Ranibizumab Blocks Progression of Retinal Vein Nonperfusion

October 31, 2011 (Orlando, Florida) — Excessive production of vascular endothelial growth factor (VEGF) in patients with retinal vein occlusion promotes retinal nonperfusion, according to new research presented here at the American Academy of Ophthalmology (AAO) 2011 Annual Meeting.

This can be prevented by blocking VEGF production with intraocular injections of ranibizumab (Lucentis, Genentech), said Peter A. Campochiaro, MD, from the Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland.

"We never understood why, in patients with vein occlusion, there is a progressive increase in capillary nonperfusion. Now, for the first time, we know it's because of high levels of VEGF," Dr. Campochiaro told Medscape Medical News.

The development of specific anti-VEGF antagonists has allowed researchers to investigate certain issues regarding pathogenesis that are very difficult to examine in animal models, he continued.

"What we've learned from our research is that it's not simply the original obstruction or occlusion (either central vein or branch vein occlusion) that leads to capillary nonperfusion," Dr. Campochiaro said. "Instead, the occlusion causes retinal ischemia, which upregulates VEGF, and it's those high levels of VEGF that cause progressive capillary nonperfusion."

Dr. Campochiaro and his team sought to assess the effect of intraocular injections of ranibizumab on retinal nonperfusion in patients with retinal vein occlusion in the BRAVO and CRUISE trials. The main results of these trials have been previously reported.

The BRAVO trial randomly assigned 397 patients with macular edema secondary to branch retinal vein occlusion to receive ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injections once a month for 6 months. In the CRUISE trial, 392 patients with macular edema secondary to central retinal vein occlusion were randomly assigned to the same treatment groups.

The primary endpoint (mean change from baseline best corrected visual acuity [BCVA]) and secondary endpoint (percentage of patients who gained at least 3 lines, or 15 letters of BCVA, at 6 months) were the same for the 2 trials.

The outcomes of both trials showed significant improvement in visual acuity in patients who received either dose of ranibizumab compared with patients who received sham injections.

In BRAVO, the mean gain from baseline in BCVA was 16.6 letters in patients receiving 0.3 mg of ranibizumab, 18.3 letters in those receiving 0.5 mg, and 7.3 letters in those receiving sham injections. The percentage of patients who gained at least 3 lines or 15 letters of BCVA was 55.2% in the 0.3-mg group, 61.1% in the 0.5-mg group, and 28.8% in the sham group.

In CRUISE, the mean gain from baseline was 12.7 letters in patients who received 0.3 mg ranibizumab, 14.9 letters in those who received 0.5 mg ranibizumab, and 0.8 letters in those who received sham injections. The percentage of patients who gained at least 3 lines or 15 letters of BCVA was 46.2% in the 0.3-mg ranibizumab group, 47.7% in the 0.5-mg group, and 16.9% in the sham group.

In the current study, Dr. Campochiaro looked at the effects of ranibizumab injections on another outcome (retinal nonperfusion) at 6 months, and again 6 months later, after the sham patients had been crossed over to receive ranibizumab injections as needed.

The results with retinal nonperfusion were equally impressive, Dr. Campochiaro noted.

At the end of 6 months in the BRAVO trial, the percentage of patients with no retinal nonperfusion was 48.1% in the 0.3-mg ranibizumab group and 51.0% in the 0.5-mg group compared with 32.7% in the sham group.

Between 6 and 12 months, patients in the sham group had a mean of 3.8 injections with ranibizumab 0.5 mg. Patients who had been receiving ranibizumab 0.3 mg in the first 6 months of the study went on to have a mean number of 2.7 ranibizumab injections, and those who had been receiving ranibizumab 0.5 mg had a mean of 2.8 injections.

At month 12, the percentage of patients with no retinal nonperfusion was 39.0% in patients in the ranibizumab 0.5-mg group, 44.8% in patients in the 0.3-mg group, and 41.4% in patients in the sham group who had started receiving 0.5-mg ranibizumab injections at month 6 of the study.

In the CRUISE trial, the percentage of patients with no retinal nonperfusion at 6 months was 82.0% in the ranibizumab 0.3-mg group and 84.0% in the 0.5-mg group compared with 67% in the sham group.

Between 6 and 12 months, patients in the sham group had a mean of 3.8 injections with ranibizumab 0.5 mg, patients in the ranibizumab 0.3-mg group had a mean of 3.9 injections, and patients in the ranibizumab 0.5-mg group had a mean of 3.6 injections.

At month 12, the percentage of patients with no retinal nonperfusion was 78.9% in the ranibizumab 0.5-mg group, 78.2% in the 0.3-mg group, and 79.3% in the original sham group.

"When ranibizumab injections were given to patients in the sham group and reduced in the treatment groups, the difference in retinal nonperfusion that was seen earlier was eliminated," Dr. Campochiaro said.

"These data suggest that [VEGF] plays an important role in retinal nonperfusion in patients with retinal vein occlusion, and that it is suppressed by treatment with ranibizumab," he said.

New Focus for Treatment of Retinal Vein Occlusion

Dr. Mark W. Johnson

Mark W. Johnson, MD, professor of ophthalmology at the University of Michigan Kellogg Eye Center, Ann Arbor, who moderated the oral paper session, told Medscape Medical News: "This was probably one of the more interesting papers of the morning, because to this point, all of the focus on using anti-VEGF agents in vein occlusions, as well as in diabetes, has been to reduce the swelling in the macula, the macular edema."

Dr. Johnson, who was not part of the study, continued: "The study provides evidence, for the first time, that there may be other benefits, which is to prevent progression of the disease in terms of further blood vessel closure.

"It doesn't provide hard evidence, but it provides at least a consideration of using these drugs, at least in the beginning, when the patient first presents, as a way of stabilizing the overall disease process and preventing some of the progression that we otherwise see," he said. "This is a new concept that we all have to digest, and figure out how to use it in our approach to patients."

Dr. Campochiaro reports financial relationships with Alcon Laboratories, Alimera, Allergan, Amira, Genentech, Genzyme, GlaxoSmithKline, Lpath, and Oxford BioMedica. Dr. Johnson reports financial relationships with Ophthotech, Oraya, Regeneron, and Thrombogenics.

American Academy of Ophthalmology (AAO) 2011 Annual Meeting: Abstract PA034. Presented October 24, 2011.