• Retinal Diseases Ophthalmology Clinical Trials
• Diabetes Mellitus

• Retinal Diseases
• Ophthalmology
• Ophthalmology Clinical Trials
• Diabetes Mellitus

Marco Zarbin, MD, PhD, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA, described a post hoc analysis of 5 studies of the humanized monoclonal antibody ranibizumab directed against vascular endothelial growth factor (VEGF)-A in the treatment of diabetic macular edema (DME) [Gaudreault J et al. Retina. 2007]. The analysis focused on the arterial thromboembolic events (ATEs) associated with ranibizumab that have been reported in controlled clinical trials.

VEGF suppression in patients with cancer increases the risk of hypertension and ATEs [Semeraro F et al. Expert Opin Drug Saf. 2014], but the situation is less clear in patients being treated for DME. The analysis looked at the long-term incidence (up to 3 years) of ATEs in patients with DME who were receiving ranibizumab.

Data from 5 studies collectively involving 881 patients were pooled and analyzed. The 1-year RESOLVE study used 0.3, 0.5, 0.6, and 1.0 mg ranibizumab PRN [Massin P et al. Diabetes Care. 2010]. The remaining studies—the 1-year RESTORE and REVEAL studies [Mitchell P et al. Ophthalmology. 2011], the 2-year RESTORE extension study [Lang GE et al. Ophthalmology. 2013], the 2-year RETAIN study [NCT01183468], and the 3-year RESTORE extension study [Schmidt-Erfurth U et al. Ophthalmology. 2014]—used ranibizumab 0.5 mg PRN.

The baseline characteristics—age, sex, ethnicity, hemoglobin A_1c, and duration of diabetes—across the 5 trials were similar after exclusion of patients with prior ATEs.

In the RESOLVE, RESTORE, and REVEAL trials, the 1-year incidence of ATEs was similar in the ranibizumab arm (2.9%; n = 350 in the treatment arm) and in the control arm (3.8%; n = 287 in the sham/laser arm). The annualized proportion of nonmyocardial ATEs in ranibizumab-treated patients was 1.7% annually at 1 year, 2.8% annually at 2 years (RESTORE extension and RETAIN trials), and 1.6% annually at 3 years (RESTORE extension trial). The annualized rate of myocardial infarction was 1.7%, 0.6%, and 0.0% annually at 1, 2, and 3 years, respectively. The incidence of vascular death in patients receiving ranibizumab 0.5 mg was similar to controls, and was comparable in patients treated for 2 or 3 years.

The analysis has several limitations. The 5 studies were not powered to detect differences in safety events. Data are also insufficient on the use of anti-VEGF drugs in patients at high risk of DME, which reflects a tendency to exclude patients that are predisposed to treatment complications. For example, data on file with Novartis indicate that 3.4% of the patients in DME trials treated with ranibizumab 0.5 mg had experienced a prior stroke or transient ischemic attack. More knowledge on the patients who are at greater risk of complications is warranted.

Such real-world evidence will be forthcoming in the LUMINOUS study [NCT01318941] being coordinated by Novartis, which has enrolled 30 000 patients at approximately 500 sites from > 40 countries globally. The prospective 5-year observational study will evaluate the long-term safety and efficacy of ranibizumab in real-world clinical practice.

For now, there is no evidence to suggest any difference in safety between ranibizumab 0.5 mg and the control (sham/laser) in the 5 studies.

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