Ranibizumab Fails to Beat Saline in Avoiding Vitrectomy

Daniel M. Keller, PhD

January 31, 2013

Patients with vitreous hemorrhage from proliferative diabetic retinopathy (PDR) experienced about the same rates of vitrectomy by 16 weeks whether they received intravitreal injections of ranibizumab (Lucentis, Genentech) or saline. The results of this short-term study, published online January 31 in JAMA Ophthalmology, suggest little likelihood of a clinically meaningful difference on vitrectomy between the 2 interventions. Longer follow-up is planned.

Vitreous hemorrhage can preclude panretinal photocoagulation, the standard treatment for PDR. Because of the role of vascular endothelial growth factor (VEGF) in PDR, the Diabetic Retinopathy Clinical Research Network deemed it important to test the efficacy of ranibizumab, an anti-VEGF agent, in reducing vitrectomy rates in the setting of PDR.

In a phase 3, double-masked, randomized, multicenter study, 261 eyes in 261 patients were injected with 0.05 mL containing 0.5 mg ranibizumab (n = 125) or saline (n = 136) at baseline and at weeks 4 and 8. At baseline, patients (52% women) were at least 18 years old (mean age, 58 years), had type 1 or 2 diabetes (mean HbA1c level, 8.0% ± 1.7%), and had vitreous hemorrhage from PDR precluding panretinal photocoagulation.

"The study found that the rate of vitrectomy by 16 weeks was not significantly reduced compared to eyes that received control saline injections," wrote Lee M. Jampol, MD, in response to questions from Medscape Medical News. Dr. Jampol is professor of ophthalmology at Northwestern University Feinberg School of Medicine, Chicago, Illinois, and chair of the Diabetic Retinopathy Clinical Research Network. By 16 weeks, the primary outcome of the cumulative probability of vitrectomy was 12% for the eyes receiving ranibizumab and 17% for eyes getting saline (hazard ratio, 0.74; 95% confidence interval, 0.38 - 1.43; P = .37). Failure to substantially clear the vitreous hemorrhage was the most frequent reason for vitrectomy in either group.

"We cannot say with certainty whether with longer follow-up, the injections would reduce the need for vitrectomy," Dr. Jampol said. "However, given the low need for vitrectomy in both groups, such a study would be difficult."

Benefits With Ranibizumab

Secondary outcomes suggest some benefit of ranibizumab over saline, at least in the short term. Ranibizumab treatment allowed performance of panretinal photocoagulation without vitrectomy in 44% of treated eyes vs 31% in the saline group by 16 weeks (hazard ratio, 1.54; 95% confidence interval, 1.03 - 2.30; P = .05).

The ranibizumab-treated eyes also showed some improvement in mean visual acuity between baseline and 12 weeks: 22 ± 23 letters compared with 16 ± 31 letters for the saline group (P = .04). Visual acuity approximately equivalent to Snellen 20/40 or better occurred in 45% of the ranibizumab group and in 33% of the saline group (P = .08).

"These results, in totality, suggest that ranibizumab did have a biologic effect," said Dr. Jampol.

Recurrent vitreous hemorrhage within 16 weeks affected 6% and 17% of the ranibizumab and control eyes, respectively (P = .01). One eye in the saline group developed endophthalmitis.

The study had no observation-only group, but the authors write that a previous study showed that eyes injected with saline were 3 times more likely to have improvement in visual acuity (36.3%) compared with watchful waiting (11.1%).

A survey by the American Society of Retina Specialists showed that a third of retina specialists frequently use anti-VEGF products in eyes before vitrectomy. Given the fact that vitrectomy involves greater costs, more time to initiate treatment, longer intervention and recovery times, and risks of adverse effects, the authors recommend continued study of ranibizumab in eyes with PDR.

However, Pravin Dugel, MD, managing partner of Retinal Consultants of Arizona, Ltd, in Phoenix and an expert correspondent for the American Academy of Ophthalmology, commented to Medscape Medical News that although the study was useful and that "the conclusions were very balanced and very appropriate," an anti-VEGF drug primarily affects vascular permeability but "is not a clot buster." He noted that the etiology of a vitreous hemorrhage is more an acute leakage than the chronic ones that ranibizumab may prevent.

He said one might have predicted that ranibizumab was not going to work for this indication "because it's not the mechanism of action of this drug.... However, I think it's a very important study that had to be done because a lot of people do use it or were using it for this purpose." He added that the study reaffirms the role of vitrectomy in clearing vitreous hemorrhage, "as we have made tremendous advances in vitrectomy surgery going to smaller gauge instruments and having surgery that I think is a lot less invasive, a lot more elegant, and a lot more effective."

"There was not a dramatic effect of the injection upon the necessity for vitrectomy," Dr. Jampol said. "This may persuade some ophthalmologists not to use ranibizumab for this indication. However, others might interpret the positive secondary outcomes as indications that injections may be helpful."

But Dr. Dugel advised not making too much of the secondary outcomes because of study limitations and because one should have a proposed mechanism to explain them, which probably does not exist at this point for ranibizumab.

Genentech provided ranibizumab for the study and provided funds to the Diabetic Retinopathy Clinical Research Network to defray clinical site costs. Dr. Dugel has disclosed no relevant financial relationships.

JAMA Ophthalmol. Published online January 31, 2013. Abstract