Anti-vascular Endothelial Growth Factor Therapy for Neovascular Age-related Macular Degeneration, Diabetic Macular Edema, and Diabetic Retinopathy: Outcomes of Recent Long-term Clinical Trials

Report from the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO)
Seattle, Washington   |  May 1-5, 2016

By David Assaad, MD, FRCSC

Anti-vascular endothelial growth factor (VEGF) therapy has now become the standard of care for retinal vascular disorders associated with neovascularization and edema, notably neo­vascular age-related macular degeneration (wet AMD) and ­diabetic macular edema (DME). After more than a decade validating use of anti-VEGF agents in the treatment of these disorders, impact of their use on long-term vision outcomes and the natural history of these diseases are becoming more clearly defined. Despite a better understanding of baseline patient and disease-related characteristics that impact response to treatment, emerging trends from long-term clinical trial data are defining the scope of unmet needs and potential targets for future therapeutic improvements. In the interim, review of these trends can be used to frame guidelines for use of the ­currently available anti-VEGF drugs to optimize vision outcomes. The goal of this Ophthalmology Scientific Update is to present an overview of clinical presentations and discussions that took place at the 2016 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) as they relate to treatment of retinal disease in everyday Canadian ophthalmic practice.

Protocol T: 2-Year Outcomes

With the publication of the 5-year results of the Diabetic Retinopathy Clinical Research Network’s (DRCR.net) Protocol I, anti-vascular endothelial growth factor (VEGF) therapy has emerged as the gold standard of care in the treatment of diabetic macular edema (DME), largely supplanting the need for grid laser.[1-3] The efficacy and safety of both aflibercept and ranibizumab in this patient population has been further validated by numerous randomized and industry-sponsored registration trials.[4-6] To date, Protocol T is the only randomized trial providing a head-to-head comparison of the 3 available anti-VEGF agents[7,8] – aflibercept 2.0 mg, bevacizumab 1.25 mg, and ranibizumab 0.3 mg – for patients with DME. The 1-year outcomes are the source of widespread clinical debate, in some part due to the inclusion of the 0.3-mg dose of ranibizumab (approved by the United States Food and Drug Administration) as compared to the 0.5-mg dose commonly used in Canada and other countries worldwide.

At 1 year, the difference in efficacy between the 3 anti-VEGF agents was dependent on the baseline level of visual acuity (VA).[7] In patients with VA better than 20/40 (approximately 50% of the study cohort), all 3 agents demonstrated similar efficacy with a mean gain of about 8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. However, in patients with VA worse than 20/50, mean gain with aflibercept was significantly better than with either ranibizumab (18.9 versus 14.2 letters; P=0.003) or bevacizumab (18.9 versus 11.8 letters; P<0.001). There was no statistically significant difference between ranibizumab and bevacizumab.
At 1 year, both aflibercept and ranibizumab were more effective in reducing mean central subfield thickness (CST; -169±138 µm, and -147±134 µm, respectively) compared with bevacizumab (-101±121 µm).

The 2-year Protocol T data, presented by John Wells, MD (Carolina Retina Center, Columbia, South Carolina), demonstrated that, in patients with VA worse than 20/50, the difference in VA between aflibercept and ranibizumab was no longer statistically significant.[8] Mean VA improvement from baseline was 12.8 letters with aflibercept, 10.0 letters with bevacizumab and 12.3 letters with ranibizumab (pairwise comparisons: P=0.02 for aflibercept versus bevacizumab; P=0.47 for aflibercept versus ranibizumab; and P=0.11 for ranibizumab versus bevacizumab). The results for overall VA and for both subgroups (VA ≥20/40 and ≤20/50) are shown in Figure 1. Other treatment outcomes previously noted at Year 1 were also seen at Year 2. Roughly 50% of patients with baseline VA worse than 20/50 experienced a ≥15-letter improvement. A loss of ≥15  letters occurred in 4% of patients treated with bevacizumab and in 2% of those receiving either aflibercept or ranibizumab. Use of focal/grid laser, in accordance with protocol-defined criteria, was required in 64%, 52% and 41% of bevacizumab, ranibizumab, and aflibercept-treated patients, respectively.[8]

Figure 1: Protocol T:8 BCVA at 2 years according to baseline VA

1A. Overall mean 2-year VA improvement from baseline was 12.8±12.4 letters for aflibercept, 10.0±11.8 letters for bevacizumab, and 12.3±10.5 letters for ranibizumab. 1B. When initial VA letter score was 20/50 or worse, mean ETDRS letter score improvement from baseline to the 2-year visit was 18.1±13.8 letters, 13.3±13.4 letters, and 16.1±12.1 letters, respectively. Only the difference between aflibercept and bevacizumab was statistically significant (P=0.02). 1C. When initial VA was 20/32 to 20/40, mean improvement at the 2-year visit was 7.8±8.4 letters, 6.8±8.8 letters, and 8.6±7.0 letters, respectively; differences between groups were not statistically significant.

BCVA = best-corrected visual acuity; VA = visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study

 

Reproduced with permission from Wells JA et al. Ophthalmology. 2016;123(6):1351-1359. Copyright © 2016, American Academy of Ophthalmology.

Overall, bevacizumab was less effective at reducing retinal thickness than the other 2 anti-VEGF agents. In eyes with baseline VA worse than 20/50, CST at 2 years decreased by averages of 211±155 µm, 185±158 µm, and 174±159 µm with aflibercept, bevacizumab and ranibizumab, respectively. In patients with ­baseline VA of 20/32–20/40, CST decreased by averages of 133±115 µm with aflibercept, 68±98 µm with bevacizumab and 125±118 µm with ranibizumab. At Year 2, CST <250 µm was attained by 41% of patients treated with bevacizumab, 65% of those taking ranibizumab, and 71% of aflibercept patients (Figure 2).

Figure 2: Protocol T:[8] OCT CST 2-year outcomes

­­­Mean change (µm) ± SD

                              -211±155        -185±158     -174±159

• Aflibercept versus

   bevacizumab*               -42.1 (-77.2 to -7.0) P=0.01

• Aflibercept versus

   ranibizumab*                -19.3 (-47.8 to +9.3) P=0.19

• Ranibizumab versus

   bevacizumab*               -22.8 (-52.2 to +6.6) P=0.19        

Mean change (µm) ± SD

                                 -133±115                -68±98            -125±118

• Aflibercept versus

   bevacizumab*               -57.3 (-82.7 to -31.9); P<0.001

• Aflibercept versus

   ranibizumab*                -11.8 (-32.4 to +8.8); P=0.26

• Ranibizumab versus

   bevacizumab*               -45.4 (-69.6 to -21.3); P<0.001        

*Treatment group comparisons: differences in mean change or difference in proportions (adjusted 95% confidence interval), and adjusted P value

 

OCT = optical coherence tomography; CST = central subfield thickness; SD = standard deviation

Over the 2-year period, higher rates of Antiplatelet Trialists’ Collaboration (APTC) events, mainly nonfatal strokes and vascular deaths, were noted in patients treated with ranibizumab compared to the other 2 agents. However, once adjustments were made for imbalances in baseline characteristics – including any prior history of myocardial infarction, coronary artery disease, stroke and transient ischemic attacks (TIAs) – the difference in the rate of APTC events was no longer significant. Additionally, the adverse events reported in Protocol T for ranibizumab were inconsistent with previously reported safety data from other Phase III studies,[9,10] notably Protocol I,[1] in which the 2-year APTC rate for ranibizumab group (7%) was lower than in the control (laser) group (13%).

Protocol S: The First Major Advance in the Treatment of Diabetic Retinopathy (DR) in 40 Years

The improvement in diabetic retinopathy (DR) scores[11] – and reduced risk of worsening retinopathy –
seen in patients treated with anti-VEGF therapy in DME trials provided the impetus and rationale for the Protocol S trial.

Protocol S enrolled 305 participants with proliferative DR in one or both eyes at 55 clinical sites across the United States.[12] Eyes were randomly assigned to treatment with ranibizumab 0.5 mg (3 monthly loading doses followed by monthly injections PRN based on a structured retreatment protocol) or panretinal photocoagulation (PRP) completed in 1-3 sessions. Eyes in both treatment arms were eligible to receive ranibizumab for treatment of DME. The primary outcome was mean improvement in VA at 2 years
(using a 5-letter noninferiority margin).

At 2 years, mean VA improved from baseline by 2.8 letters in the ranibizumab group and by -0.2 letters in the PRP group (mean difference of +2.2 letters (95% confidence interval [CI]: -0.5 to +5.0; P <0.001) (Table  1). Mean treatment group difference in VA area under the curve at 2 years was +4.5 letters for the ranibizumab compared with -0.3 letters for the PRP group (mean difference, +4.2 letters; 95% CI: +3.0 to +5.4; P<0.001). For eyes with DME at baseline (35% of patients), mean difference in VA letter score was +3.0  letters (95% CI: -4.2 to +10.3) between the ranibizumab and PRP groups For eyes without DME at baseline, mean difference in VA letter score was +1.4 letters (95% CI: -1.5 to +4.4; P=0.84).

Table 1: Protocol S:[10] change in VA over time

a Two-year data were missing from 31 and 35 eyes in the ranibizumab and PRP groups, respectively; b group differences and 95% CIs were determined using analysis of covariance, adjusted for baseline VA, number of study eyes, and correlation between 2 study eyes of the same participant, with multiple imputation for missing data when indicated; c intention-to-treat analysis with multiple imputation; d observed data.

 

AUC = area under the curve; PRP = panretinal photocoagulation; CI = confidence interval.

Over half of eyes in the PRP group (53%) required ranibizumab injections for treatment of DME, while only 6% of eyes randomized to ranibizumab required laser therapy to treat vitreous hemorrhage or retinal detachment. Mean peripheral visual field loss was greater in the PRP group (-422 dB) than in the ranibizumab group (-23 dB). Rates of vitrectomy were also higher in patients receiving PRP (15%) than in those treated with ranibizumab (4%). Among eyes without DME at baseline, development of DME and vision impairment was more frequently observed in the PRP group (28%) than in the ranibizumab group (9%) suggesting a possible vision-sparing effect of anti-VEGF therapy.

Overall, no significant safety concerns emerged as a result of treatment with ranibizumab. Despite one reported case of endophthalmitis in the ranibizumab group, patients treated with PRP reported more frequent inflammation, higher incidence of cataract surgery, and elevation in intraocular pressure. Jeffrey Gross, MD (Carolina Retina Center, Columbia, South Carolina), suggested that anti-VEGF therapy may become a viable, and in some patients preferred, initial therapy for patients with proliferative DR.

Lessons Learned From the Comparison of AMD Treatment Trial (CATT) Follow-up

The 5-year follow-up results of the CATT trial were presented by Daniel Martin, MD (Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, and CATT study chair).[13] The CATT trial was a multicentre, single-blind,
non-inferiority trial comparing vision outcomes in patients with wet age-related macular degeneration (AMD) treated with intravitreal injections of either ranibizumab or bevacizumab on a fixed monthly or PRN basis for 2 years.[14,15] The objective of the 5-year analysis was to evaluate the long-term vision outcomes of patients with AMD treated with anti-VEGF therapy rather than a comparison of the efficacy of the 2 agents used.

Data from 647 of 1185 patients initially enrolled in CATT (328 ranibizumab and 319 bevacizumab) were included in the analysis. In comparison to patients who did not elect to participate in the follow-up study, those who remained in the study were, on average, 2.3 years younger at baseline (77.5 years of age), had better VA – both at baseline (62.2 vs. 59.1 letters) and at 2 years (69.7 vs. 64.3 letters) – and had received 2 more PRN injections over 2  years. The mean number of treatments over 3  years of follow-up was 15.4 and the mean number of visits was 25.3. The disparity between the number of visits and treatments is consistent with the use of a PRN dosing protocol rather than the treat-and-extend (T&E) regimen frequently used by many Canadian practitioners.

Although more than 90% of participants continued their follow-up care at a designated CATT centre after release from the trial, the majority of patients did not continue exclusive monotherapy with the drug to which they had been randomized. Only 19.5% of the ranibizumab patients were maintained on ranibizumab and only 31.0% of the bevacizumab patients were maintained on bevacizumab, thereby limiting the utility of any long-term efficacy comparison between drugs. Perhaps of greater significance, given the natural history of untreated disease, is that no additional treatment was administered over the follow-up period in up to 14.0% of ranibizumab patients and in 15.7% of bevacizumab patients.

Over a 3.5-year follow-up period after release from CATT, patients received an average of 4-5 injections per year and mean VA decreased by 11 letters (from 70 at Year 2 to 59 by Year 4; Figure 3). At 5 years, however, almost 50% of patients retained VA ≥20/40 (Table 2). For historical context, prior to the availability of anti-VEGF therapy, fewer than 15% of patients retained VA ≥20/40 and roughly 40% experienced VA ≤20/200. Accordingly, despite the potential for improved therapeutic outcomes in the treatment of wet AMD in the future, the switch to anti-VEGF drugs as the mainstay of therapy has significantly altered the natural history and long-term visual prognosis associated with treatment of wet AMD.

Figure 3: CATT follow-up study:[13] mean VA over time

CATT = Comparison of Age-related Macular Degeneration (AMD) Treatment Trial Reproduced with permission from the
CATT Research Group. Ophthalmology. 2016;123(8):1751-1761. Copyright © 2016, American Academy of Ophthalmology.

Table 2: CATT follow-up study:[13] distribution of VA over time 

During the 2-year CATT trial, the risk of experiencing at least one serious systemic adverse event was significantly higher in patients treated with bevacizumab than in those treated with ranibizumab (39.9% versus 31.7%; P=0.004).[15] These results must be interpreted with caution, however, due to the relatively high rate of discontinuation of the initially assigned anti-VEGF drug.

The impact of morphologic features on response to treatment and long-term outcomes in CATT was discussed by Glenn Jaffe, MD (Duke University, Durham, North Carolina).[16] Over 5 years, choroidal neovascularization (CNV) evolved with evidence of persistent disease activity in many eyes. Intra-retinal, subretinal and subretinal pigment ephithelium (RPE) fluid were present in 458 of 552 eyes (83%), for which spectral-domain optical coherence tomography (SD-OCT) scans were available. At 5 years, the percentage of patients with sub-retinal (38%) and sub-RPE fluid (36%) did not differ significantly from the percentages reported at Year 2. The percentage of patients with intraretinal fluid increased from 50% at 2 years to 61% at 5 years. The presence of foveal and nonfoveal geographic atrophy (GA) increased from 20% at Year 2 to 41% at Year 5. Statistical analysis of macular morphology revealed worse VA in eyes with intraretinal fluid, thicker subretinal tissue complex, the presence of very thin retina (<120 µm), subretinal hyperreflective material, geographic atrophy, and fibrosis. Presence of subretinal and sub-RPE fluid were associated with better VA.

A sub-analysis of CATT data presented by Juan Grunwald, MD (Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania)[17] demonstrated higher GA growth rate in eyes without sub-RPE fluid compared to eyes with both foveal and nonfoveal sub-RPE fluid (0.35, 0.31 and 0.21 mm/year, respectively; P=0.02). Predominantly classic lesions were associated with higher GA growth rate than occult lesions (0.38 versus 0.24 mm/year; P=0.04). There was no significant difference in GA growth rate in eyes treated with ranibizumab compared to bevacizumab (P=0.12).The proportion of eyes with abnormally thin retina increased over the follow-up period from 22% in Year 2 to 36% at Year 5.

With respect to the impact of various morphologic characteristics on vision outcomes, presence of subretinal and sub-RPE fluid were the only variables associated with better VA. At 5 years, mean ETDRS scores were higher in patients with sub-retinal fluid (68 letters) compared to patients without (61 letters). Presence of
sub-RPE fluid had an even greater impact: patients with sub-RPE fluid had ETDRS scores of 73 letters as compared to 60 letters in patients without. All other morphologic variables – intra-retinal fluid, abnormally thin retina (<120 µm), subretinal hyperreflective material, GA and fibrosis – were associated with worse VA scores. These anatomic biomarkers may be helpful in framing the scope of unmet needs in the treatment of neovascular AMD and point to potential targets for future therapies.

Impact of Data on the Use of Anti-VEGF Therapy in the Treatment of
DME, Proliferative DR (PDR), and AMD in Canada

The 2 Year Protocol T data validated the efficacy of anti-VEGF drugs as the mainstay of therapy for DME. The second year of therapy was associated with a reduction in the number of injections given as well as the need for protocol-mandated rescue focal/grid laser treatment. Perhaps most noteworthy, the therapeutic efficacy difference seen between aflibercept and ranibizumab, in patients with VA worse than 20/50 at 1 year, was no longer statistically significant after 2 years of treatment. These findings, in conjunction with the inclusion of the lower 0.3-mg dose of ranibizumab, may help to further support speculation that there is no clinically significant difference in efficacy between the 2 drugs at the standard doses used in Canada – aflibercept 2 mg and ranibizumab 0.5 mg – across a broader range of patients with DME.

The most relevant predictive variable for determination of best-corrected VA gain, as determined by a computerized predictive model (Schmidt–Erfurth et al)[18] was intraretinal cystoid fluid volume. Accordingly, choosing an anti-VEGF agent with the better efficacy in the reduction of intraretinal cystoid changes might, in theory, help to optimize vision and function-related outcomes. A study by Costa et al[19] demonstrated that a decrease in central retinal thickness (CRT) ≥9% after the first intravitreal injection was associated with better VA at both 3 and 6 months, independent of baseline VA or CRT. A sub­analysis of RESTORE data identified baseline VA ≥ 20/40, shorter duration of diabetes and thinner baseline CRT as predictive of future VA ≥ 20/40.[20] The inclusion of relevant, well-established predictive variables in the decision-making process – including drug selection – may be associated with better clinical decision-making and improved vision outcomes.

Through 2 years, both ranibizumab and aflibercept were superior to bevacizumab at reducing retinal thickness and intraretinal cystoid fluid volume.[7,8] This difference in efficacy,  and its potential impact on
long-term vision outcomes, may be of particular relevance in the context of policy-making decisions for drug reimbursement. Some consideration to differential efficacy may now be required to offset the relatively high cost disparity frequently cited between bevacizumab and the other 2 agents.

Protocol S has validated the use of anti-VEGF therapy as a viable therapeutic option in the treatment of PDR. Although anti-VEGF therapy has by no means supplanted the use of PRP, clinicians are becoming increasingly aware of the potential adverse effects associated with PRP, particularly the risk of developing DME and worsening field loss. Increased clinical vigilance for concomitant DME and long-term follow-up data of
anti-VEGF therapy in patients with PDR will help delineate the differential role of injections and PRP in the treatment of PDR in the future.

Long-term follow-up data from CATT have established the detrimental effect of intraretinal fluid on long-term vision outcomes in patients with AMD. A post hoc analysis of the EXCITE study (N=353) – in which patients were treated either monthly or every 12 weeks after a monthly loading phase – confirmed the early recurrence of intraretinal fluid and loss of the initial vision gain in patients treated every 12 weeks.[21] A more intensive treatment protocol, such as the T&E strategy more commonly used in Canadian retinal practice, may provide the opportunity to optimize vision outcomes using a more individualized, patient-centred approach.

The Canadian Treat and Extend Analysis Trial With Ranibizumab (CAN-TREAT) study – a randomized,
open-label, multicentre noninferiority study – is currently underway. The objective of the study is to compare the efficacy of ranibizumab injections in patients with wet AMD using an OCT-guided T&E regimen compared to injections given on a fixed, monthly basis. Peter Kertes, MD (Sunnybrook Health Sciences Centre, Toronto, Ontario), presented the 1-year interim results of CAN-TREAT.[22] Over 12 months, patients in the T&E and monthly arms received a mean of 9.7 and 11.8 injections, respectively. Mean VA improvement was 8.5 letters for patients treated with T&E and 6.0 letters for patients treated monthly. These interim results suggest that the T&E approach is likely a viable treatment strategy and numerous presentations at ARVO 2016 indicated that the T&E approach is being adopted more widely in countries across the world, not only in the context of AMD,[23-28] but also for DME.[29]

Conclusion

In 2016, anti-VEGF therapy has become the standard of care in an increasing number of retinal disorders, including wet AMD and DME. Despite some unmet needs and the potential for future therapeutic improvements, anti-VEGF therapy has led to vastly improved vision outcomes over the last decade. Increasing evidence from long-term follow-up and clinical trial data has validated the importance of
intra-retinal fluid, in particular, as a critical biomarker in terms of its impact on visual outcomes. Use of an intensive treatment approach and appropriate drug selection are the tools available to treating Canadian retinal practitioners at present. Increased clinical vigilance and a better understanding of the relevant anatomic and demographic variables that can alter long-term prognosis will enhance the ability of treating physicians in clinical decision-making in order to optimize vision and functional outcomes.

Dr. Assaad is a lecturer, Department of Ophthalmology & Vision Sciences, University of Toronto, and an ophthalmology staff member at St. Michael’s Hospital and Kensington Eye Institute, Toronto, Ontario.

References:

  1. Diabetic Retinopathy Clinical Research Network; Elman MJ, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.

  2. Diabetic Retinopathy Clinical Research Network; Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312-2318.

  3. Elman MJ, Ayala A, Bressler NM, et al; Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375-381.

  4. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4): 615-625.

  5. 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.

  6. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.

  7. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015; 372(13):1193-1203.

  8. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359.

  9. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355: 1419-1431.

  10. 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;355(14):1432-1444.

  11. Clark WL, Ehrlich JS, Chen D. Intravitreal ranibizumab modifies the natural history of diabetic retinopathy: 36-month data from the RISE and RIDE Phase III trials. Presented at the 31st Annual Meeting of the American Society of Retina Specialists. Toronto (ON): August 24-28, 2013.

  12. Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314(20):2137-2146.

  13. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration. Ophthalmology. 2016;123(8)1751-1761.

  14. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20): 1897-1908.

  15. CATT Research Group; Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1389.

  16. Jaffe GJ. CATT Presentation. Presented at the ARVO Workshop session entitled “Two NEI Clinical trials on Anti-VEGF Therapy for Neovascular AMD and Diabetic Retinopathy."  Seattle (WA): May 1-5, 2016.

  17. Grunwald JE, Pistilli M, Daniel E, et al. Size and growth of geographic atrophy during 5 years of follow up in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Presented at the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO). Seattle (WA): May 1-5, 2016. Abstract 4293.

  18. Schmidt-Erfurth U, Bogunovic H, Schlegl T, et al. Prognostic factors in the treatment of diabetic macular edema (DME) using aflibercept, ranibizumab and bevacizumab (DRCR.net Protocol T*). Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 2082.

  19. Costa M, Santos AR, Nunes S, et al. OCT retinal thickness response after first intravitreal injection is a predictor of visual acuity response to anti-VEGF treatment of DME. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 2080.

  20. Chong V, Alsop J, Margaron P, Mitchell P. Achievement of ≥20/40 vision with ranibizumab in patients with diabetic macular edema: a post hoc analysis of the RESTORE study. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 2079.

  21. Waldstein SM, Chong V, Larsen M, et al. Association of fluid recurrence with visual maintenance following the loading phase in anti-VEGF therapy for neovascular AMD. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 533.

  22. Kertes P, Sheidow T, Greve W, et al. Canadian TReat and Extend Analysis Trial with ranibizumab in patients with nAMD: interim analysis of the CANTREAT study. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 538.

  23. Barthelmes D, Nguyen V, Arnold J, et al. Twelve-month outcomes of “treat and extend” aflibercept therapy for neovascular age-related macular degeneration. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 521.

  24. Hosokawa M, Morizane Y, Kimura S, et al. Two-year results of intravitreal aflibercept injections for neovascular age-related macular degeneration using a treat and extend regimen. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 529.

  25. Akika K, Yamamoto M, Yasui A, et al. Two-year results of “treat and extend” intravitreal aflibercept injection for exudative age-related macular degeneration. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract. 2667.

  26. Granstam E, Sjövall K, Paul A, et al. Anti-VEGF treatment for wet AMD according to a treat-and-extend protocol at a Swedish county hospital: clinical outcomes at 12 months. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract. 2668.

  27. Nizawa T, Kitahashi M, Yokouchi H, et al. One-year outcomes of intravitreal aflibercept for wet AMD using modified treat and extend regimen. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 2669.

  28. Rufai SR, Almuhtaseb H, Lee H. A systematic review to assess the “Treat-and-Extend” dosing regimen compared to monthly and as-needed dosing for neovascular age-related macular degeneration using ranibizumab. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 3367

  29. Payne J, Wykoff CC, Clark WL, et al. Prospective trial comparing ranibizumab monthly to treat & extend with & without angiography-guided laser for DME: TREX-DME 1-year outcomes. Presented at ARVO 2016. Seattle (WA): May 1-5, 2016. Abstract 2315.

 

Disclosure Statement: Dr. Assaad has acted as a consultant for Novartis and Bayer.

SNELL Medical Communication acknowledges that it has received an unrestricted educational grant from Novartis Pharmaceuticals Canada to support the ­distribution of this issue of Ophthalmology ­Scientific Update. Acceptance of this grant was conditional upon the sponsors’ acceptance of the policy established by the ­Department of Ophthalmology and Vision ­Sciences and SNELL Medical Communication guaranteeing the ­educational integrity of the publication. This policy ensures that the author and editor will at all times ­exercise unrestricted, rigorous, ­scientific independence free of interference from any other party. This publication may include discussion of products or product indications that have not been granted approval by Health Canada. This content is intended for medical, scientific, and educational purposes only.

© 2016 Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, which is solely responsible for the contents.
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