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. 2019 Nov 1;137(11):1256-1264.
doi: 10.1001/jamaophthalmol.2019.3305.

Clinical Effectiveness of Intravitreal Therapy With Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema Secondary to Central Retinal Vein Occlusion: A Randomized Clinical Trial

Philip Hykin  1 , A Toby Prevost  2 , Joana C Vasconcelos  2 , Caroline Murphy  3 , Joanna Kelly  3 , Jayashree Ramu  1 , Barry Hounsome  3 , Yit Yang  4 , Simon P Harding  5 , Andrew Lotery  6 , Usha Chakravarthy  7 , Sobha Sivaprasad  1 ; LEAVO Study Group
Affiliations

Clinical Effectiveness of Intravitreal Therapy With Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema Secondary to Central Retinal Vein Occlusion: A Randomized Clinical Trial

Philip Hykin et al. JAMA Ophthalmol. .

Abstract

Importance: The comparative clinical effectiveness of ranibizumab, aflibercept, and bevacizumab for the management of macular edema due to central retinal vein occlusion (CRVO) is unclear.

Objective: To determine whether intravitreal aflibercept or bevacizumab compared with ranibizumab results in a noninferior mean change in vision at 100 weeks for eyes with CRVO-related macular edema.

Design, setting, and participants: This prospective, 3-arm, double-masked, randomized noninferiority trial (Lucentis, Eylea, Avastin in Vein Occlusion [LEAVO] Study) took place from December 12, 2014, through December 16, 2016, at 44 UK National Health Service ophthalmology departments. Inclusion criteria included age 18 years or older, visual impairment due to CRVO-related macular edema of less than 12 months with best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent) in the study eye between 19 (20/400) and 78 (20/32), and spectral domain optical coherence tomography imaging central subfield thickness of 320 μm or greater. Data were analyzed from March 4, 2019, to April 26, 2019.

Interventions: Participants were randomized (1:1:1) to receive repeated intravitreal injections of ranibizumab (0.5 mg/0.05 mL) (n = 155), aflibercept (2.0 mg/0.05 mL) (n = 154), or bevacizumab (1.25 mg/0.05 mL) (n = 154) for 100 weeks.

Main outcomes and measures: Adjusted mean change in BCVA in the study eye at 100 weeks wherein noninferiority was concluded if the lower bounds of the 95% CI of both the intention-to-treat and the per protocol analyses were above -5 letters.

Results: Of 463 participants, 265 (57.2%) were male, with a mean (SD) age of 69.1 (13.0) years. The mean (SD) gain in BCVA letter score was 12.5 (21.1) for ranibizumab, 15.1 (18.7) for aflibercept, and 9.8 (21.4) for bevacizumab at 100 weeks. Aflibercept was noninferior to ranibizumab (intention-to-treat-adjusted mean BCVA difference, 2.23 letters; 95% CI, -2.17 to 6.63 letters; P < .001). Bevacizumab was not noninferior to ranibizumab (intention-to-treat-adjusted mean BCVA difference, -1.73 letters; 95% CI, -6.12 to 2.67 letters; P = .07). The per protocol analysis conclusions were similar. Fewer mean injections were given in the aflibercept group (10.0) than in the ranibizumab (11.8) group (mean difference at 100 weeks, -1.9; 95% CI, -2.9 to -0.8).

Conclusions and relevance: Mean changes in vision after treatment of macular edema due to CRVO were no worse using aflibercept compared with ranibizumab. Mean changes in vision using bevacizumab compared with ranibizumab were inconclusive regarding vision outcomes (ie, the change in visual acuity from baseline, on average, may be worse or may not be worse when using bevacizumab compared with ranibizumab).

Trial registration: ISRCTN13623634.

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Conflict of interest statement

Conflict of Interest Disclosures: Mr Hykin reported receiving research grants from Novartis Allergan and Bayer, travel grants from Novartis Allergan and Bayer, speaker fees from Novartis Allergan and Bayer, and attending advisory board meetings for Novartis, Bayer, and Allergan. Dr Sivaprasad reported receiving research grants from Novartis, Bayer, Allergan, Roche, Boehringer Ingelheim, and Optos Plc, travel grants from Novartis and Bayer, speaker fees from Novartis, Bayer, and Optos Plc, and attending advisory board meetings for Novartis, Bayer, Allergan, Roche, Boehringer Ingelheim, Optos Plc, and Heidelberg Engineering. Dr Hounsome reported receiving a grant from the National Institute for Health Research (NIHR) and was paid by the Kings Clinical Trials Unit with a portion of the LEAVO study NIHR grant. Dr Yang reported receiving research grants from Novartis, Bayer, Allergan, and Roche, travel grants from Novartis, Bayer, Allergan and Roche, speaker fees from Novartis, Bayer, Allergan, and Roche, and attending advisory board meetings for Novartis, Bayer, Allergan, and Roche. Dr Chakravathy reported receiving research grants from the NIHR, Allergan, and Novartis. Dr Harding reported receiving research grants from NIHR and Roche. Dr Lotery reported receiving travel grants from Novartis, Bayer, and Allergan, speaker fees from Novartis, Bayer, and Allergan, and attending advisory board meetings for Novartis, Bayer and Allergan. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram for the LEAVO Trial
ITT indicates intention-to-treat; LEAVO trial, Lucentis, Eylea, Avastin in Vein Occlusion trial; PP, per protocol. aModels include all participants who have had at least 1 follow-up milestone visit.
Figure 2.
Figure 2.. Adjusted Mean Best-Corrected Visual Acuity Letter Score and Adjusted Mean Optical Coherence Tomography (OCT) Central Subfield Thickness Across Groups to 100 Weeks
A, Adjusted mean difference between groups at 100 weeks: aflibercept vs ranibizumab, –29.3 (95% CI, –60.9 to 2.3); bevacizumab vs ranibizumab, –21.9 (95% CI, –9.7 to 53.4). B, Adjusted mean difference between groups at 100 weeks: aflibercept vs ranibizumab, –29.3 (95% CI, –60.9 to 2.3); bevacizumab vs ranibizumab, 21.9 (95% CI, –9.7 to 53.4).
Figure 3.
Figure 3.. Forest Plot of the Primary Outcome Intention-to-Treat (ITT) and Per Protocol (PP) Analyses
BCVA indicates best-corrected visual acuity.
Figure 4.
Figure 4.. Mean Number of Injections Across Treatment Groups by Week
Markers indicate means and whiskers, 95% CIs.
See this image and copyright information in PMC

References

    1. Rogers S, McIntosh RL, Cheung N, et al. ; International Eye Disease Consortium . The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-319.e1. doi:10.1016/j.ophtha.2009.07.017 - DOI - PMC - PubMed
    1. Ponto KA, Elbaz H, Peto T, et al. . Prevalence and risk factors of retinal vein occlusion: the Gutenberg Health Study. J Thromb Haemost. 2015;13(7):1254-1263. doi:10.1111/jth.12982 - DOI - PubMed
    1. Campochiaro PA, Brown DM, Awh CC, et al. . Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10):2041-2049. doi:10.1016/j.ophtha.2011.02.038 - DOI - PubMed
    1. Brown DM, Heier JS, Clark WL, et al. . Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-437.e7. doi:10.1016/j.ajo.2012.09.026 - DOI - PubMed
    1. Korobelnik JF, Holz FG, Roider J, et al. ; GALILEO Study Group . Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology. 2014;121(1):202-208. doi:10.1016/j.ophtha.2013.08.012 - DOI - PubMed