Extend-and-Treat Bevacizumab Regimen Ups Vision in Wet AMD

Daniel M. Keller, PhD

February 25, 2012

February 25, 2012 — Eyes with neovascular ("wet") age-related macular degeneration (AMD) that were treated with intravitreal bevacizumab on an extend-and-treat regimen showed significant visual improvement. Compared with fixed monthly intravitreal injections of bevacizumab, patients receiving the extend-and-treat regimen had fewer office visits, ancillary tests, and injections, report Gary Shienbaum, MD, and colleagues in the Retina Service at Wills Eye Institute of Thomas Jefferson University in Philadelphia, Pennsylvania, in an article published in the March issue of the American Journal of Ophthalmology.

In this retrospective, interventional, consecutive case series study, the researchers, all of whom were from a single practice, treated 74 treatment-naive eyes of 73 patients with neovascular AMD, using intravitreal bevacizumab on a monthly basis until no intraretinal or subretinal fluid was detected using optical coherence tomography (OCT). Thereafter, treatment intervals were sequentially lengthened by 2 weeks until exudation recurred or there was a new macular hemorrhage, choroidal neovascularization (CNV) lesion growth or leakage, or loss of visual acuity, at which time treatment intervals were then shortened by 2 weeks to maintain exudate-free maculae.

The treat-and-extend regimen has been proposed as an alternative to fixed monthly injections or to as-needed regimens.

Eligibility and Patient Demographics

Eyes with subfoveal choroidal neovascularization secondary to neovascular AMD were included. Occult with no classic CNV eyes had to have presumed disease progression with recent loss of visual acuity, known CNV enlargement, or signs of macular hemorrhage. Eyes with any prior treatment for neovascular AMD were excluded.

Coauthor Omesh Gupta, MD, MBA, assistant professor of ophthalmology at Thomas Jefferson University and a member of the Retina Service at Wills Eye Institute, explained to Medscape Medical News, "We wanted treatment-naive [patients] to show the use of bevacizumab as a monotherapy and so that they have minimal scar tissue. If there's an improvement, we can say that it's from bevacizumab, not from some preexisting treatment."

The mean age of the patients was 81.1 years (range, 53 - 98 years), 74% were women, all were white, and 63.5% of eyes were pseudophakic. Visual symptoms had existed for a mean of 94.5 days before treatment (range, 1 - 365 days), and 45.9% of eyes were treated within 1 month of symptom onset. The mean CNV lesion size was 1.21 disc areas (range, 0.5 - 10 disc areas), and 33% of the lesions had some degree of macular hemorrhage. Minimum follow-up was 6 months, and the mean follow-up period was 1.41 years (range, 0.5 - 3.7 years).

Durable Improvement in Visual Acuity

Snellen visual acuity improved from baseline to 1 year and persisted at 2 years. At 1 year, 95.8% of the patients had lost fewer than 3 lines of Snellen visual acuity, and 35.2% had gained 3 or more lines.

"The visual acuity significantly improved at the 6-month, 12-month, and 24-month time point," Dr. Gupta said. "Within the first 6 months to 9 months, you start to see a dramatic improvement in the vision, and then you become more in the maintenance phase, you may not need as many injections in the maintenance phase that you do in the loading phase and in the induction phase."

Improvement in Mean Snellen Visual Acuity

  Baseline 3 Months 6 Months 9 Months 12 Months 18 Months 24 Months
Snellen visual acuity* 20/230 20/134 20/118 20/134 20/109 20/107 20/106

*All P < .001 vs baseline except P = .007 at 18 months.

OCT central retinal thickness decreased from baseline to 1 year. The mean OCT central retinal thickness decreased from 316 μm at baseline to a minimum of 212 μm, and was 239 μm at 1 year of follow-up (P < .001). After the achievement of exudate-free maculae, 52.7% of eyes had no exudative recurrences, 29.7% had 1 recurrence, and the remaining 17.7% had from 2 to 5 or persistent recurrences. Exudates recurred a mean of 330 days (range, 138 - 788 days) after the start of treatment.

"When there's hemorrhage and/or leakage into the macula, the macula becomes thickened, and the OCT is an objective way to measure that," Dr. Gupta said. If left untreated, blood and persistent edema can cause permanent scarring. "Before bevacizumab or ranibizumab were available, a lot of patients had scarring that left them, unfortunately, with poor vision," he said.

The longest treatment interval was 92.4 days. The mean number of injections during the first year was 7.94, decreasing to 5.60 between years 1 and 2. The authors reported no adverse ocular or systemic events during the study.

Direct Medical Cost Savings

The annual mean direct medical cost of the treat-and-extend regimen during year 1 was $3493.85 (range, $1330.85 - $10,475.31) per patient. Between years 1 and 2, the mean cost per patient was $1852.88 (range, $1157.33 - $2991.79). In a previous study using a treat-and-extend regimen of ranibizumab by some of the same authors, the mean direct medical costs per patient during year 1 and between years 1 and 2 were $16,114.52 and $13,971.44, respectively.

The current study was limited by the relatively small sample size, the lack of a control group, its retrospective nature, and the use of Snellen visual acuity measures.

With retrospective studies, there is the possibility of selection bias, in that only patients who do well remain in the study, and other participants drop out or switch to other therapies. In fact, in this study, only 14 patients were available for a 24-month evaluation, either because they had a shorter follow-up time or because they had left the study.

Treatment Implications

"One of the advantages of this treatment regimen is that it limits the injections while maximizing [patients'] visions," Dr. Gupta noted. An alternative regimen is treat-and-observe, in which treatment continues until the macula is dry with no bleeding or swelling. Patients then return at a fixed interval even if they do not receive an injection. So, "there's a lot of visit charges that the patient has to incur," Dr. Gupta said. In addition, family members may be inconvenienced or lose work to bring the patient to the physician visit.

A treat-and-extend regimen potentially extends the time between visits and can minimize direct and indirect costs. "Everyone has an individualized interval that you can find out by using this method," he noted.

Dr. Gupta makes no specific recommendations based on this study, but said it shows that patients have options beyond monthly dosing. "[T]here are a bunch of treatment regimens that seem to be as effective as monthly dosing," he said. "And I think that's probably the biggest conclusion that we can make."

He emphasized that bevacizumab and ranibizumab "have literally redefined the way in which we think about macular degeneration. Before, we used to think about letters lost: How many letters lost did [photodynamic therapy] or Macugen [pegaptanib] result in at 6 months and a year? Now, you can't even enter into the discussion about a new drug unless you're talking about 3 lines of letters gained...because that's what these drugs have done. They've completely shifted the focus in terms of what an acceptable outcome is now."

He said it is still early in the discovery phase of how best to treat neovascular AMD with these drugs and others coming along, including sequencing of different medications and new drug delivery systems for patients who "fall into that recalcitrant category."

George Williams, MD, chairman of the Department of Ophthalmology and director of the Beaumont Eye Institute at William Beaumont Hospital in Royal Oak, Michigan; clinical professor of ophthalmology and biomedical sciences at Oakland University William Beaumont School of Medicine; and an expert correspondent for the American Academy of Ophthalmology, cautioned against drawing too many conclusions from the small retrospective study. He told Medscape Medical News that although the study does show that a treat-and-extend regimen of bevacizumab can improve vision in most patients, "it does not establish how this approach compares to other dosing regimens." Nonetheless, it "does provide additional real-world experience on this treatment approach," he said.

Surveys indicate that approximately 30% of retina specialists use treat-and-extend to individualize therapy and diminish the treatment burden associated with monthly follow-up. Dr. Williams believes that retina specialists who already use a treat-and-extend approach will see the study results as validation of their approach, but thinks the results will be unlikely to change other specialists' practice.

However, Dr. Williams said, the need for regular follow-up visits "is a significant logistical issue for retina practices," because once patients begin therapy, they require follow-up indefinitely. Treat-and-extend may be a way to lessen the burden, especially as the demographics of AMD in an aging population drive additional new patient visits.

Caution in Using Bevacizumab

Intravitreal bevacizumab is an off-label use of the drug, but surveys indicate that about 60% of retina specialists use it as their initial antivascular endothelial growth factor therapy of choice instead of the similar, approved, ranibizumab. Several retrospective and prospective studies have shown intravitreal bevacizumab to be safe and effective. One-year results of the Comparison of AMD Treatments Trials comparing the 2 drugs head-to-head showed equivalent effects on visual acuity at all times when the drugs were used on the same schedule. Two-year results are expected in May.

However, Dr. Williams noted several reports of contaminated bevacizumab causing serious eye infections. The source of the contamination appears to be poor sterile technique at the compounding pharmacy when the drug is divided into aliquots from the multiuse vials that the drug comes in. He pointed to recent guidance from the American Academy of Ophthalmology on how to minimize this risk.

The study received no commercial support. One coauthor is a consultant to Genentech Inc, Novartis Pharmaceuticals Corp, GlaxoSmithKline, and Alcon Laboratories Inc, and has received research grants from Genentech, Novartis, QLT, Regeneron, NeoVista, Alcon, and GlaxoSmithKline. One coauthor is a consultant to Ophthotec Corp, NeoVista, Inc, and Alimera Sciences Inc, and has received research grants from Genentech, Novartis, QLT, Regeneron, NeoVista, Alcon, and GlaxoSmithKline. The other authors have disclosed no relevant financial relationships. Dr. Williams is a consultant/advisor to Alcon Laboratories, Allergan, Neurotech, OptiMedica, Pfizer, and Thrombogenics. He has received grant support from Alcon Laboratories, Allergan, Genentech, and Neurotech; is an equity owner of Nu-Vue Technologies, OptiMedica, and Thrombogenics; and has patent/royalty income from Nu-Vue Technologies.

Am J Ophthalmol. 2012;153:468-473. Abstract


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