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Howard Snow, Natasha Singh, Soumil Parikh, Steven Francom, Cornelia Dunger-Baldauf, Zdenka Haskova, Philippe Margaron, Anthony P Adamis; Cardiovascular and cerebrovascular safety of ranibizumab (RBZ) in diabetic macular edema (DME): A comprehensive patient-level meta-analysis at month 12. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1506.
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Nguyen-Khoa et al reported that the rates of hospitalized cerebrovascular accidents and myocardial infarctions (MI) in patients with DME were 2.0 and 2.5 times higher than the rates in age- and gender-matched diabetic controls, respectively (BMC Ophthalmology 2012 12:11). Knowing that DME patients are vulnerable to systemic vascular safety events, and to better understand other 12-month published datasets, including the recently available DRCR.net Protocol T report, we conducted this 12-month analysis of cardiovascular and cerebrovascular safety of RBZ using a large pooled database from Novartis and Genentech conducted studies in DME with patient-level data and sham and/or laser controls.
This safety data meta-analysis of the initial 12 months’ study exposure included 6 controlled Phase III DME clinical trials (1767 total patients, 1186 RBZ treated patients) with pairwise comparisons of 0.3 mg RBZ vs control (sham) and 0.5 mg RBZ vs control (sham or laser). MedDRA-based safety events were examined including cerebrovascular and cardiovascular events. Additionally, Antiplatelet Trialists’ Collaboration (APTC) events, vascular deaths, and “Any Cardiovascular Event” (as defined by DRCR.net +/- hypertension) were evaluated.
At Month 12, MedDRA-based analyses of cerebrovascular/cardiovascular events revealed minimal or no differences in the pairwise comparisons of RBZ 0.3 mg vs control and RBZ 0.5 mg vs control (stroke without transient ischemic attack [TIA]: 0.8% vs 1.2%; 1.0% vs 0.9%; stroke with TIA: 1.2% vs 2.4%, 1.1% vs 1.4%; and MI: 3.2% vs 2.4%, 1.3% vs 1.4%; respectively). Minimal differences were also observed for APTC events: 4.4% vs. 3.6%, 2.2% vs 2.4%; for vascular death: 0.4% vs 0.4%, 0.4% vs 0.3%; and for “Any Cardiovascular Event” with hypertension (22.4% vs 20.7%, 16.0% vs 16.0%) and without hypertension (12.0% vs 12.4%, 9.4% vs 8.8%).
In this comprehensive meta-analysis of safety data from 1767 patients, there were no meaningful differences in cardiovascular/cerebrovascular safety for 0.3 mg and 0.5 mg RBZ doses compared with control patients who did not receive any anti-VEGF agent. This includes ATPC events, and the “Any Cardiovascular Event” endpoint used in DRCR.net Protocol T. The safety data from these 6 controlled phase 3 trials are consistent with the established safety profile of RBZ.
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