Newer treatments for neovascular age-related macular degeneration are not associated with increased risks of mortality, myocardial infarction, bleeding, or stroke when compared with older therapies, according to a new study in the October 2010 issue of Archives of Ophthalmology.
The Food and Drug Administration approved ranibizumab (Lucentis) for the treatment of neovascular AMD in June 2006. Since 2005, ophthalmologists have used bevacizumab (Avastin), a cancer treatment that has a similar mechanism to ranibizumab, as an off-label treatment for AMD. The relative safety of these treatments, however, was unknown.
With that in mind, Dr. Lesley H. Curtis, Ph.D., and fellow researchers from Duke University in Durham, N.C., conducted a retrospective cohort study of adverse events involving 146,942 Medicare beneficiaries aged 65 years or older whose records they obtained between Jan. 1, 2004, and Dec. 31, 2007 (Arch. Ophthalmol. 2010;128:1273-9).
They identified Medicare patients with a diagnosis of AMD between Jan. 1, 2005, and Dec. 31, 2006, then classified patients into four treatment groups: the control group of 52,256 patients who received photodynamic therapy (PDT), 36,942 who received pegaptanib octasodium (Macugen), 38,718 who received bevacizumab, and 19,026 patients who received ranibizumab.
Specifically, the researchers looked at these AMD therapies and the risks of the following:
–All-cause mortality. Cumulative incidence of all-cause mortality was 4.8% in those who received pegaptanib, 4.1% in both the PDT (control) and the ranibizumab groups, and 4.4% in the bevacizumab group, a statistically significant difference.
– Myocardial infarction. The risk of MI in the PDT and pegaptanib groups (1.3% each) was slightly higher than, but not statistically significant from, the risk in the bevacizumab and ranibizumab groups (1.2% and 1.1%, respectively).
– Bleeding events. Rates were 5.8% for the PDT group, 5.9% for the pegaptanib group, 5.5% for the bevacizumab group, and 5.8% for the ranibizumab group – the differences were not statistically significant.
– Stroke. Rates were 2% each for the photodynamic therapy and pegaptanib groups, 2.1% for the bevacizumab group, and 1.8% for the ranibizumab group – again, not statistically significant.
After adjusting for baseline characteristics and comorbid conditions, the researchers found significantly lower hazards of mortality MI with ranibizumab than with PDT or pegaptanib and a significantly lower risk of MI with ranibizumab vs. PDT. They also found no significant differences in the hazard of mortality or MI between bevacizumab use and other treatments.
The overall tests for differences in bleeding and stroke across treatment groups were not statistically significant.
By the end of the study, clinicians used bevacizumab or ranibizumab as first-line therapy on all neovascular AMD patients. A secondary analysis, limited to new users of bevacizumab or ranibizumab, found significantly lower risk of mortality and stroke with ranibizumab vs. bevacizumab.
Serious adverse systemic effects have not been associated with PDT or pegaptanib in clinical trials, so why did this study find that the risk is lowest with ranibizumab? The researchers dismissed the possibility that recipients of ranibizumab may have been healthier than other subjects or that the risk of thromboembolic events declined over time. They speculated instead that the size of the observed population was great enough to detect rarer adverse reactions, compared with the small study sizes used in authentic clinical trials.
The study was limited in that therapies were not randomly assigned and there were no untreated patients as a control group, the researchers said. Also, the claims data lacked clinical detail about the severity of comorbid conditions and ophthalmologic outcomes.
Dr. Curtis received research support from a number of pharmaceutical and biotechnology companies, including Novartis Pharmaceuticals, LTD (manufacturer of ranibizumab), Genentech (manufacturer of bevacizumab), and Pfizer (manufacturer of pegaptanib). Another investigator serves as an investigator/collaborator for clinical research, grantee and paid scientific adviser/consultant for Genentech and Eyetech. This study was supported by a research agreement between OSI Eyetech and Duke University.