Damian McNamara

May 15, 2013

SEATTLE, Washington — Bevacizumab (Avastin, Genentech) shows promise, compared with ranibizumab (Lucentis, Genentech), for improving visual acuity in patients with age-related macular degeneration at 2 years, report investigators.

However, "we have picked up an important safety signal," Simon Harding, MD, from the University of Liverpool in the United Kingdom, told a capacity crowd during a special session here at the Association for Research in Vision 2013 Annual Meeting.

"The drugs do appear to have similar efficacy," Dr. Harding told Medscape Medical News. The findings confirm the 1-year results from the pivotal Inhibit Vascular Endothelial Growth Factor in Age-Related Choroidal Neovascularisation (IVAN) trial (Ophthalmology. 2012;119:1399-1411).

But concern arose when Dr. Harding and his team pooled their data from the 2-year IVAN trial with 2-year results from the large Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) (Ophthalmology. 2012;119:1388-1398).

The 1-year results favored bevacizumab because it had fewer adverse events (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.05 - 1.07; P = 03).

In the 2-year updated data, "we found no statistically significant difference regarding death or arteriothromboembolic events...but we did find more systemic adverse events in the bevacizumab group than in the ranibizumab group, mostly from the CATT data," said study coauthor Chris Rogers, PhD, from the University of Bristol in the United Kingdom.

"Our signal in the 1-year data is no longer statistically significant for an arteriothromboembolic event or heart failure," Dr. Rogers emphasized.

This finding, Dr. Harding pointed out, "should be given less weight than the mortality finding about the continuous vs discontinuous groups."

During the 2 first years of the IVAN trial, 30 participants died. There were significantly more deaths in the discontinuous treatment group (= .01), representing a significant 2-fold risk in mortality, Dr. Harding explained.

Table. Mortality Risk by Treatment Strategy From IVAN at 2 Years

Regimen Median Number of Injections Deaths Mortality rate (%)
Continuous 23 10 3.2
Discontinuous 30 20 6.6

 

"The continuous vs discontinuous mortality difference is very interesting," said session moderator Daniel Martin, MD, chair of the Cole Eye Institute at the Cleveland Clinic in Ohio. "Other studies have looked at this and not found a difference. Even though it's a P value of .01, there are other studies that don't have the same suggestion."

To try to understand this more, "we looked at the causes of death for the 30 patients who died," Dr. Rogers said. "They are a mixture of cancer and cardiovascular events, nothing obvious that gives us a clue why we saw more deaths with the discontinuous therapy than the continuous treatment."

This increased mortality of 3.4% "should be given important weight," Dr. Harding said, "possibly over the geographic atrophy findings."

Dr. Harding pointed to an approximately 7% higher absolute risk for the development of new geographic atrophy in the continuous group. Although the odds ratios for the continuous and discontinuous groups were not significantly different (1.56 vs 1.47), the finding should be considered against the advantages of the continuous treatment.

 
Maybe monthly bevacizumab offers the best compromise in terms of safety and cost without compromise in efficacy.
 

"We can say the continuous regimen gives slightly better visual outcomes, but you have to think about the more frequent development of geographic atrophy," Dr. Harding noted.

He concluded that "at 2 years in IVAN, neither the drug nor the treatment regimen was conclusive. When we pooled the data in the meta-analysis, the results were consistent — bevacizumab is not inferior to ranibizumab. Also, discontinuous treatment is inferior to monthly treatment. However, both differences are small from a clinical perspective."

"We suggest that maybe monthly bevacizumab offers the best compromise in terms of safety and cost without compromise in efficacy," he said.

The audience, which had been silent up to this point in the presentation, erupted in hushed conversation.

Dr. Harding acknowledged the controversial conclusion during the question period after his talk, and added that "there is still a lot to do before we strongly recommend a switch to monthly bevacizumab."

This study was supported by the National Health Service in the United Kingdom. Dr. Harding and Dr. Rogers report receiving financial support from Novartis. Dr. Martin has disclosed no relevant financial relationships.

Association for Research in Vision and Ophthalmology (ARVO) 2013 Annual Meeting. Presented May 7, 2013.

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