Long-term follow-up of Vascular Endothelial Growth Factor Inhibitor Therapy for Neovascular Age-related Macular Degeneration

Adrienne W. Scott; Susan B. Bressler


Curr Opin Ophthalmol. 2013;24(3):190-196. 

In This Article

Abstract and Introduction


Purpose of review To discuss the most recent literature regarding the long-term use (≥52 weeks of follow-up) of antivascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (NVAMD).

Recent findings Intravitreal ranibizumab has been demonstrated to provide outstanding vision outcomes relative to the standard therapy in patients with NVAMD. The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD studies showed that patients managed with intravitreal aflibercept achieved visual acuity and anatomic improvements similar to individuals managed with monthly ranibizumab while receiving an average of five fewer injections during the first 12 months of treatment. In the Comparison of AMD Treatment Trials, intravitreal bevacizumab dosed monthly met noninferiority to ranibizumab monthly, as well as noninferiority to ranibizumab dosed as-needed with respect to change in visual acuity 1 year after the treatment initiation. Furthermore, patients switched to as-needed regimens in their second year of follow-up from monthly dosing during the first year demonstrated an incremental loss of visual acuity during the second year of follow-up irrespective of the drug used. To date, trials evaluating anti-VEGF therapy for NVAMD demonstrate a low incidence of serious ocular or systemic adverse events. However, the potential for deleterious effects of long-term (beyond 2 years) pan-VEGF blockade remains unknown.

Summary Patients with NVAMD enjoy heretofore unprecedented vision gains when managed with anti-VEGF therapy, and the limited body of evidence to date regarding long-term anti-VEGF treatment shows these vision gains can be maintained through 2 years. Further investigation is needed to explore the effects of long-term anti-VEGF therapy beyond 2 years.


Historically, age-related macular degeneration (AMD) has been described as the leading cause of irreversible central vision loss among individuals over the age of 65 in North America and Europe.[1–3] In most cases, neovascular AMD (NVAMD), one of the two forms of advanced AMD, carries a devastating visual prognosis if left untreated.[3]

The pivotal ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) and MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) trials established the efficacy of monthly ranibizumab (Lucentis; Genentech Inc., South San Francisco, California, USA) for all fluorescein angiographic subtypes of predominantly choroidal neovascular (CNV) lesions. These trials demonstrated long-term (2 years) anatomic and functional benefits, including identification of unprecedented visual gains compared to standard therapies when patients were treated with this pan-vascular endothelial growth factor-A (VEGF) inhibitor agent. These trials showed that monthly ranibizumab therapy resulted in avoidance of moderate visual acuity loss in almost all participants, whereas approximately one-third of treated participants experienced moderate visual gain (≥3 lines of acuity) at 1 and 2 years following treatment initiation.[4–6]

Intravitreal bevacizumab (Avastin; Genentech Inc., South San Francisco, California, USA), an alternate pan-VEGF-A inhibitor, is another widely utilized drug for managing NVAMD. Bevacizumab differs from ranibizumab in that it is a full-length humanized antibody to VEGF compared to an affinity matured antibody fragment, and it may have a longer intravitreal half-life, yet reduced retinal penetrance. In addition, its half-life in the eye and systemic circulation may be longer relative to ranibizumab.[7,8] Although not approved for intravitreal use, off-label bevacizumab rapidly became the most commonly utilized intravitreal anti-VEGF therapy, while physicians awaited commercial availability of ranibizumab.

The Comparison of AMD Treatment Trials (CATT) was the first trial to provide robust Level 1 evidence supporting the use of bevacizumab therapy in NVAMD.[9] CATT was designed as a noninferiority study focusing on the mean change in visual acuity at 1 year between patients randomly assigned to intravitreal ranibizumab or bevacizumab on a monthly schedule or on an as-needed [pro re nata (PRN)] regimen with monthly evaluation. Patients in each of the PRN groups were dosed when the lesion showed activity, which was largely driven by ocular coherence tomography (OCT) evidence of fluid. The monthly ranibizumab group gained +8.5 letters at week 52, whereas the monthly bevacizumab, ranibizumab PRN, and bevacizumab PRN groups gained +8, +6.8, and +5.9 letters, respectively. The following comparisons met the predefined noninferiority margin of 5 letters for the difference between the mean change in visual acuity among treatment arms: ranibizumab monthly/bevacizumab monthly, ranibizumab monthly/ranibizumab PRN, ranibizumab PRN/bevacizumab PRN and ranibizumab PRN/bevacizumab monthly. However, the ranibizumab monthly/bevacizumab PRN and the bevacizumab monthly/bevacizumab PRN comparisons did not meet the noninferiority criteria, leading to inconclusive results for these comparisons (i.e. bevacizumab PRN may be 'equivalent' or inferior to ranibizumab or bevacizumab monthly). Both anti-VEGF inhibitors dramatically decreased subretinal and intraretinal fluid as imaged on OCT; however, ranibizumab, especially when dosed monthly, did so more frequently relative to bevacizumab.[9] With monthly assessments for disease activity, the mean number of intravitreal injections was 6.9 and 7.7 in the ranibizumab and bevacizumab PRN groups, respectively, compared to the maximum of 13 injections possible in the mandatory monthly dosing groups. Although noninferiority was demonstrated for some of the alternate drug and dosing regimens, the mean increase in visual acuity (point estimates) always favored the ranibizumab monthly regimen, as did the anatomic findings evaluated on OCT and fluorescein angiography.[9]

The Inhibit VEGF in Age-related Choroidal Neovascularization (IVAN) trial, conducted in the United Kingdom, compared ranibizumab and bevacizumab, as well as fixed monthly and variable or discontinuous dosing regimens in a noninferiority protocol.[10] IVAN differs from CATT in that IVAN enrolled about half as many participants (n = 610 IVAN vs. n = 1208 CATT), and all participants in IVAN were treated at visits 0, 1, and 2. In the discontinuous dosing arms of IVAN, participants were not retreated after visit 2 unless prespecified clinical and OCT criteria for active disease were met. When active disease activity was confirmed, three consecutive monthly intravitreal injections were administered before an eye was eligible for treatment deferral. The primary efficacy measures (distance acuity) and safety (arteriothrombotic events or heart failure) in IVAN are to be reported at 2 years following treatment initiation. A prespecified interim analysis of IVAN outcomes at year 1 yielded inconclusive findings for the ranibizumab–bevacizumab comparison with regard to visual acuity; and the IVAN authors described the visual acuities between the continuous and discontinuous groups as equivalent. The CATT authors, however, reported distance visual acuity after 1 year as equivalent for the two drugs, but only within each dosing regimen. The median number of injections was 12 in the continuous arms compared to 7 in the discontinuous arms. Although no difference in OCT measured foveal thickness was identified by the drug, eyes assigned to continuous treatment had 9% thinner measurements than those receiving discontinuous treatment (P = 0.005). In contrast to the CATT, in which serious systemic adverse events were higher among bevacizumab-treated participants (24.1 vs. 19.0% for bevacizumab and ranibizumab, respectively [P = 0.04]),[9] in IVAN, there was no difference between drugs in the proportion experiencing a serious systemic adverse event (odds ratio [OR], 1.35; 95% confidence interval [CI], 0.80–2.27; P = 0.25)[8] and fewer participants receiving bevacizumab compared to ranibizumab reported an arteriothrombotic event or heart failure (OR, 0.23; 95% CI, 0.05–1.07; P = 0.03). Two-year IVAN analyses are pending.[10]

VEGF-Trap Eye (VTE) (aflibercept or EYLEA; Regeneron, Tarrytown, New York, USA) is another intravitreal agent that clearly provides vision benefits to eyes with treatment-naïve NVAMD.[11] Aflibercept is a fusion protein with binding domains from native VEGF receptors which binds VEGF-A, VEGF-B, and placental growth factor (PlGF). The VIEW trials (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD 1 and 2) are two multicenter, randomized trials involving a total of 2457 participants in a comparison of three dosing regimens of VTE (2 mg every 4 weeks [2q4], 0.5 mg every 4 weeks [0.5q4], and 2 mg every 8 weeks following 3 doses every 4 weeks [2q8]) to 0.5 mg ranibizumab every 4 weeks [Rq4]. The primary outcome of each trial was met in that aflibercept was found to be noninferior to ranibizumab when comparing the proportion of patients who lost fewer than 15 letters from baseline to week 52. At week 52, each dosing regimen of VTE was found noninferior to ranibizumab, with 95–96% of participants avoiding a 15-letter loss in each of the VTE arms compared with 94% in the Rq4 arm. All VTE participants had reductions in OCT central retinal thickness similar to those seen for the monthly ranibizumab group. In an analysis integrating VIEW-1/VIEW-2 results, the mean visual acuity improvement from baseline to week 52 was +8.7 letters in the Rq4 group compared to +8.3, +9.3, and +8.4 letters in the 0.5q4, 2q4 group, and 2q8 VTE groups, respectively. The incidence of ocular and serious systemic adverse events was similar across all treatment groups, including those of particular interest when administering a VEGF inhibitor. All participants were examined every 4 weeks; however, the mean number of intravitreal injections was 7.5 among the 2q8 VTE eyes compared with 12.1–12.5 in each of the other arms. Thus, the 52-week evaluation from the VIEW-1 and VIEW-2 studies showed that VTE provides similar visual and anatomic outcomes compared to monthly ranibizumab therapy, and that these gains may be achieved with a fixed dosing schedule that requires fewer injections than monthly aflibercept treatment.[11]

Data from the MARINA, ANCHOR, CATT, IVAN, and VIEW-1/2 studies established intravitreal anti-VEGF treatment as the new gold-standard therapy for NVAMD. This discussion will review the more recently available published literature regarding longer term outcomes of anti-VEGF therapy, which will be defined as greater than 52 weeks following the treatment initiation.