutropenia.
Analysis 1.8
Analysis 1.8
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 8 Non-ocular haemorrhage.
Analysis 1.9
Analysis 1.9
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 9 Stroke.
Analysis 1.11
Analysis 1.11
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 11 Vascular events associated with anti-VEGF treatment.
Analysis 1.12
Analysis 1.12
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 12 Cardiac disorders MedDRA Class.
Analysis 1.13
Analysis 1.13
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 13 Gastrointestinal disorders MedDRA Class.
Analysis 1.14
Analysis 1.14
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 14 General disorders and administration site conditions MedDRA Class.
Analysis 1.15
Analysis 1.15
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 15 Neoplasms benign, malignant, and unspecified MedDRA Class.
Analysis 1.16
Analysis 1.16
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 16 Nervous system disorders MedDRA Class.
Analysis 1.17
Analysis 1.17
Comparison 1 Bevacizumab versus ranibizumab, longest follow-up, Outcome 17 Respiratory, thoracic, and mediastinal disorders MedDRA Class.
Analysis 2.1
Analysis 2.1
Comparison 2 Bevacizumab versus ranibizumab, one-year of follow-up, primary outcomes, Outcome 1 All-cause death.
Analysis 2.2
Analysis 2.2
Comparison 2 Bevacizumab versus ranibizumab, one-year of follow-up, primary outcomes, Outcome 2 All serious systemic adverse events.
Analysis 3.1
Analysis 3.1
Comparison 3 Bevacizumab versus ranibizumab, influence analysis: all SSAEs excluding CATT, Outcome 1 All serious systemic adverse events.
Analysis 4.1
Analysis 4.1
Comparison 4 Bevacizumab versus ranibizumab, influence analysis: all SSAEs excluding LUCAS, Outcome 1 All serious systemic adverse events.
Analysis 5.1
Analysis 5.1
Comparison 5 Bevacizumab versus ranibizumab, influence analysis: primary outcomes excluding unpublished studies, Outcome 1 All-cause death.
Analysis 5.2
Analysis 5.2
Comparison 5 Bevacizumab versus ranibizumab, influence analysis: primary outcomes excluding unpublished studies, Outcome 2 All serious systemic adverse events.
Analysis 6.1
Analysis 6.1
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 1 All-cause death.
Analysis 6.2
Analysis 6.2
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 2 All serious systemic adverse events.
Analysis 6.3
Analysis 6.3
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 3 Arterial thromboembolic event.
Analysis 6.4
Analysis 6.4
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 4 Gastrointestinal perforation.
Analysis 6.5
Analysis 6.5
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 5 Infections.
Analysis 6.6
Analysis 6.6
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 6 Myocardial infarction.
Analysis 6.7
Analysis 6.7
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 7 Neutropenia.
Analysis 6.8
Analysis 6.8
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 8 Non-ocular haemorrhage.
Analysis 6.9
Analysis 6.9
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 9 Stroke.
Analysis 6.11
Analysis 6.11
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 11 Vascular events associated with anti-VEGF treatment.
Analysis 6.12
Analysis 6.12
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 12 Cardiac disorders MedDRA Class.
Analysis 6.13
Analysis 6.13
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 13 Gastrointestinal disorders MedDRA Class.
Analysis 6.14
Analysis 6.14
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 14 General disorders and administration site conditions MedDRA Class.
Analysis 6.15
Analysis 6.15
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 15 Neoplasms benign, malignant, and unspecified MedDRA Class.
Analysis 6.16
Analysis 6.16
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 16 Nervous system disorders MedDRA Class.
Analysis 6.17
Analysis 6.17
Comparison 6 Bevacizumab versus ranibizumab, secondary analysis: fixed-effect analyses, Outcome 17 Respiratory, thoracic, and mediastinal disorders MedDRA Class.
Figure 1
Figure 1
Study flow diagram for screened, included, and excluded study reports
Figure 2
Figure 2
’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study.
Figure 3
Figure 3
Forest plot of comparison: 1 Bevacizumab versus ranibizumab, primary analysis at longest follow-up, outcome: 1.1 All-cause death.
Figure 4
Figure 4
Forest plot of comparison: 1 Bevacizumab versus ranibizumab, longest follow-up, outcome: 1.2 All serious systemic adverse events.
See this image and copyright information in PMC

References

References to studies included in this review

    1. Biswas P, Sengupta S, Choudhary R, Home S, Paul A, Sinha S. Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration. Indian Journal of Ophthalmology. 2011;59(3):191–6. - PMC - PubMed
    1. Schauwvlieghe A-SM, Dijkman G, Hooymans JM, Verbraak FD, Dijkgraaf MG, Peto T, et al. Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. BRAMD. Investigative Ophthalmology and Visual Science. 2014;55 ARVO E-Abstract 870. - PMC - PubMed
    1. Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–98. - PMC - PubMed
    2. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. New England Journal of Medicine. 2011;364(20):1897–908. - PMC - PubMed
    1. Kodjikian L, Souied EH, Mimoun G, Mauget-Faysse M, Behar-Cohen F, Decullier E, et al. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120(11):2300–9. - PubMed
    1. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258–67. - PubMed
    2. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399–411. - PubMed

Additional references

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    1. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. British Journal of Ophthalmology. 2014 Jul 7; Epub ahead of print. - PMC - PubMed
    1. Bassler D, Montori VM, Briel M, Glasziou P, Walter SD, Ramsay T, et al. Reflections on meta-analyses involving trials stopped early for benefit: is there a problem and if so, what is it? Statistical Methods in Medical Research. 2013;22(2):159–68. - PubMed
    1. Bosco JL, Silliman RA, Thwin SS, Geiger AM, Buist DS, Prout MN, et al. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. Journal of Clinical Epidemiology. 2010;63(1):64–74. - PMC - PubMed
    1. Braithwaite T, Nanji AA, Lindsley K, Greenberg PB. Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion. Cochrane Database of Systematic Reviews. 2014;(5) doi: 10.1002/14651858.CD007325.pub3. - DOI - PMC - PubMed

References to other published versions of this review

    1. Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews. 2014;(7) doi: 10.1002/14651858.CD011230. - DOI - PMC - PubMed

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