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Anti-VEGF Therapies and Ocular Systemic Impact Update

By: Peter K. Kaiser, MD, Moderator; David S. Boyer, MD; John W. Kitchens, MD

This course has expired. You can still review the content but course credit is no longer available.

Supplement Credits: 1

Expiration Date: Monday, October 31, 2016
Release Date: October 2015

Learning Objectives

Upon completion of this activity participants should be able to:

• Understand the most recent monotherapy and combination therapy clinical study evidence using available antiVEGF therapies for common retinal diseases, including AMD, RVO and DME
• Discuss the ocular and systemic effects of anti-VEGF therapies and how to educate patients on appropriate expectations
• Develop plans to initiate treatment for conditions such as AMD, RVO and DME using anti-VEGF agents, as well as better understand when to change therapeutic strategies

Accreditation and Designation Statement

Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Evolve Medical Education and Retina Today.

Credit Designation Statement

Evolve Medical Education LLC is accredited by the ACCME to provide continuing education for physicians. Evolve Medical Education LLC designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit. ™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Participation Method

Participants should read the CME activity in its entirety. After reviewing the material, please complete the self-assessment test, which consists of a series of multiple choice questions. To answer these questions online and receive real-time results, please visit www.dulaneyfoundation.org and click “Online Courses.” Upon completing the activity and achieving a passing score of over 70% on the self-assessment test, you may print out a CME credit letter awarding 1 AMA PRA Category 1 Credit.™ The estimated time to complete this activity is 1 hour.

Statement of Need

The increasing number of patients presenting to retina specialists and ophthalmologists for treatment of retinal diseases such as age-related macular degeneration (AMD), retinal vein occlusion (RVO) and diabetic macular edema (DME) escalates the need for discussion of long-term ocular and systemic effects of the multiple treatment options now available and under study.1-8 As with any medical therapy, the importance of patient education about treatment options and expected disease impact, along with potential short versus long-term risks, is inherent to the process of determining and delivering appropriate treatment. Particularly in the rapidly developing environment of retinal disease therapy with anti-VEGF agents, there is a continual burden placed on retinal specialists and ophthalmologists using these agents to remain current on the latest clinical study results. As increasing numbers of patients are treated in clinical real-world environments, new and ongoing evaluations of long-term ocular and systemic effects of intravitreal anti-VEGF agents needs to be considered when initiating new treatment or changing therapeutic strategies for receiving therapy.9,10 A recent literature review has found intravitreal anti-VEGF monoclonal anitbodies are not associated with significant increases in either major cardiovascular or nonocular hemorrhagic events, but most studies are not powered enough to correctly assess potential risks.8,11 The process of ocular and systemic effects of anti-VEGF therapies is further complicated as patients progress in age and may develop additional unrelated health issues that require drug therapy. Thus, interpreting the analysis of ocular and systemic VEGF load before and during anti-VEGF therapy is more complex than ever.
Potentially complicating the issue for retinal specialists is that anti-VEGFs agents designed for use in cancer treatments are associated with several adverse events, including thromboembolic events, myocardial infarction, stroke, hypertension, gastrointestinal perforations, and kidney disease. Since the intravitreal formulation of these agents can also be detected systemically, the potential exists for systemic adverse events after intravitreal anti-VEGF use.12 Rare systemic events have been reported with the intravitreal formulations, however, including acute decrease in kidney function, hallucinations, and erectile dysfunction. A causative association has yet to be established.12 Additionally important to the discussion of short and longterm effects from anti-VEGF agents is the understanding of past and current testing assays available to determine ocular and systemic potency and drug clearance.13-15 Due to the long path of development and completion of large-scale clinical studies, new methods of evaluating the effects of therapies used in pivotal studies may not have been available during original protocol development. Understanding the utility of established and new testing assays can provide some further understanding of the key differences between available therapies, as well as new treatment regimens under study. As biological testing and imaging methods continue to develop, it is important to keep the interpretation of results in the proper context given similar, but often unique study designs.

Anti-VEGF therapy: AMD Ranibizumab (Lucentis, Genentech), which has been approved by the US Food and Drug Administration (FDA) since 2006, has been shown to stabilize or improve vision in those with neovascular AMD,16,17 but a common complaint is that dosing needs to be monthly for the effects to be maintained. Another study, PrONTO (Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Lucentis), evaluated patients treated with 3 monthly injections of ranibizumab, and then dosing on a p.r.n. basis. The preliminary results suggested patients maintained visual auity gains and were able to halve their monthly dosing schedule.18 Some retina specialists have used off-label bevacizumab (Avastin, Genentech), a full-length recombinant humanized monoclonal antibody directed against VEGF first approved for the treatment of metastatic colorectal cancer. There have been questions, however, as to how safe and effective off-label use of bevacizumab is compared to ranibizumab for the treatment of neovascular AMD, and a recent analysis of Part B Medicare expenditures suggests that off-label use is prevalent.19 Anecdotal and survey results from retinal specialists confirm the overwhelming use of bevacizumab as a first-line therapy in treating neovascular AMD. To address the questions of efficacy and safety of this offlabel use in comparison to the on-label treatment of wet AMD with ranibizumab, the National Eye Institute funded a large multicenter study to compare the two treatments. The results of the Comparison of AMD Treatments Trial (CATT) demonstrated noninferiority of intravitreal bevacizumab in comparison to ranibizumab for the treatment of wet AMD.20 The study authors noted, however, that differences in rates of serious system adverse events require further study. Outside the US, the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial found similar results, and noted serum VEGF was lower with bevacizumab, but there were no differences in the proportion of serious systemic adverse events.1,21 Aflibercept (Eylea, Regeneron) is the most recent addition to available anti-VEGF treatments for retinal disorders. Aflibercept was approved for neovascular AMD by the FDA in 2011, for central RVO in 2012, and for DME in 2014. VIEW 1 and 2 were parallel phase 3 clinical trials evaluating the efficacy of aflibercept for the treatment of wet AMD.2,7 VIEW 1 and 2 showed that aflibercept dosed every other month after 3 loading doses was noninferior to ranibizumab for the treatment of wet AMD. Most recently, data from the phase 3 HARBOR study were released. This trial evaluated the effects of a higher dose of ranibizumab, 2.0 mg versus the FDA-approved dose of 0.5 mg in once monthly and prn dosing formats. The results did not meet efficacy endpoint for superiority of 2 mg ranibizumab monthly, nor did it meet the secondary endpoint of noninferiority in the p.r.n. arm.22
Anti-VEGF and other therapy: RVO RVO is a common ocular disease that remains poorly understood due to the multifactorial nature of the presentation and contributing systemic factors. Several associated systemic factors have been identified and continue to be studied for their impact on RVO, including hypertension, diabetes, hypercholesterolemia, thyroid disorder, and ischemic heart disease. Increased intraocular pressure and axial length are other factors that play roles in this disease.23,24 For many years, clinicians have followed the recommendations set forth by the Branch Vein Occlusion Study25 and the Central Vein Occlusion Study.26 The former study demonstrated that grid laser photocoagulation leads to a higher improvement of visual acuity than natural history, but the latter showed grid laser photocoagulation did not improve visual acuity even though the macular edema decreased. The SCORE CRVO trial found that patients treated with intravitreal steroid experienced a substantial visual gain of 3 or more lines that persisted up to 2 years.27 Ranibizumab was FDA-approved for macular edema following both branch retinal vein occlusion (BRVO) and central retina vein occlusion (CRVO) in June 2010, based on the positive results of the BRAVO and CRUISE studies.28,29 Aflibercept was approved by the FDA in September 2012 for the treatment of macular edema secondary to CRVO. The COPERNICUS study evaluated aflibercept for the treatment of macular edema secondary to CRVO and found that patients in the treatment arms gained a significantly higher number of letters of vision.30 The dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) was approved by the FDA for the treatment of macular edema secondary to RVO in June 2009, and for DME in October 2014.31 Data from GENEVA showed was a visual acuity gain and reduction in macular edema at 2 months that was not observed in those in the placebo arm of the study.32 A second steroid, fluocinolone acetonide (Iluvien, Alimera Sciences) was also approved in October 2014 for treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure.33 A third corticosteroid, triamcinolone (Triesence, Alcon), has been approved for the treatment of uveitis and visualization during ocular surgery, but is often used off-label to treat the more common retinal disorders.34

Anti-VEGF and other therapy: DME/DR The diabetic patient population brings with it increased scrutiny of systemic safety when managing the ophthalmic manifestations. For instance, this group is already at a heightened risk of infection, so concerns about endophthalmitis are warranted,35 as are concerns about postoperative macular edema.36-42 Concerns about the systemic safety of the antiVEGF treatments also are heightened in the vasculopathic DME population. In this patient group, a decrease in retrobulbar blood flow parameters, retinal arteriolar vasoconstriction, and worsening of macular ischemia after intravitreal anti-VEGF administration has been reported.12 As might be expected, chronic use of the anti-VEGF agents in this patient population warrants close monitoring by fluorescein angiography or optical coherence tomography. Both ranibizumab and aflibercept were approved for treatment of DME by the FDA in 2014. In the phase 3 RISE and RIDE studies that compared ranibizumab 0.3 and 0.5 mg, the higher dose was associated with more deaths without providing any efficacy advantage compared to the lower dose.43 As a result of these studies, ranibizumab 0.3mg is the approved dose for treating DME. In the DaVINCI studies, intravitreal aflibercept resulted in visual acuity gains of up to 8.5 letters, with 34% of patients gaining 15 or more letters.44 However, common systemic adverse events included hypertension, nausea, and congestive heart failure after intravitreal aflibercept, although the study was not powered to sufficiently uncover associations.45 Although there was a higher incidence of cardiac events/ deaths in the aflibercept groups, the baseline characteristics showed the aflibercept groups to have roughly twice the prior incidence of cardiac disease than the laser group, which may have been reflected in the systemic AEs.44 The study of Intravitreal Administration of VEGF Trap-Eye (BAY86-5321) in Patients with Diabetic Macular Edema (VISTA DME), VEGF Trap-Eye in Vision Impairment Due to DME (VIVID-DME) and VIVID Japan found no increased rates of death, stroke, or myocardial infarction in the aflibercept groups; safety outcomes across all groups were similar.46 The dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) was approved in 2014 for the treatment of DME, but was initially granted approval only in select patient groups (pseudophakes and phakic patients scheduled to undergo cataract surgery).31 Approval had been limited because of the increased number of adverse events—namely, cataract formation and intraocular pressure spikes.47 The FDA removed the restrictions on lens status in October 2014. Fluocinolone acetonide has been approved for the treatment of DME.33 As with the other steroids, however, Iluvien is associated with increased cataract formation, increased IOP, and the necessity for surgical treatment of elevated IOP.48 As a result, its approval has been limited to patients who have previously shown no significant rise in IOP.33 Intravitreal triamcinolone has been shown in a few smaller studies to improve visual acuity in eyes with recalcitrant diffuse DME, but results have been inconclusive when compared to laser photocoagulation.48 Further, people treated with the steroid had significantly higher rates of increased intraocular pressure and close to 50% of study patients developed cataract while on the steroid. While approved in the US, its use for the treatment of DME remains off-label. Continued understanding of this landscape of available retinal therapies and their ocular and systemic effects is a process of putting recent clinical trials data in the proper context with longer term patient outcomes. As the complexity of treatment options also involves the cost and timing of repeated patient treatments, ophthalmologists using anti-VEGF treatments for common retinal diseases need to update their knowledge in order to provide their patients with the best understanding of treatment expectations and minimization of risks.

1. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial. Ophthalmology. 2012;119(7):1399-1411.
2. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-4258.
3. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and Bevacizumab for Treatment of Neovascular Agerelated Macular Degeneration: Two-Year Results. Ophthalmology. 2012;119(7):1388-1398.
4. Brown D. Intravitreal Aflibercept Injection (IAI) for Diabetic Macular Edema (DME): Primary and Additional Endpoint Results from the 12-Month Phase 3 VISTA-DME and VIVID-DME Studies. Association for Research in Vision and Ophthalmology. Orlando, FL, 2014.
5. Brown DM, Nguyen QD, Marcus DM, et al. Long-term Outcomes of Ranibizumab Therapy for Diabetic Macular Edema: The 36-Month Results from Two Phase III Trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022.
6. Chavan R, Panneerselvam S, Adhana P, et al. Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration. Clin Ophthalmol. 2014;8:717-723.
7. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.
8. Stefanini FR, Badaro E, Falabella P, et al. Anti-VEGF for the management of diabetic macular edema. J Immunol Res. 2014;2014:632307. 9. Chang AA, Li H, Broadhead GK, et al. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology. 2014;121(1):188-192.
10. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56(2):95-113.
11. Thulliez M, Angoulvant D, Le Lez ML, et al. Cardiovascular Events and Bleeding Risk Associated With Intravitreal Antivascular Endothelial Growth Factor Monoclonal Antibodies: Systematic Review and Meta-analysis. JAMA Ophthalmol. 2014.
12. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of antiVEGF agents: a review of literature. Eye (Lond). 2013;27(7):787-794.
13. Malik D, Tarek M, Caceres del Carpio J, et al. Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J Ophthalmol. 2014;98 Suppl 1:i11-6.
14. Schnichels S, Hagemann U, Januschowski K, et al. Comparative toxicity and proliferation testing of aflibercept, bevacizumab and ranibizumab on different ocular cells. Br J Ophthalmol. 2013;97(7):917-923.
15. Ammar DA, Mandava N, Kahook MY. The effects of aflibercept on the viability and metabolism of ocular cells in vitro. Retina. 2013;33(5):1056-61.
16. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
17. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
18. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143(4):566-583.
19. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol. 2011;151(5):887-895 e1.
20. Group CR, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
21. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013; 12;382(9900):1258-1267.
22. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120(5):1046-1056.
23. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4):513-518.
24. Ariturk N, Oge Y, Erkan D, et al. Relation between retinal vein occlusions and axial length. Br J Ophthalmol. 1996;80(7):633-636.
25. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98(3):271-282.
26. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):1425-1433.
27. Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) Study Results. National Eye Institute, National Institutes of Health, 2009; v. 2012.
28. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133 e1.
29. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112 e1.
30. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-37 e7.
31. Ozurdex [package insert]. Irvine, CA: Allergan Inc., 2014.
32. Haller JA, Bandello F, Belfort R, Jr., et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146 e3.
33. Iluvien [package insert]. Atlanta, GA: Alimera Sciences Inc., 2014.
34. Spitzer MS, Ziemssen F, Yoruk E, et al. [Preservative-free triamcinolone versus purified triamcinolone preparations]. Klin Monbl Augenheilkd. 2011;228(7):626-630.
35. Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrinol Metab. 2013;4(6):151-69.
36. Degenring RF, Vey S, Kamppeter B, et al. Effect 1of uncomplicated phacoemulsification on the central retina in diabetic and non-diabetic subjects. Graefes Arch Clin Exp Ophthalmol. 2007;245(1):18-23.
37. Benson WE. Cataract surgery and diabetic retinopathy. Curr Opin Ophthalmol. 1992;3(3):396-400.
38. Johnson MW. Etiology and treatment of macular edema. Am J Ophthalmol. 2009;147(1):11-21 e1.
39. Hayashi K, Igarashi C, Hirata A, Hayashi H. Changes in diabetic macular oedema after phacoemulsification surgery. Eye (Lond). 2009;23(2):389-396.
40. Nielsen NV, Vinding T. The prevalence of cataract in insulin-dependent and non-insulin-dependent-diabetes mellitus. Acta Ophthalmol (Copenh). 1984;62(4):595-602.
41. Cho H, Wolf KJ, Wolf EJ. Management of ocular inflammation and pain following cataract surgery: focus on bromfenac ophthalmic solution. Clin Ophthalmol. 2009;3:199-210.
42. Sahin M, Cingu AK, Gozum N. Evaluation of cystoid macular edema using optical coherence tomography and fundus autofluorescence after uncomplicated phacoemulsification surgery. J Ophthalmol. 2013;2013:376013.
43. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
44. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118(9):1819-1826.
45. Moradi A, Sepah YJ, Sadiq MA, et al. Vascular endothelial growth factor trap-eye (Aflibercept) for the management of diabetic macular edema. World J Diabetes. 2013;4(6):303-209.
46. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal Aflibercept for Diabetic Macular Edema. Ophthalmology. 2014; 121(11):2247-2254.
47. Diabetic Retinopathy Clinical Research N. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447-1449, 9 e1-10.
48. Messenger WB, Beardsley RM, Flaxel CJ. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular edema. Drug Des Devel Ther. 2013;7:425-434.

Faculty and Disclosures

David S. Boyer, MD had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board/Speaker’s Bureau: Aerpio Therapeutics; Alcon, Inc; Allegro Ophthalmics, LLC; Allergan, Inc.; Bausch + Lomb Incorporated; Bayer; Genentech, Inc.; KalVista Pharmaceuticals; Neurotech Pharmaceuticals; Novartis; Ora, Inc.; Pfizer Inc.; QLT Inc.; Regeneron Pharmaceuticals, Inc.; Roche USA; and ThromboGenics. Stockholder: Allegro Ophthalmics, LLC; Other: Data Safety Monitoring Board: StemCells, Inc.
Peter K. Kaiser, MD had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Alcon, Inc; Alimera Sciences; Allegro Ophthalmics, LLC; Bayer; Biogen Idec; Chengdu Kanghong Biotechnology Co, Ltd; DigiSight Technologies Inc; Genentech, Inc; InSitu; Novartis; OHR Pharmaceutical Inc; Ophthotech Corporation; Oraya Therapeutics, Inc; Regeneron Pharmaceuticals, Inc; and ThromboGenics NV; Stockholder: Allegro Ophthalmics, LLC; OHR Pharmaceutical Inc; and Ophthotech Corporation.
John W. Kitchens, MD had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Allergan, Inc; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; Synergetics USA, Inc.; and ThromboGenics.
Editorial Support Disclosure
Cheryl Cavanaugh, MS; Michelle Dalton and Melanie Lawler, PhD have no relevant commercial interests to disclose.


The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of The Dulaney Foundation and Retina Today.

Policy on Privacy and Confidentiality

In accordance with the disclosure policies of the Dulaney Foundation and to conform with ACCME and US Food and Drug Administration guidelines, anyone in a position to affect the content of a CME activity is required to disclose to the activity participants (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices or providers of commercial services and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

Anti-VEGF Therapies and Ocular Systemic Impact Update