Purpose: To analyze cerebrovascular accidents (CVAs) pooled from large, randomized, controlled clinical trials of ranibizumab treatment for neovascular age-related macular degeneration.
Methods: Events in five trials (FOCUS, MARINA, ANCHOR, PIER, and SAILOR) were analyzed using a standard safety monitoring process. Exact methods, stratified by study, were used to test for treatment differences based on odds ratios. A stepwise logistic regression model was fit to classify subjects' risk for CVA based on medical history. Treatment differences in CVA rates at 1 year or 2 years were evaluated within risk groups using stratified exact methods.
Results: Pooled 2-year CVA rates were <3%; odds ratios (95% confidence intervals) for CVA risk were 1.2 (0.4–4.4) for ranibizumab 0.3-mg versus control, 2.2 (0.8–7.1) for 0.5 mg versus control, and 1.5 (0.8–3.0) for 0.5-mg versus 0.3-mg ranibizumab. No substantial increased risk of CVA for 0.5 mg versus 0.3 mg was identified in pooled analyses or any of the individual trials. In pooled analyses, the difference between 0.5-mg ranibizumab and control was larger (7.7 [1.2–177]) among high-risk CVA patients.
Conclusion: This analysis provided some evidence, although not definitive, of a potential increased risk of CVA with ranibizumab versus control or with 0.5-mg versus 0.3-mg ranibizumab. Continued monitoring for CVA within clinical trials seems warrented.
This analysis provided some evidence, although not definitive, of a potential increased risk of cerebrovascular accident with ranibizumab versus control or with 0.5-mg versus 0.3-mg ranibizumab. Continued monitoring for cerebrovascular accident within clinical trials seems warranted.
*Retina Division, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland
†Retina-Vitreous Associates Medical Group, Los Angeles, California
‡VitreoRetinal Surgery, PA, Minneapolis, Minnesota
§Genentech, South San Francisco, California.
Reprint requests: Neil M. Bressler, MD, Retina Division, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine and Hospital, Maumenee 752, 600 North, Wolfe Street, Baltimore, MD 21287; e-mail: firstname.lastname@example.org
Supported financially by Genentech, Inc., South San Francisco, CA. Dr. N. M. Bressler's employer, Department of Ophthalmology, the Johns Hopkins University (JHU) but Dr. N. M. Bressler does not receive funding from Allergan, Bausch & Lomb, Carl Zeiss Meditec, Genentech, Notal Vision, Inc., Novartis, Othera, QLT, Regeneron, and Steba Pharmaceuticals for sponsored projects in which he is an investigator. He receives salary support for these sponsored projects; the terms of these projects are negotiated and administered by JHU's Office of Research Administration. Under JHU's policy, support for the costs of research, administered by the institution, does not constitute a conflict of interest. Dr. D. S. Boyer has been a consultant to Alcon, Allergan, Genentech, Novartis, QLT, Regeneron, and Pfizer, and he has been a speaker for Alcon, Genentech, Novartis, and Pfizer. Dr. D. F. Williams has provided consulting services to Genentech. Drs. S. Butler, S. F. Francom, B. Brown, F. Di Nucci, T. Cramm, L. L. Tuomi, T. Ianchulev, and R. G. Rubio are employees of Genentech. The studies analyzed for this report were cosponsored by Genentech, Inc, South San Francisco, CA, and Novartis Pharma, A.G., Basel, Switzerland.
Presented at 2008 American Academy of Ophthalmology Annual Meeting Retina Subspecialty Day, Atlanta, Georgia, November 7–8, 2008. “Meta-Analysis of APTC Events in Key Phase II and III Studies With Ranibizumab in Wet AMD.” D. S. Boyer (Presenter).
The authors declare no conflict of interest.
The design and conduct of this study, as well as the data collection, management, and analysis and interpretation of the data, were supported by Genentech, Inc. Writing assistance, but not editorial content sufficient to meet ICMJE authorship criteria, was provided by Genentech, Inc. Dr. N. M. Bressler, as corresponding author, and per JHU policy, had complete access to all data of this article and complete control over editorial content.
The FOCUS, MARINA, ANCHOR, and SAILOR Research Group members who contributed data for the patients enrolled in these clinical trials have been listed elsewhere.