The treat-and-extend approach to wet AMD

Evidence shows an anti-VEGF therapy strategy can reduce treatment visits while preserving visual acuity.

By Jaclyn L. Kovach, MD

Current management of wet AMD involves the intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents including bevacizumab (Avastin, Genentech), ranibizumab (Lucentis, Genentech) or aflibercept (Eylea, Regeneron) or a combination. The therapy’s goal is preserving or improving vision. This is achieved by keeping the macula dry, without any signs of active wet AMD as seen on OCT, fundus and examination or fluorescein angiography (FA) or both.

In 2006, monthly treatment was introduced as the first evidence-based strategy for anti-VEGF therapy for wet AMD. While unprecedented gains in visual acuity were achieved with monthly treatment, this protocol placed a significant burden on patients, their families and our healthcare system, compounded by the potential risks of frequent intravitreal injections. Since that time alternative treatment strategies, including as-needed and treat-and-extend, have offered the possibility of individualized therapy with the goal of maximizing visual acuity gains and minimizing the frequency of patient visits, recurrences and the accompanying risks of treatment.

The merit of the treat-and-extend protocol was touted in the recently released one-year results of LUCAS. This is the strongest evidence to date in support of treat-and-extend as a means of achieving similar visual acuity gains as monthly therapy while alleviating some of the burden of monthly visits on patients and containing healthcare costs.

This article will review the basis for this strategy and the current supporting literature.

TREAT-AND-EXTEND HISTORY

Initial protocol

The treat-and-extend management protocol for anti-VEGF therapy for wet AMD was first described by Richard Spaide, MD, and K. Bailey Freund, MD, as a way to maximize visual outcomes and safety while minimizing recurrences and treatment frequency. This strategy involves initial monthly injections of bevacizumab or ranibizumab until OCT shows the macula is dry.

Then, treatment continues at intervals increasing by two weeks per visit, to a maximum of 10 to 12 weeks. If clinical or OCT evidence shows persistent or recurrent fluid at any point, the interval is shortened and then progressively extended as allowable.^1-3

Other management strategies

Before Spaide and Freund’s research, monthly therapy with ranibizumab was the initial evidence-based management strategy for anti-VEGF therapy for wet AMD, as supported by the ANCHOR and MARINA trials.^4,5 In a search to maximize vision outcomes and minimize treatment frequency, the PIER and EXCITE trials showed inferiority compared to a monthly regimen with regular, quarterly injections following an initial loading dose of three monthly injections. This suggested that individualized therapy based on need was the only potential efficacious alternative to monthly therapy.^6,7

The CATT, GEFAL and MANTA trials substantiated the efficacy of individualized, as-needed therapy when compared with monthly treatment for bevacizumab and ranibizumab, but the burden and cost of monthly monitoring visits and the potential for multiple recurrences with as-needed therapy persisted.^8-10

Efficacy

A handful of studies have investigated the efficacy of the treat-and-extend protocol for anti-VEGF therapy for type 1 and type 3 neovascularization.^11-17 While most are retrospective case series involving 100 to 200 patients, considerable differences exist between these studies, including study design, medication evaluated, patient follow-up duration and patient treatment history.

Despite the differences, the studies produced similar promising results: visual and anatomical outcomes consistent with clinical trials involving monthly ranibizumab, but lower cost and treatment burden. For example, one study evaluated visual outcome, number of injections and direct medical cost of the treat-and-extend regimen with ranibizumab for wet AMD in 92 treatment-naïve eyes over a mean of 1.52 years.¹⁶ On average, patients required about eight injections. Patients incurred a direct annual medical cost of $16,114.52 for the treat-and-extend regimen compared with a range of $15,880.07 to $28,314.16 for previous monthly clinical trial protocols.

LUCAS CLINICAL STUDY

Overview

Lucentis Compared to Avastin Study (LUCAS) one-year results were published earlier this year. The first large randomized, multicenter, double blind, non-inferiority trial using a treat-and-extend protocol for comparison of ranibizumab and bevacizumab for the treatment of wet AMD included 441 randomized patients at 10 ophthalmological centers across Norway between March 2009 and July 2012. Eligibility included age at least 50 years, treatment naïve active neovascular AMD and BCVA between 20/25 and 20/320.

Randomized patients received either ranibizumab or bevacizumab injected every four weeks until no signs of active wet AMD existed. Then, patients received a new injection, and the period between treatments was extended by two weeks at a time, up to 12 weeks. Recurrent wet AMD was defined as any fluid on OCT, new or persistent hemorrhage on fundus exam, or dye leakage or increased lesion size on FA. If recurrent disease was identified, the interval was shortened by two weeks at a time until the disease was considered inactive. The interval extension then restarted with the maximum final interval two weeks less than the time interval of the previous recurrence.

The study protocol allowed for withdrawal of patients who were considered nonresponders (those with unchanged or increased central retinal thickness (CRT) after three consecutive injections). If patients had no response to treatment four weeks after the third injection, they were removed from the study.

The primary outcome measure was the change in ETDRS BCVA at one year, and secondary outcomes included the number of injections, change in the CRT on OCT and change of lesion size on FA. The safety outcome was the occurrence of arteriothrombotic events.

Study outcomes

Results analysis was performed on 371 patients who completed the one-year visit — 20 patients were labeled nonresponders. No considerable differences were observed with the bevacizumab and ranibizumab groups at baseline other than a larger history of myocardial infarctions (MI) in the ranibizumab group (12 vs. 26 individuals).

Change in BCVA at one year with bevacizumab was equivalent to ranibizumab when using the treat-and-extend protocol. Both groups gained approximately eight letters and about 26% of patients in both groups gained ≥15 letters. The improvement in visual acuity in these two groups was comparable to that found in the group with monthly treatment in CATT.

Significant differences between the groups: the number of injections and visits during year one. Bevacizumab patients received about 8.9 injections compared with eight injections for the ranibizumab group. More bevacizumab patients received injections every four weeks, while more ranibizumab patients received injections every 12 weeks (Figure).

Figure. The number of patients receiving ranibizumab versus bevacizumab in each treatment group in the LUCAS trial at one year.

The groups had no significant difference between CRT at one year, but more patients in the ranibizumab group were fluid-free on OCT and leakage-free on FA at the end of one year. Also, change of mean lesion area on FA from baseline to one year was similar.

This study was not powered to detect differences in adverse events between medications; however, the incidence of arteriothrombotic events in the bevacizumab group was found to be lower than the ranibizumab group along with significantly more nonfatal MIs and cardiac events in the ranibizumab group. Of note, significantly more patients in the ranibizumab group had a history of MI at baseline.

Overall, LUCAS demonstrated that bevacizumab and ranibizumab at one year are equivalent regarding the gain in visual acuity and reduction of CRT when administered according to the treat-and-extend protocol. Perhaps even more important, the visual acuity results in LUCAS are comparable to those achieved with a monthly treatment regimen. This is the strongest evidence to date that supports excellent visual acuity gains with fewer visits and treatments.

Consistent with the results from CATT, a slightly larger CRT existed in the bevacizumab compared with the ranibizumab group, but this was not statistically significant.

CONTINUING THE TREAT-AND-EXTEND STRATEGY

Providing good management of wet AMD

During this era of anti-VEGF therapy for wet AMD, we have made strides to minimize the burden of frequent visits and treatments for our patients, their families, and our health care system, while maximizing visual outcomes and safety. On the 2014 ASRS Preferences and Trends survey, 78% of retina specialists reported that they already use the treat-and-extend protocol as their primary treatment regimen for anti-VEGF therapy. Because of the release of one-year data from LUCAS, the retina community now has its strongest evidence to date that supports the efficacy of this protocol.

While many questions regarding this strategy still exist, the evidence in support of early diagnosis and individualized treatment as the best strategy for management of wet AMD continues to grow. OM

REFERENCES

About the Author
	Jaclyn L. Kovach, MD, is an assistant professor of Clinical Ophthalmology at Bascom Palmer Eye Institute in Naples, Fla., specializing in medial retina. She manages patients with AMD, retinal vascular diseases and other macular degenerations and dystrophies. She can be reached at jkovach@med.miami.edu. Disclosure: Dr. Kovach has no relevant financial disclosures.