Phase 3 registration trials for drugs that inhibit the actions of vascular endothelial growth factor (VEGF) demonstrated that regular-interval dosing of pegaptanib (6 weeks),1 ranibizumab (4 weeks),2-4 and aflibercept (4 weeks or 8 weeks)5,6 produced clinically and statistically superior visual acuity (VA) improvements over the comparator or baseline in eyes with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Patients experience clinically meaningful improvements in VA, but monthly therapy is often burdensome for physicians, patients, and caregivers, and concerns over the sustainability of these intensive treatment regimens have been voiced.7 Attempts to reduce the injection frequency to every 3 months obliterated gains in VA that had been obtained with a short course of monthly induction therapy.8-10 Investigators soon observed that frequent, regular dosing was not needed to produce satisfactory results for all patients and that individualized therapy could potentially reduce the direct and indirect costs of therapy, the number of injections, and possibly the number of visits to physicians’ offices.
HISTORY OF INDIVIDUALIZED THERAPY
The Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular AMD Treated With Intraocular Ranibizumab (PrONTO) trial11 demonstrated that pro re nata (PRN) treatment of nAMD improves best corrected visual acuity (BCVA) comparably to what was achieved in the registration trials and the Protocol I trial by the Diabetic Retinopathy Clinical Research Network12 produced similar BCVA improvements (after at least 4 monthly injections) in patients with DME. Subsequent trials, however, showed that PRN regimens for nAMD usually underperform monthly-injection regimens by approximately 2 letters without decreasing the need for monthly clinic visits and examinations.13-15 Some investigators expressed concerns that the prolonged treatment-free intervals, coupled with frequent recurrences that are inherent to PRN regimens, may increase the risk of subretinal hemorrhages.16,17
TREAT AND EXTEND FOR MACULAR DEGENERATION
The treat and extend (T&E) regimen, also referred to as inject and extend, was developed to decrease both injections and clinic visits without sacrificing the improvements in BCVA that are achieved with monthly injections. Treat and extend was formally introduced in 2007,18 but published studies did not appear for an additional 2 years.17,19-22 The early publications were predominantly retrospective analyses of nonrandomized studies. Gupta et al20 reported 92 patients treated with ranibizumab with an average follow-up of 1.6 years. Visual acuity results were impressive as 96% of patients lost fewer than 3 lines, 32% gained at least 3 lines, and the mean improvement was 2 lines. Patients received an average of 8.3 injections through 12 months. Oubraham et al22 retrospectively compared 38 patients treated according to T&E with 52 patients treated PRN. Mean improvements in VA at 1 year were +10.8 letters (T&E) and +2.3 letters (PRN) (P=.036). Patients treated according to T&E received more injections (7.8 vs 5.2).
Visual acuity results after 3 years of T&E varied among small cohorts of patients with type 3 choroidal neovascular membrane (CNVM; improved VA)17 and type 1 CNVM (stable VA).19 A large retrospective series (212 treatment-naïve eyes from 196 patients) reported the results of 12 months to 36 months (mean 1.88 years) of T&E treatment with ranibizumab or bevacizumab.23 Mean BCVA improved from 20/139 to 20/79 at 1 year, 20/69 at 2 years, and 20/64 at 3 years (P<.001 for each time point). Ninety-four percent of eyes lost fewer than 3 lines of VA and 34% gained at least 3 lines. Mean central retinal thickness (CRT) improved from 351 µm to 285 µm at 1 year, 275 µm at 2 years, and 276 µm at 3 years (P<.001 for each time point). Approximately 52% of eyes had persistent CNVM activity (presence of intraretinal or subretinal fluid) at 1 year, 2 years, and 3 years. Patients received means of 7.4, 5.7, and 5.8 injections during each of the 3 years. The average treatment interval was 11.4 weeks, 13.7 weeks, and 13.9 weeks during each of the 3 years. Only 2 patients developed submacular hemorrhage. Retrospective studies have shown that patients with type 1, 2, and 3 CNVM experience 1 to 2 lines of VA improvement when treated with aflibercept.24,25
A systematic review of PRN and T&E studies published through 2013 found that patients treated with bevacizumab and ranibizumab experienced mean BCVA improvements of 5.4 letters (PRN) and 10.4 letters (T&E) while receiving 5.6 injections and 8.1 injections through 1 year.26 The authors warned that the results from these predominantly retrospective studies should be interpreted with caution and they stressed the need for comparative, randomized, prospective trials.
The first prospective T&E study included 42 patients treated with ranibizumab for 1 year.27 Mean improvements in BCVA were 1.3 lines and patients were extended to an average of 9.1 weeks. A single-arm, 2-year, prospective study produced VA gains similar to those from the pivotal monthly ranibizumab trials.28
The most influential T&E trial was the Norwegian multicenter, randomized, double-blind Lucentis Compared to Avastin Study (LUCAS) trial that compared bevacizumab with ranibizumab.29 Patients received monthly injections (no minimum number) until signs of disease activity were absent. At 1 year, BCVA for patients receiving bevacizumab and ranibizumab were +7.9 letters and +8.2 letters, with mean decreases in CRT of 112 µm and 120 µm, after the administration of 8.9 injections and 8.0 injections, respectively. Similar results were seen at 2 years, with mean BCVA improvements of 7.4 letters and 6.6 letters, decreases in CRT of 113 μm and 122 μm, and total injections of 18.2 and 16.0 (P<.001).30
The Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration (TREX-AMD) trial has been the only randomized, prospective trial to compare T&E with monthly injections.31 Mean improvements in BCVA at 1 year were 10.5 letters and 9.2 letters (P=.60) after 10.1 injections and 13.0 injections (P<.0001), respectively. Eighteen percent of patients were maximally extended (12 weeks) and 45% were extended to 8 weeks or more.
TREAT AND EXTEND FOR DIABETIC MACULAR EDEMA
A prospective, randomized, single-blind, 24-month trial compared T&E with or without laser photocoagulation with PRN ranibizumab in 370 patients with DME.32 Both T&E regimens produced BCVA improvements comparable to PRN (+8.3, +6.5, +8.1 letters). Patients treated according to T&E received more injections than those treated PRN (12.4, 12.8, 10.7) but required 46% fewer clinical visits. Table 1 lists many of the published studies that included patients treated according to T&E protocols for nAMD and DME.
|AUTHOR, JOURNAL, YEAR||IMPORTANT CHARACTERISTICS||IMPORTANT FINDINGS|
|Engelbert et al17
Type 3 CNVM
|BCVA 20/80 to 20/40 at 36 months (P<.04)
Decrease in center point thickness (320 µm to 180-230 µm; P<.02)
Number of injections: 7 in year 1, 6 in year 2, 7 in year 3
|Engelbert et al19
Type 1 CNVM
|Change in BCVA from LogMAR 0.53 to LogMAR 0.52 at 36 months
Mean of 20 injections
No vision-threatening hemorrhages
|Gupta et al20
|With mean follow-up of 1.6 years:
|Oubraham et al22
|38 with T&E vs 52 with PRN
|Mean BCVA improvements at 1 year:
|Shienbaum et al21
Am J Ophthal 2012
|Mean BCVA improvements at 1 year (20/230 to 20/109; P<.001)
Mean CRT improvement at 1 year (316 µm to 239 µm; P<.001)
Mean of 7.9 injections
|Rayess et al23
Am J Ophthal 2015
|Mean BCVA improvements at 3 years (20/139 to 20/64; P<.001)
Mean CRT improvement at 1 year (351 µm to 276 µm; P<.001)
|Houston et al33
153 without VMA
51 eyes with VMA
|Mean BCVA improvements at 2 years:
|Rahimy et al34
|42 Eyes with VA
|Mean BCVA changes at 2 years (LogMAR 0.226 vs LogMAR 0.267)
Mean CRT improvement at 2 years (306 µm to 266 µm; P=.015)
BCVA of ≥20/40 maintained in 75% of eyes
|Castro-Navarro et al24
|Mean BCVA improvements at 1 year (LogMAR 0.61 vs LogMAR 0.38)
No difference among CNV subtypes
|Ohnaka et al25
Graefes Arch Clin Exp Oph 2016
|Mean BCVA improvements at 1 year (LogMAR 0.48 vs LogMAR 0.40)
Interval of ≥8 weeks in 64.7%
|Chin-Yee et al26
Br J Oph 2015
8 included manuscripts
|Mean BCVA improvements:
|Toalster et al27
|Ranibizumab||BCVA improved by mean of 1.3 lines (P=.008)
Three-line gainers: 26%; 3-line losers: 5%
|Abedi et al28
|Mean improvements in BCVA of +9.5 letters (1 year) and +8.0 letters (2 years)
Mean numbers of injections: 8.6 (1st year) and 5.6 (2nd year)
|LUCAS (Berg et al)29,30
Ophthalmology 2015, 2016
Ranibizumab vs bevacizumab
|Mean BCVA improvements at 1 year and 2 years:
|TREX-AMD (Wykoff et al)31
|T&E vs. monthly
|Mean BCVA improvements at month 12:
|Prünte et al32
Br J Ophthal 2016
|Diabetic macular edema
T&E + laser, T&E, or PRN
|Mean BCVA improvements at month 24:
|BCVA, BEST CORRECTED VISUAL ACUITY; CNVM, CHOROIDAL NEOVASCULAR MEMBRANE; PRN, PRO RE NATA; T&E, TREAT AND EXTEND; VMA, VITREOMACULAR ADHESION; CRT, CENTRAL RETINAL THICKNESS.|
IMPLEMENTING THE STRATEGY
The algorithm directing performance of T&E is well known to most retinal specialists, but it will be briefly discussed with emphasis on decision points where physicians can further individualize therapy (Figure 1). Eyes are injected monthly until neovascular activity has ceased or the physician believes that maximum improvement has been achieved. The interval to the next visit (which includes an injection) is then extended by 2 weeks, a practice that is continued until recurrent disease is noted. At this point, the interval is shortened by 2 weeks and treatment continues indefinitely with this visit interval. Criteria used to diagnose recurrent activity differ among studies but generally include the following: persistent or new subretinal or intraretinal fluid, new hemorrhage, macular thickening of at least 50 µm or 100 µm, decrease in vision of 5 ETDRS letters, and persistent neovascularization on fluorescein angiography. Once the longest injection interval that maintains a stable macula has been determined, the patient can be repeatedly treated for long periods of time, with reasonable assurance that disease activation or worsening will not occur between injections.
The longest interval to which patients can be safely extended while still benefiting from the injections has not been determined, but many physicians will not extend beyond 12 weeks. Because 20% of eyes with nAMD can be successfully treated with single injections and many eyes with DME require no additional injections after an initial period of intensive therapy, attempting to identify these eyes is a reasonable strategy. If patients can be successfully extended to 12 weeks, then many physicians will observe without additional treatments.
PHARMACOKINETIC RATIONALE FOR TREAT AND EXTEND
The duration of clinical action attributable to an intravitreal drug injection probably depends on several factors — size of the eye, liquefaction of the vitreous, vitreomacular traction/adhesion, permeability of the retina, composition of the neovascular lesion, and contribution of other chemokines and cytokines to neovascular growth — and probably others that have yet to be determined.35 Mathematical models have been developed to predict the duration of clinical actions of the anti-VEGF drugs, but they are capable of determining only relative and not absolute durations of action. Predicting the clinical response of an eye to anti-VEGF therapy a priori is not yet possible.
Muether et al analyzed the time-dependent intraocular VEGF concentrations, macula appearances on OCT, and visual acuities in cohorts of patients with treatment-naïve nAMD35 and DME.36 Intraocular VEGF concentrations were measured before each ranibizumab injection and compared to OCT scans and VA measurements. The authors found that the duration of VEGF suppression in patients with nAMD ranged from 26 days to 49 days, OCT evidence of neovascular activity was seen at a mean of 93.7 days, and VA decreased at a mean of 114 days. Intraocular VEGF concentrations were never suppressed at the time of recurrence, and VEGF concentration at the time of recurrence resembled those at baseline. These data suggest that OCT can be used to diagnose recurrence before VA becomes affected. But more importantly for each patient, the duration of ranibizumab action after each injection remains stable over periods up to 3 years.37 Similar results, but with shorter disease-free intervals, were seen in eyes with DME.36 This suggests that the duration of drug action in each eye is quite stable, which is an important requirement for the success of T&E. This pattern of stable disease-free intervals was validated in a prospective study38 and led to the “observe and plan (O&P)” regimen. With O&P, patients are treated until dry, examined monthly (until 8 weeks) without repeat injections until disease recurrence is observed. This period (less 2 weeks) is used as the extended interval.39
ADVANTAGES AND DISADVANTAGES OF TREAT AND EXTEND
Treat and extend is implemented with the hope that each patient can be treated after the longest possible interval that still prevents reactivation of disease and that in doing so, the number of injections is minimized. Rayess et al23 found that their patients received a mean of 13.3 injections through 2 years compared to 9.9 received by patients in the PrONTO trial. During this period, patients treated with T&E received 50% fewer examinations and OCT tests. By preventing disease reactivation, it is believed that VA gains with T&E exceed those with PRN therapy and are comparable to monthly injections.
FUTURE OF TREAT AND EXTEND
Results from the LUCAS trial and other recently published studies suggest that T&E may be as effective as monthly therapy. The TREX-AMD trial provides the only direct comparison of T&E with monthly therapy, and additional studies are still needed to validate efficacy. The LUCAS trial showed that ranibizumab has a slightly longer duration of action than bevacizumab (fewer injections) but direct comparisons with aflibercept have not been done.
Most investigators begin a T&E regimen with 3 monthly injections before they consider extending by 2 weeks. LUCAS has been the only prospective T&E trial to allow extension after the first injection, similar to how the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) required only a single “loading dose” after each recurrence. Current data do not support the necessity of a 3-injection loading dose, so extension after the first anti-VEGF injection — if the disease activity has ceased — would seem to be a reasonable strategy.
Both experimental data and prospective clinical studies show that disease-free intervals after injections fluctuate little for each patient. Treat and extend eventually identifies this interval after repeated injections, observations, and extensions. The O&E strategy aims to identify the same disease-free interval, but much earlier in the course of treatment. Thus, patients treated with O&E have their office visits “front-loaded” are not treated at each of the early visits, but require nearly the same number of injections during the first year. Additional randomized, prospective studies with this strategy are needed to fully characterize its efficacy.
Treat and extend was adopted rapidly by US physicians despite the early lack of supportive clinical trial data. By 2010 it had become the first choice of 37% of American Society of Retinal Specialists members for the treatment of nAMD40 and only 3 years later was preferred by 77% of specialists as determined by its Preferences and Trends survey.41 Use of T&E appears to be less frequent in other parts of the world. In the United Kingdom, an expert panel recommended T&E (up to 12 weeks) be considered for patients with stable AMD after 1 year of bimonthly aflibercept42 and a Delphi study found that T&E is used infrequently in Spain.43 Though international patterns of regimen use depend upon many factors, including drug labeling and regulatory guidance, the burden placed on physicians by the increasing number of patients receiving anti-VEGF therapy may serve to increase the use of T&E throughout the world. RP
- Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805-2816.
- Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;334(14):1432-1444.
- Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
- Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
- Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548.
- Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.
- Oishi A, Mandai M, Nishida A, Hata M, Matsuki T, Kurimoto Y. Remission and dropout rate of anti-VEGF therapy for age-related macular degeneration. Eur J Ophthalmol 2011;21:777-782.
- Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010;150(3):315-324.
- 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.
- Schmidt-Erfurth U, Eldem B, Guymer R, et al; EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology. 2011;118(5):831-839.
- Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148(1):43-58.
- Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614.
- Martin DF, Maguire MG, Fine SL, et al; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.
- Chakravarthy U, Harding SP, Rogers CA, et al; IVAN study investigators. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-1267.
- Ho AC, Busbee BG, Regillo CD, et al; HARBOR Study Group. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014;121(11):2181-2192.
- Levine JP, Marcus I, Sorenson JA, Spaide RF, Cooney MJ, Freund KB. Macular hemorrhage in neovascular age-related macular degeneration after stabilization with antiangiogenic therapy. Retina. 2009;29(8):1074-1079.
- Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina. 2009;29(10):1424-1431.
- Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol. 2007;143(4):679-680.
- Engelbert M, Zweifel S, Freund KB. Long-term follow-up for type 1 (subretinal pigment epithelium) neovascularization using a modified “treat and extend” dosing regimen of intravitreal antivascular endothelial growth factor therapy. Retina. 2010;30(9):1368-1375.
- Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology. 2010;117(11):2134-2140.
- Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD. Bevacizumab for neovascular age-related macular degeneration using a treat and-extend regimen: clinical and economic impact. Am J Ophthalmol. 2012;153(3):468-473.
- Oubraham H, Cohen SY, Samimi S, et al. Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-related macular degeneration. Retina. 2011;31(1):26-30.
- Rayess N, Houston SK 3rd, Gupta OP, Ho AC, Regillo CD. Treatment outcomes after 3 years in neovascular age-related macular degeneration using a treat-and-extend regimen. Am J Ophthalmol. 2015;159(1):3-8.
- Castro-Navarro V, Cervera-Taulet E, Montero-Hernández J, Navarro-Palop C. One-year outcomes of the treat-and-extend approach with aflibercept in age-related macular degeneration: effects on typical choroidal neovascularization and retinal angiomatous proliferation. Ophthalmologica. 2016;236(4):215-222.
- Ohnaka M, Nagai Y, Sho K, et al. A modified treat-and-extend regimen of aflibercept for treatment-naïve patients with neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2016 Oct 14. [Epub ahead of print]
- Chin-Yee D, Eck T, Fowler S, Hardi A, Apte RS. A systematic review of as needed versus treat and extend ranibizumab or bevacizumab treatment regimens for neovascular age-related macular degeneration. Br J Ophthalmol. 2015 Oct 29. [Epub ahead of print]
- Toalster N, Russell M, Ng P. A 12-month prospective trial of inject and extend regimen for ranibizumab treatment of age-related macular degeneration. Retina. 2013;33(7):1351-1358.
- Abedi F, Wickremasinghe S, Islam AF, Inglis KM, Guymer RH. Anti-VEGF treatment in neovascular age-related macular degeneration: a treat-and-extend protocol over 2 years. Retina. 2014;34(8):1531-1538.
- Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122(1):146-152.
- Berg K, Hadzalic E, Gjertsen I, et al. Ranibizumab or bevacizumab for neovascular age-related macular degeneration according to the Lucentis compared to Avastin study treat-and-extend protocol: two-year results. Ophthalmology. 2016;123(1):51-59.
- Wykoff CC, Croft DE, Brown DM, et al; TREX-AMD Study Group. Prospective trial of treat-and extend versus monthly dosing for neovascular age-related macular degeneration. TREX-AMD 1-year results. Ophthalmology. 2015;122(12):2514-2522.
- Prünte C, Fajnkuchen F, Mahmood S, et al; RETAIN Study Group. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic oedema: the RETAIN study. Br J Ophthalmol. 2016;100(6):787-795.
- Houston SK 3rd, Rayess N, Cohen MN, Ho AC, Regillo CD. Influence of vitreomacular interface on anti-vascular endothelial growth factor therapy using treat and extend treatment protocol for age-related macular degeneration (VINTREX). Retina. 2015;35(9):1757-1764.
- Rahimy E, Rayess N, Ho AC, Regillo CD. Treatment outcomes for neovascular age-related macular degeneration patients with initial vision better than 20/40 using a treat-and-extend regimen. Retina. 2016;36(5):875-880.
- Muether PS, Hermann MM, Viebahn U, Kirchhof B, Fauser S. Vascular endothelial growth factor in patients with exudative age-related macular degeneration treated with ranibizumab. Ophthalmology. 2012;119(10):2082-2086.
- Muether PS, Droege KM, Fauser S. Vascular endothelial growth factor suppression times in patients with diabetic macular oedema treated with ranibizumab. Br J Ophthalmol. 2014;98(2):179-181.
- Muether PS, Hermann MM, Droge K, Kirchhof B, Fauser S. Long-term stability of vascular endothelial growth factor suppression time under ranibizumab treatment in age-related macular degeneration. Am J Ophthalmol. 2013;156(5):989-993,e982.
- Mantel I, Deli A, Iglesias K, Ambresin A. Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2013;251(3):697-704.
- Mantel I, Niderprim SA, Gianniou C, Deli A, Ambresin A. Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen. Br J Ophthalmol. 2014;98(9):1192-1196.
- Mittra RA, Jumper JM, eds. ASRS 2011 Preferences and Trends Membership Survey. Chicago: American Society of Retina Specialists; 2010.
- Stone TW. 2013 Preferences and Trends (PAT) Survey. Toronto: American Society of Retina Specialists; 2013.
- McKibbin M, Devonport H, Gale R, et al. Aflibercept in wet AMD beyond the first year of treatment: recommendations by an expert roundtable panel. Eye (Lond). 2015;29:S1-S11.
- Garcia-Layana A, Arias L, Figueroa MS, et al. A Delphi study to detect deficiencies and propose actions in real life treatment of neovascular age-related macular degeneration. J Ophthalmol. 2014;2014:595132.