Updated guidelines on use of anti-VEGF alter treatment course for exudative AMD

Clinicians examine post hoc analysis from leading clinical trials on exudative AMD treatment.

Daniele Veritti

The treatment of neovascular age-related macular degeneration is undeniably one of the hottest topics in ophthalmology because of the aging of society and increasing life expectancy.

If left untreated, neovascular AMD causes progressive and irreversible vision loss, often leading to legal blindness. With the advent of intravitreal anti-VEGF drugs, many steps have been made in the treatment of this disease in the past decade. Intravitreal Lucentis (ranibizumab, Genentech/Novartis) has set a new standard for vision outcomes.

Data from several large randomized clinical trials can be extrapolated to generate evidence-based recommendations for treatment indication and assessment, re-treatment, and monitoring. Evidence suggests that a loading phase consisting of three monthly injections of ranibizumab 0.5 mg results in a rapid visual acuity gain, mostly occurring after the first injection. The treatment should start as soon as possible after its indication. To inject within 2 weeks from diagnosis is ideal, whereas to wait more than 1 month seems to lead to further visual loss.

Appropriate injection intervals

Randomized clinical trials such as MARINA, ANCHOR, EXCITE and CATT showed that a maintenance phase with continued monthly injections has provided the best visual acuity outcomes. Longer re-injection intervals, such as the quarterly re-injection regimen of the PIER and EXCITE studies, resulted in less favorable outcomes after the loading phase.

If continued monthly injections are not feasible after initiation, a flexible strategy appears viable, with monthly monitoring of lesion activity recommended. Continuous careful monitoring with flexible re-treatment might help avoid vision loss to recur. In fact, data from the SAILOR trial suggest that quarterly visits are insufficient, whereas monthly monitoring (CATT, SUSTAIN, MONT BLANC) with re-injections on an as-needed basis warrants better outcomes.

Response variations

Variations in patients’ responses to ranibizumab therapy have been observed, and data from large clinical trials have assisted in recognizing predictive parameters that could optimize treatment and monitoring regimens. Post hoc analysis has shown that:

• Baseline visual acuity score has little predictive value for visual acuity in patients treated with monthly ranibizumab. However, lower baseline visual acuity seems to predict greater visual acuity gains (MARINA, ANCHOR).
• Smaller baseline lesions appear to respond better (MARINA, ANCHOR, SUSTAIN, EXCITE).
• Absence of retinal hemorrhage is associated with favorable visual acuity outcomes (SUSTAIN).
• Visual acuity change between month 3 and month 5 appears predictive of 12-month visual acuity stability (EXCITE).
• Intraretinal cysts at baseline reduce the potential for visual gain (MARINA, ANCHOR).
• Recurrence of subretinal fluid has an additional negative effect on visual function (MARINA, ANCHOR).

Also, polypoidal choroidal vasculopathy and retinal angiomatous proliferation subtypes are often excluded from clinical trials. The EVEREST trial suggests that in a majority of patients, photodynamic therapy, alone or in combination with ranibizumab, may lead to complete regression of the polypoidal choroidal vasculopathy.

On the other hand, no protocols can be established for the management of retinal angiomatous proliferation due to the paucity of evidence available.

CATT

Off-label Avastin (bevacizumab, Genentech) and on-label ranibizumab were compared in CATT as treatments for wet AMD. Patients were randomly assigned to one of four possible treatment regimens for a year. Regimens consisted of ranibizumab monthly or as needed and bevacizumab monthly or as needed.

The 1-year results for 1,185 patients treated at the 43 clinical centers in the U.S. have recently been reported. In the monthly treatment arms, bevacizumab was found non-inferior to ranibizumab, with a visual acuity gain of 8.0 and 8.5 letters, respectively. Also in the as-needed arms, bevacizumab displayed non-inferior results with respect to ranibizumab, with 5.9 and 6.8 letters gained.

The study did not meet the non-inferiority endpoint when comparing fixed regimens to as-needed regimens.

A higher number of injections were required with as-needed bevacizumab (7.7) compared to as-needed ranibizumab (6.9).

Central retinal thickness was more reduced in the monthly ranibizumab group (196 ìm) than in the other groups (152 µm to 168 µm, P = .03 by analysis of variance).

In addition, myocardial infarction, stroke and death rates were similar in patients receiving either ranibizumab or bevacizumab. Bevacizumab produced a higher proportion of serious systemic adverse events requiring hospitalization compared to ranibizumab.

In conclusion, with the advent of ranibizumab therapy, the prognosis of choroidal neovascularization has changed dramatically. Data from well-conducted clinical trials suggest that ranibizumab is effective and well-tolerated in patients. Evidence-based guidelines will help to optimize treatment outcomes with ranibizumab in neovascular age-related macular degeneration.

References:

• Bolz M, Schmidt-Erfurth U. Ranibizumab EXCITE study: Exploring the value of optical coherence tomography for the management of ranibizumab therapy in age-related macular degeneration. Paper presented at: 8th Euretina Congress; May 22-25, 2008; Vienna, Austria.
• Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. New Engl J Med. 2006;355(14):1432-1444.
• Meyer CH, Eter N, Holz FG. Ranibizumab in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Interim results from the SUSTAIN trial. Invest Ophthalmol Vis Sci. 2008;49:E-abstract 273.
• Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145(2):239-248.
• Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. New Engl J Med. 2006;355(14):1419-1431.
• Schmidt-Erfurth U. Correlation of retinal morphology and function under anti-VEGF therapy in patients with neovascular age-related macular degeneration (nAMD).Paper presented at: Retina Society Annual Meeting; September 21-25, 2011; Rome, Italy.

• Daniele Veritti, MD, can be reached at Department of Ophthalmology, University of Udine, p.le S. Maria della Misericordia, 33100 Udine, Italy 33100; +39-0432-559907; email: verittidaniele@gmail.com.
• Disclosures: Dr. Veritti and Dr. Gabai have no relevant financial disclosures.