Study: Cardiovascular risk not affected by AMD therapies

Treatment of age-related macular degeneration using either bevacizumab or ranibizumab may not be associated with increased risks for myocardial infarction, bleeding, stroke or mortality, according to a study.

The retrospective study categorized 146,942 Medicare beneficiaries who submitted a claim for AMD between Jan. 1, 2005, and Dec. 31, 2006, into four groups based on initial treatment. If a patient switched to a different therapy at any point during the study, all data on the patient from that point forward was censored.

The control group included those who received photodynamic therapy, while the remaining three groups consisted of patients who received intravitreous Macugen (pegaptanib, Eyetech/Pfizer), Avastin (bevacizumab, Genentech) or Lucentis (ranibizumab, Genentech).

“Because we show that the therapies are all relatively safe, our findings should allay concerns that some drugs for [AMD] increase patients’ risk for myocardial infarction, bleeding, stroke and death,” Lesley H. Curtis, PhD, an author of the study, said in an e-mail interview with Ocular Surgery News.

In addition to assessing AMD therapy risks, the study also analyzed associations among the four treatments. Earlier clinical trials sought to determine the safety of individual treatments, but the comparative safety of PDT, intravitreous pegaptanib, bevacizumab and ranibizumab was not previously analyzed, the study authors wrote.

Secondary analyses

Primary data analysis was done after adjustment for baseline characteristics and comorbid conditions. Dr. Curtis and colleagues also ran two secondary analyses to account for confounding factors that became evident as the study progressed.

In one secondary analysis, the study population was limited to new users of bevacizumab or ranibizumab who began treatment between July and December 2006. This analysis accounted for the fact that, by the end of the study, almost all newly treated patients were prescribed one of these two drugs.

The second of these analyses accounted for a potential selection bias among patients who received ranibizumab; patients with a higher socioeconomic status may have been more likely to receive ranibizumab, the more expensive of the two drugs.

“We suspect that recipients of ranibizumab may have been healthier in ways that we cannot measure in claims data,” Dr. Curtis said. “The cost difference between ranibizumab and bevacizumab would suggest that patients of higher socioeconomic status, often associated with better overall health, were more likely to receive ranibizumab.”

Consequently, in this secondary analysis, Dr. Curtis and colleagues only included patients who received bevacizumab or ranibizumab in a medical practice that prescribed a single drug exclusively.

Results

In addition to finding that neither bevacizumab nor ranibizumab was associated with a statistically significant increase in cardiovascular risk, the study suggests that the risk for systemic adverse events was lower with ranibizumab. Percentage of all-cause deaths in the group treated with ranibizumab was lower than in the groups treated with PDT or pegaptanib. Myocardial infarction was also less common in patients treated with ranibizumab compared with those in the PDT control group.

No statistically significant difference was found between bevacizumab and other therapies in terms of risks for mortality and myocardial infarction, and the incidence of bleeding or stroke was not statistically different for any one AMD therapy.

Dr. Curtis said that the lower incidence of risk associated with ranibizumab may be attributed to the healthier state of those who can afford to purchase the drug.

“The second sensitivity analysis of ‘exclusive’ providers lends some support to this explanation but needs to be replicated,” she said.

For those patients whose medical practitioners used either drug exclusively, risks of mortality, myocardial infarction and stroke did not differ across treatment groups, meaning that ranibizumab was not associated with a lower risk for these adverse events. However, the small sample size for this secondary analysis downplays the validity of such findings and, according to Dr. Curtis, encourages further research.

“We are also eager to understand how anti-VEGF therapies are used in clinical practice (eg, timing and frequency) and to show that the drugs are safe across various high-risk groups,” she said. – by Michelle Pagnani

Reference:

• Curtis LH, et al. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128(10):1273-1279.

• Lesley H. Curtis, PhD, can be reached at the Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715; 919-668-8101; e-mail: lesley.curtis@duke.edu.
• Disclosure: The work was funded through a research contract from OSI Eyetech. Dr. Curtis reports research or other support from Allergan, Eli Lilly, GlaxoSmithKline, Medtronic, Merck, Johnson & Johnson, Novartis, OSI Eyetech, Pfizer and Sanofi-Aventis.

The study authors found that the risk of all-cause mortality was approximately 15% lower with ranibizumab than with either photodynamic therapy or pegaptanib, and that the risk of myocardial infarction was approximately 25% lower with ranibizumab compared with photodynamic therapy. It should be noted, however, that the size of the data set drove much of the statistical significance and that both the event rates and the absolute differences reported for all-cause mortality and myocardial infarction were small. Moreover, the authors failed to provide a compelling explanation for why ranibizumab should be associated with fewer myocardial infarctions and deaths. That being said, these results are important, because they demonstrate that the risk of cardiovascular adverse events or death in patients with neovascular AMD is low and similar, regardless of whether photodynamic therapy or an anti-VEGF agent is used, at least for the first year following treatment. It would appear, therefore, that the choice of therapy should be driven primarily by anticipated efficacy and individual patient tolerability.

– Emmett T. Cunningham Jr., MD, PhD, MPH
OSN Retina/Vitreous Board Member
Disclosure:Dr.Cunningham has no relevant financial disclosures.