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Anti-VEGF Therapies: Ocular and Systemic Impact

By: Peter Kaiser, MD, Moderator; Thomas Albini, MD; Audina Berrocal, MD; Ross Lakhanpal, MD; Andrew Moshfeghi, MD, MBA; and Charles C. Wykoff, MD, PhD

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

Supplement Credits: 1

This continuing medical education (CME) activity captures content from a CME roundtable held in August of 2014 in Philadelphia, PA.

Expiration Date: Monday, November 30, 2015
Release Date: November 2014

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 anti-VEGF therapies for common retinal diseases, including AMD, RVO, and DME
• Appreciate the relevance of key assay methods to determine ocular and systemic effects of anti-VEGF therapies
• 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

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Dulaney Foundation and Retina Today. The Dulaney Foundation is accredited by the ACCME to provide continuing education for physicians. The Dulaney Foundation 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.


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 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.
Especially in the rapidly developing environment of retinal disease therapy with antivascular endothelial growth factor (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. In addition, due to the larger population that has now received treatment in the past, new and ongoing evaluations of long-term ocular and systemic effects of intravitreal anti-VEGF agents need to be considered when initiating new treatment or changing therapeutic strategies for undergoing therapy.9
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.
Additionally important to the discussion of short- and long-term effects from anti-VEGF agents is the understanding of past and current testing assays available to determine ocular and systemic potency and drug clearance.10-12 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.
To address the questions of safety and efficacy of this off-label 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 2 treatments. The results of the Comparison of AMD Treatments Trial (CATT), which were recently made available, demonstrated noninferiority of intravitreal bevacizumab in comparison to ranibizumab for the treatment of wet AMD.13 The study authors noted, however, that differences in rates of serious system adverse events require further study.
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 as-needed 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 as-needed arm.14
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.15,16
For many years, clinicians have followed the recommendations set forth by the Branch Vein Occlusion Study17 and the Central Vein Occlusion Study.18 The former study demonstrated that grid laser photocoagulation leads to a higher improvement of VA than natural history, but the latter showed grid laser photocoagulation did not improve VA even though the macular edema decreased. The SCORE CRVO trial found that patients treated with intravitreal steroids experienced a substantial visual gain of 3 or more lines that persisted up to 2 years.19
Continued understanding of this landscape of available anti-VEGF 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. 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.
2. Chavan R, Panneerselvam S, Adhana P, Narendran N, Yang Y. 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.
3. Scott AW, Bressler SB. Long-term follow-up of vascular endothelial growth factor inhibitor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2013;24(3):190-196.
4. Brown DM, Nguyen QD, Marcus DM, et al; RIDE and RISE Research Group. 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.
5. Do DV. Intravitreal aflibercept injection (IAI) for diabetic macular edema (DME): 12-month results of VISTA-DME and VIVID-DME. Paper presented at: the 2013 Annual Meeting of the American Academy of Ophthalmology; November 16-19, 2013; New Orleans, LA.
6. IVAN Study Investigators, 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.
7. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two year results. Ophthalmology 2012;119:1388–1398.
8. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537–2548.
9. Chang AA, Li H, Broadhead GK, Hong T, Schlub TE, Wijeyakumar W, Zhu M. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology. 2014 Jan;121(1):188-192.
10. 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-i16.
11. 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.
12. Ammar DA, Mandava N, Kahook MY. The effects of aflibercept on the viability and metabolism of ocular cells in vitro. Retina. 2013;33(5):1056-1061.
13. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
14. Heier JS. VEGF Trap-Eye Phase III Trial Results. VIEW 1 results. Paper presented at: Angiogenesis, Exudation, and Degeneration 2011; Miami, FL; February 12, 2011.
15. Schmidt-Erfurth U. VEGF Trap-Eye Phase III Trial Results. VIEW 2 results. Paper presented at: Angiogenesis, Exudation, and Degeneration 2011; Miami, FL; February 12, 2011.
16. Ho A. Results of HARBOR phase III study the efficacy of 2 mg ranibizumab. Paper presented at Retina Subspecialty Day at the American Academy of Ophthalmology. October 2011; Orlando, FL.
17. 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.
18. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein

Faculty and Disclosures

Thomas Albini, MD
Associate Professor of Clinical Ophthalmology
University of Miami
Bascom Palmer Eye Institute
Miami, FL

Audina Berrocal, MD
Professor of Clinical Ophthalmology
University of Miami
Bascom Palmer Eye Institute
Miami, FL

Peter K. Kaiser, MD,
Professor of Ophthalmology
Cleveland Clinic Lerner College of Medicine
Staff Surgeon, Vitreoretinal Department
Cole Eye Institute, Cleveland Clinic
Cleveland, OH

Rohit Ross Lakhanpal, MD
Retina Specialist
The Eye and Cosmetic Surgery Center
Mercy Medical Center
Baltimore, MD

Andrew Moshfeghi, MD, MBA
Associate Professor of Clinical Ophthalmology
Director of Clinical Trials Unit
University of Southern California
Los Angeles, CA.

Charles C. Wykoff, MD, PhD
Clinical Assistant Professor of Ophthalmology
Weill Cornell Medical College
Retina Consultants of Houston
Houston, TX

Thomas Albini, MD: Allergan, Inc; Bausch + Lomb; Eleven Biotherapeutics; Genentech.; and ThromboGenics.

Audina Berrocal, MD: No financial affiliations or disclosures:

Peter K. Kaiser, MD: Alcon; Bayer AG; Novartis International, AG; Oraya Therapeutic; Regeneron Pharmaceuticals; ThromboGenics NV; and Valeant Pharmaceuticals International.

Rohit Ross Lakhanpal, MD: Allergan; Alcon; and ThromboGenics.

Andrew Moshfeghi, MD, MBA: Allergan; Alexion Pharmaceuticals; Genentech; and Regeneron Pharmaceuticals.

Charles C. Wykoff, MD, PhD: Alcon; Allergan; Alimieria Sciences; Genentech; Regeneron Pharmaceuticals; Synergetics; and ThromboGenics.

All of those involved in the planning, editing, and peer review of this educational activity report no relevant financial relationships.


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, Retina Today, and Regeneron Pharmaceuticals.

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: Ocular and Systemic Impact

Peter Kaiser, MD, Moderator; Thomas Albini, MD; Audina Berrocal, MD; Ross Lakhanpal, MD; Andrew Moshfeghi, MD, MBA; and Charles C. Wykoff, MD, PhD