Macular Degeneration: Treatments Have Similar Efficacy

Damian McNamara

July 26, 2013

The 2-year results from a randomized controlled trial comparing the efficacy of bevacizumab (Avastin, Genentech/Roche) and ranibizumab (Lucentis, Genentech/Novartis) in patients with neovascular age-related macular degeneration are definitive, according to the researchers involved.

"In my view the drugs are interchangeable," Usha Chakravarthy, PhD, from the Institute of Clinical Science at the Queen's University of Belfast, United Kingdom, told Medscape Medical News. Dr. Chakravarthy is lead author of the Inhibition of VEGF in Age-related choroidal Neovascularization (IVAN) 2-year results, published online July 19 in the Lancet.

"On the question of effectiveness over the 2-year period when the drugs are given every month, there is no doubt in my mind that the 2 drugs have similar efficacy," Dr. Chakravarthy added. "We looked at best corrected acuity, which all other trials have used, and in addition we examined near acuity, reading speed, and contrast sensitivity. Even these more global measures of macular function were no different between drugs."

However, not everyone finds the evidence sufficient to spur clinicians to universally choose bevacizumab over the US Food and Drug Administration–approved ranibizumab to treat neovascular or "wet" age-related macular degeneration.

"For best corrected distance visual acuity — the primary outcome — bevacizumab was neither non-inferior nor inferior to ranibizumab," Chui Ming Gemmy Cheung, FRCOphth, and Tien Y. Wong, MD, PhD, from the Singapore Eye Research Institute, Singapore National Eye Centre; the Department of Ophthalmology, National University of Singapore; and the Eye Academic Clinical Program, Duke-National University of Singapore Graduate Medical School, note in an accompanying comment. They note the mean difference of visual acuity favored ranibizumab by only −1.37 letters (95% confidence interval [CI], −3.75 to 1.01), which is well within the prespecified noninferiority limit of 3.5 letters."

However, Dr. Cheung and Dr. Wong also note that potential safety concerns warrant further study. Although the IVAN results reveal no significant difference in frequency of death (odds ratio, 0.96; 95% CI, 0.46 - 2.02) or of an arterial thrombotic event or hospital admission for heart failure (OR, 1.69; 95% CI, 0.80 - 3.57) between agents, concerns arose when data were combined with the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) findings. "[M]ore serious adverse events were reported in the bevacizumab group than the ranibizumab group" the commentators write in reference to the combined data.

"Thus, the ultimate importance of the IVAN trial remains to be established," Dr. Cheung and Dr. Wong write. "Despite the similar efficacy between treatments, the uncertainty about safety (particularly systemic events) means ranibizumab users are unlikely to switch to bevacizumab and policy makers are unlikely to mandate such a switch."

In fact, the IVAN researchers even pointed out this combined-study safety signal during their presentation of the 2-year results at the Association for Research in Vision and Ophthalmology (ARVO) 2013 Annual Meeting, as previously reported by Medscape Medical News.

Dr. Chakravarthy addressed these concerns. "With regard to safety, IVAN showed no significant differences between drugs. However when combined with CATT, there was a small signal in terms of increased frequency of adverse events with [bevacizumab]."

The IVAN researchers not only directly compared the agents but also contrasted continuous monthly vs initial monthly/then as-needed injection strategies. Their conclusion was mixed: The continuous regimen was associated with slightly better efficacy but carried a greater risk for development of geographic atrophy. Importantly, fewer patients treated on a continuous basis died during the 2 years. The reasons for more deaths in the discontinuous group remain unknown, Simon Harding, MD, from the University of Liverpool in the United Kingdom, one of Dr. Chakravarthy colleagues, told Medscape Medical News after results were announced at ARVO 2013.

When asked to comment on the study for Medscape Medical News, Mark Fromer, MD, an ophthalmologist at Lenox Hill Hospital in New York City, acknowledged these risk–benefit considerations. The study authors "concluded that discontinuous treatment has a slight disadvantage in mortality rates. Continuous treatment has a slight disadvantage towards the formation of retinal geographic atrophy. The drugs, however, performed similarly." Dr. Fromer was not involved in the study.

Ultimately, Dr. Fromer said, price remains an important consideration. "The importance of the study lies in the fact that a course of treatment with [ranibizumab] may cost thousands of dollars (over $2000 per treatment). The cost of treatment with [bevacizumab] is approximately $50 to $60 per treatment." He added, "[Bevacizumab], although off-label, has been used by physicians worldwide because of its efficacy and lower cost."

Participants received intravitreal injections of ranibizumab (0.5 mg) or bevacizumab (1.25 mg). Of the 610 evaluable patients aged 50 years or older who were initially randomly assigned to receive bevacizumab or ranibizumab, 525 participants remained at 2 years. Investigators measured the primary outcome (best corrected visual acuity) every 3 months. Secondary outcomes included other visual function measures (contrast sensitivity, near visual acuity, and reading index), lesion morphology, and generic and vision-specific health-related quality of life.

This study was supported by the National Institute for Health Research Health Technology Assessment programme. Dr. Chakravarthy and 2 coauthors are principal investigators of trials sponsored by Novartis, the manufacturers of ranibizumab. Dr. Chakravarthy has attended and been remunerated for attendance at advisory boards for Novartis, Bayer, Neovista, Oraya, Allergan, and Bausch and Lomb, and her employing institution has received payments from Novartis, Bayer, Neovista, Oraya, Alcon, and Pfizer. Several coauthors have reported various financial relationships with Novartis, Bayer, and Janssen-Cilag. Dr. Cheung is on advisory boards for Bayer, Novartis, and Roche and has received honoraria for travel and service on advisory boards and research support from these companies. Dr. Wong is on advisory boards for Abbott, Allergan, Bayer, Novartis, Roche, and Pfizer; has received honoraria for travel and service on advisory boards and research support from these companies; and has provided expert testimony to Novartis. Dr. Fromer has disclosed no relevant financial relationships.

Lancet. Published online July 19, 2013. Article abstract, Comment extract


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