Elsevier

Ophthalmology

Volume 119, Issue 7, July 2012, Pages 1399-1411
Ophthalmology

Original article
Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial

https://doi.org/10.1016/j.ophtha.2012.04.015Get rights and content

Purpose

To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD).

Design

Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560).

Participants

People >50 years of age with untreated nAMD in the study eye who read ≥25 letters on the Early Treatment Diabetic Retinopathy Study chart.

Methods

We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review.

Main Outcome Measures

The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs.

Results

Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab −1.99 letters, 95% confidence interval [CI], −4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous −0.35 letters; 95% CI, −2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001).

Conclusions

The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.

Financial Disclosure(s)

Proprietary or commercial disclosures may be found after the references.

Section snippets

Study Design, Participants, and Setting

The IVAN is a multicenter, factorial, noninferiority, randomized trial with equal allocation to each of 4 groups formed by all permutations of 2 drugs and 2 treatment regimens. Allocation to drug was masked. Allocation to treatment regimen was not masked. Further details are described in the protocol (Appendix 2, available at http://aaojournal.org).

Adults ≥50 years old with previously untreated nAMD in the study eye and best corrected visual acuity ≥25 letters on the Early Treatment Diabetic

Participants and Treatment

Between March 27, 2008, and October 15, 2010, we randomized 628 participants; 18 were withdrawn before receiving the first treatment, leaving 610 who were treated and included in analyses (Fig 1). Participants' characteristics at baseline were similar across the groups (Table 1). Nine participants were ineligible. One read <25 letters; 8 failed the independent graded angiographic eligibility criteria, although 2 had fluid on OCT suggesting an active lesion.

Regarding adequacy of masking,

Discussion

One year after randomization in the IVAN trial, the visual acuity comparison by drug was inconclusive. The mean difference between the drugs was 2 letters in favor of ranibizumab, a small difference from a clinical perspective. The difference in visual acuity between continuous and discontinuous regimens was negligible, showing that the treatment regimens were equivalent.

There were no significant differences between drugs or regimens for secondary measures of visual function or generic quality

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    Manuscript no. 2012-496.

    The IVAN study investigators are listed online (available at http://aaojournal.org).

    Financial Disclosure(s): The authors have made the following disclosures:

    Usha Chakravarthy, Principal Investigator, trials sponsored by Novartis, the manufacturers of ranibizumab, and attendance at advisory boards for Allergan, Bausch & Lomb, and Bayer; Andrew J. Lotery, Principal Investigator, trials sponsored by Novartis, the manufacturers of ranibizumab; Honoraria, Novartis; Attended Advisory Board Meetings, Novartis, Bayer. Simon P. Harding, Principal Investigator, trials sponsored by Novartis, the manufacturers of ranibizumab; Susan M. Downes, Honoraria, Novartis.

    The Queen's University of Belfast and the Belfast Trust, the University of Southampton, the University Hospital Southampton NHS Foundation Trust, and Oxford University Hospital have received payments from Novartis.

    This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) program (project number 07/36/01). The trial was designed, conducted, analyzed, and interpreted independently of the funding sources. The writing committee had full access to the data and is responsible for submitting the publication. The views and opinions expressed are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, the UK National Health Service or the Department of Health.

    Group members listed online in Appendix 1 (available at http://aaojournal.org).

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