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Evidence for anti-VEGF agent risk rates not significant at present
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COPENHAGEN — At present, there are not sufficient data to prove that any of the three anti-VEGF agents used to treat wet age-related macular degeneration has a higher risk of systemic side effects, according to a speaker. More evidence from clinical trials is needed.
Tien Y. Wong, MD, PhD, began his presentation at the meeting of the European Society of Ophthalmology with two introductory remarks. First, there are pharmacological differences in the molecules themselves, which raises the question of whether this leads to differences in safety. Second, people with AMD are at a higher risk for cardiovascular diseases compared with the normal population.
“This makes the issue of safety even more crucial,” he said.
Three clinical trials — CATT, IVAN and GEFAL — recently compared the safety of Lucentis (ranibizumab, Genentech/Novartis) and Avastin (bevacizumab, Genentech/Roche). Although a higher proportion of systemic adverse events were found with bevacizumab compared with ranibizumab in the CATT and IVAN trials, significance was not strong enough to draw conclusions, according to Wong.
“This is reassuring for those of us who use different agents in their settings,” he said.
Agents and dosing regimens
The HARBOR study on ranibizumab also showed that different dosing regimens have no impact on risk rate.
“You would expect that seven to eight injections might lead to a lower rate of events than 12, but surprisingly the opposite was true. A lower risk rate was found with monthly ranibizumab than with PRN, suggesting that the occurrence of adverse events is not dose-dependent,” Wong said. “One possible explanation is that, instead of the more intuitive dose-dependent link between anti-VEGF treatment and systemic adverse events, perhaps it is fluctuation in serum VEGF levels that is detrimental to vascular health.”
Real-world settings provided additional data. Results of a U.S. Medicare observational analysis that compared photodynamic therapy, pegaptanib, bevacizumab and ranibizumab treatment in 146,942 wet AMD patients showed that individual agents were not significantly different, except for a particular subgroup analysis that compared ranibizumab and bevacizumab.
“The bevacizumab group had higher and significant risk of death and stroke,” Wong said. However, “they were only observational data. There was no matching, and there were many different characteristics between patients in the two groups,” he said.
Other smaller, observational studies suggested a higher risk of events with the same agent.
Manipulation and repackaging
However reassuring this scenario may seem, the potential risks associated with using a therapy off-label should be considered, Wong said.
Ranibizumab and Eyelea (aflibercept, Regeneron) are developed specifically for ocular use, and each vial meets the manufacturing standards required for ophthalmic solutions. Bevacizumab is intended for intravenous administration, and the repackaging into smaller aliquots carries additional risks, including contamination, degradation and instability, according to Wong.
“Clusters of endophthalmitis associated with fractioned bevacizumab have been reported in several countries,” Wong said.
Manipulation and repackaging of the original vial may be factors contributing to the higher risk rate of bevacizumab found in real-world settings.
“The preparation of bevacizumab in trials does not reflect the compounding of the drug in clinical practice, where standards vary with suppliers. So, after all, IVAN and CATT may not provide relevant safety data,” he said.
“We need a larger population and a longer follow-up within clinical trial settings to truly assess the drug-related complications and differences with other agents, particularly for serious but not infrequent adverse events such as stroke or endophthalmitis,” Wong said. – by Michela Cimberle
- For more information:
- Tien Y. Wong, MD, PhD, can be reached at Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Ave., Singapore 168751; +65-63224571; fax: +65-63231903; email: tien_yin_wong@nuhs.edu.sg.
Disclosure: Wong is a consultant to Abbott Medical Optics, Allergan, Bayer, Novartis and Pfizer.