advances in the treatment of wet age-related …journals.lww.com/retinajournal/documents/may...

0riginal release: may 15, 2012 last review: may 1, 2012 expiration: may 31, 2013

Sponsored by The New York Eye and Ear Infirmary

In joint sponsorship with MedEdicus LLC

This continuing medical education activity is supported in large part through an unrestrictededucational grant from Regeneron Pharmaceuticals, Inc, with additional support from Optovue, Inc.

Peter K. Kaiser, MD—Program Chairman and ModeratorPravin U. Dugel, MDAllen C. Ho, MD

Daniel F. Martin, MDCarmen A. Puliafito, MD, MBA

cme supplement to

Proceedings From a Roundtable Discussion

Advances in the Treatment of

Wet Age-Related Macular Degeneration

This program is a sponsored continuing education supplement to RETINA.

018_AMD Roundtable Monograph rev 4_Layout 1 4/19/12 9:36 AM

LEARNING METHOD AND MEDIUMThis educational activity consists of a supplement and ten (10) study questions. Theparticipant should, in order, read the learning objectives contained at the beginning of thissupplement, read the supplement, answer all questions in the post test, and complete theevaluation form. To receive credit for this activity, please follow the instructions provided onthe post test and evaluation form. This educational activity should take a maximum of 2.0hours to complete.

CONTENT SOURCEThis continuing medical education (CME) activity captures content from a roundtablediscussion held on January 17, 2012, in Maui, Hawaii.

ACTIVITY DESCRIPTIONAnti-vascular endothelial growth factor (VEGF) agents have transformed the management of wet age-related macular degeneration (AMD) in patients with advanced disease. Currentmanagement of wet AMD strives to provide best visual outcomes using anti-VEGF agentswith a consideration toward minimizing the treatment burden on the patient. Recentimportant developments include the Comparison of Age-Related Macular DegenerationTreatments Trial (CATT) study, new therapy (aflibercept), and increased use of imaging-guided treatment. There is a need to clarify how therapies can be used today to providepatients with optimal visual outcomes. This educational activity will provide an update on theclinical trials in anti-VEGF therapy for neovascular AMD and expert insight into interpretingtrial outcomes for managing patients.

LEARNING OBJECTIVESAfter successfully completing this activity, you will have improved your ability to:

• Demonstrate the implications of the CATT results for monthly and PRN dosing and monitoring of currently used anti-VEGF agents in various subsets of patients• Compare and contrast the anti-VEGF agents with respect to mechanism of action and binding affinities• Discuss the results of the latest clinical trials and how anti-VEGF and other therapies may be used in patients with wet AMD• Discuss the advantages and drawbacks of various treatments and combinations in their ability to reduce treatment burden and safety risks• Employ current best practice use of OCT in guiding treatment• Apply results from the latest clinical trials to AMD patient case scenarios

TARGET AUDIENCEThis educational activity is intended for retina specialists.

ACCREDITATION STATEMENTThis activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The New York Eye and Ear Infirmary and MedEdicus LLC. The New YorkEye and Ear Infirmary is accredited by the ACCME to provide continuing medical educationfor physicians.

AMA CREDIT DESIGNATION STATEMENTThe New York Eye and Ear Infirmary designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity.

GRANTOR STATEMENTThis continuing medical education activity is supported in large part through an unrestrictededucational grant from Regeneron Pharmaceuticals, Inc, with additional support fromOptovue, Inc.

MISSION STATEMENTIt is The New York Eye and Ear Infirmary Institute for Continuing Medical Education’s statedmission to create medical education activities that will serve to increase the knowledge, skills,professional performance, and relationships that a physician uses to provide services forpatients, the public, or the chosen profession.

DISCLOSURE POLICY STATEMENTIt is the policy of The New York Eye and Ear Infirmary that the faculty and anyone in aposition to control activity content disclose any real or apparent conflicts of interest relating tothe topics of this educational activity, and also disclose discussions of unlabeled/unapproveduses of drugs or devices during their presentation(s). The New York Eye and Ear Infirmary hasestablished policies in place that will identify and resolve all conflicts of interest prior to thiseducational activity. Full disclosure of faculty/planner and their commercial relationships, ifany, follows.

DISCLOSURESPravin U. Dugel, MD, has had a financial agreement or affiliation during the past year withthe following commercial interests in the form of Consultant/Advisory Board: AbbottLaboratories; Alcon, Inc; Allergan, Inc; Arctic Dx Inc; Genentech, Inc; MacuSight, Inc;NeoVista, Inc; Ora Inc; Regeneron Pharmaceuticals, Inc; and ThromboGenics, Inc; Ownership Interest: Arctic Dx Inc; MacuSight, Inc; and NeoVista, Inc.

Allen C. Ho, MD, has had a financial agreement or affiliation during the past year with thefollowing commercial interests in the form of Consultant/Advisory Board: Alcon, Inc; Allergan,Inc; Centocor/J&J; Genentech, Inc; Merck & Co, Inc; NeoVista, Inc; Ophthotech Corporation;Oraya Therapeutics, Inc; Paloma Pharmaceuticals, Inc; Physician RecommendedNutriceuticals (PRN); QLT Inc; Regeneron Pharmaceuticals, Inc; and ThromboGenics, Inc;Contracted Research: Alcon, Inc; Allergan, Inc; Genentech, Inc; NeoVista, Inc; OphthotechCorporation; Oraya Therapeutics, Inc; Physician Recommended Nutriceuticals (PRN); QLTInc; Regeneron Pharmaceuticals, Inc; and Second Sight Medical Products, Inc.

Peter K. Kaiser, MD, has had a financial agreement or affiliation during the past year with thefollowing commercial interests in the form of Consultant/Advisory Board: Alcon, Inc; BayerHealthCare; Genentech/Novartis; and Regeneron Pharmaceuticals, Inc; Contracted Research:Alimera Sciences; Allergan, Inc; Genentech, Inc; Novartis; and Regeneron Pharmaceuticals, Inc.

Daniel F. Martin, MD, has no relevant commercial relationships to disclose.

Carmen A. Puliafito, MD, has no relevant commercial relationships to disclose.

PEER REVIEW DISCLOSURES Ingrid U. Scott, MD, MPH, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board:Genentech, Inc.

EDITORIAL SUPPORT DISCLOSURESTony Realini, MD, MPH, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Alcon, Inc;Fees from promotional, advertising or non-CME services received directly from commercial interests or their Agents (eg, Speakers Bureaus): Lumenis; Cynthia Tornallyay, RD, MBA,CCMEP; Kimberly Corbin, CCMEP; and Barbara Lyon have no relevant commercialrelationships to disclose.

DISCLOSURE ATTESTATIONEach of the contributing physicians listed above has attested to the following:1) that the relationships/affiliations noted will not bias or otherwise influence his/herinvolvement in this activity;2) that practice recommendations given relevant to the companies with whom he/she has relationships/affiliations will be supported by the best available evidence or,absent evidence, will be consistent with generally accepted medical practice; and3) that all reasonable clinical alternatives will be discussed when making practicerecommendations.

OFF-LABEL DISCUSSIONThis activity includes off-label discussion of bevacizumab for intravitreal injection.

TO OBTAIN AMA PRA CATEGORY 1 CREDIT™To obtain AMA PRA Category 1 Credit™ for this activity, read the material in its entirety andconsult referenced sources as necessary. Complete the evaluation form along with the posttest answer box within this supplement. Remove the Activity Evaluation page from the printedsupplement or print the Activity Evaluation page from the Digital Edition. Return via mail orfax to Kim Corbin, Director, ICME, The New York Eye and Ear Infirmary, 310 East 14th Street,New York, NY 10003 or fax to (212) 353-5703. Your certificate will be mailed to the address that you provide on the evaluation form. Please allow 3 weeks for mailed/faxed forms to beprocessed. Note: You must score a 70% or higher to receive credit for this activity.

DISCLAIMERThe views and opinions expressed in this educational activity are those of the faculty and donot necessarily represent the views of The New York Eye and Ear Infirmary; MedEdicus LLC;Regeneron Pharmaceuticals, Inc; Optovue, Inc; or Retina. Please refer to the officialprescribing information for each product for discussion of approved indications,contraindications, and warnings.

This CME activity is copyrighted to MedEdicus LLC ©2012. All rights reserved.

2

Program Chairman and ModeratorPeter K. Kaiser, MDChaney Family Endowed Chair for Ophthalmology ResearchProfessor of OphthalmologyCleveland Clinic Lerner College of MedicineCole Eye InstituteCleveland, Ohio

FacultyPravin U. Dugel, MDClinical Associate Professor of OphthalmologyDoheny Eye InstituteKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, CaliforniaManaging PartnerRetina Consultants of ArizonaPhoenix, Arizona

Allen C. Ho, MDProfessor of OphthalmologyThomas Jefferson UniversityWills Eye Institute Retina ServiceMid Atlantic RetinaPhiladelphia, Pennsylvania

Daniel F. Martin, MDChairmanCole Eye InstituteBarbara and A. Malachi Mixon III Institute Chair in Ophthalmology

Cleveland ClinicCleveland, Ohio

Carmen A. Puliafito, MD, MBADeanKeck School of MedicineMay S. and John Hooval Dean’s Chair in MedicineProfessor of Ophthalmology and Health ManagementDoheny Eye InstituteUniversity of Southern CaliforniaLos Angeles, California


Imaging the AMD PatientDr Kaiser: Dr Dugel, consider a treatment-naïve patientreferred to your practice for evaluation of neovascularAMD. (Figure 1)What is your approach when evaluatingthis patient?

Dr Dugel: I have different approaches for treatment-naïve and for previously treated patients. For atreatment-naïve patient, I always obtain a fluoresceinangiogram (FA) and routinely obtain optical coherencetomography (OCT) as well. (Figures 2 and 3) If theclinical examination suggests the possibility ofpolypoidal choroidal vasculopathy (PCV), I will alsoobtain dynamic indocyanine green (ICG) angiography.

Dr Kaiser: Please explain what you mean by dynamicICG.

Dr Dugel: In static ICG, single images are obtained. Indynamic ICG, a video is captured throughout the test.Dynamic ICG can reveal high-flow abnormalities in theearly seconds after dye injection that can be missed withstatic ICG. These high-flow lesions can represent PCVor other important lesions

Dr Kaiser: What features on examination might makeyou suspicious of PCV and prompt you to obtaindynamic ICG?

Dr Dugel: A pigment epithelial detachment (PED) raisesmy suspicion. A reddish appearance beneath a PED isalso suggestive of PCV. I also routinely obtain ICG onmy non-white AMD patients.

Dr Kaiser: Does anyone else on the panel have adifferent approach for treatment-naïve patients?

Dr Ho: Fluorescein angiography and OCT imaging arestandard for my new patients with wet AMD. I do notutilize ICG imaging quite as often as Dr Dugel does, butwill use it for the initial evaluation in a clinical settingsuspicious for PCV (hemorrhagic PED, nodular orangemacular or peripapillary lesions, non-white race).

Dr Kaiser: I agree with Dr Dugel on the imagingtechniques used for a treatment-naïve patient. ICG is important to rule out PCV and other masqueradesyndromes such as chronic central serous

3

IntroductionThe paradigms for both the evaluation and themanagement of neovascular age-related maculardegeneration (AMD) have evolved significantly in thepast few years and continue to do so. New imagingtechnologies have been introduced that have greatlyenhanced our ability to visualize the disease process atthe tissue level. We are now in the era of vascularendothelial growth factor (VEGF) inhibition, and noveldrugs continue to enter the marketplace. Clinicians facethe daily clinical challenge of integrating new researchfindings, new technology, and new drugs into theirpractice patterns. We have assembled a panel of expertretina specialists to discuss the advances in thetreatment of wet AMD and its evolving treatmentparadigm. Our goal is to bring some clarity to theevaluation and management of wet AMD.

—Peter K. Kaiser, MD

Figure 1. Fundus appearance of a newly diagnosed patient withneovascular AMD.

Photo Courtesy of Pravin U. Dugel, MD

Figure 2. Fluoresceinangiogram of subretinalneovascularization in thepatient with AMD whosefundus was shown inFigure 1.


Figure 3. OCT of the macula shown in Figure 1.



chorioretinopathy. For patients already receivingtreatment, I find that FA and ICG are less relevant.There is a tendency to overcall leakage from choroidalneovascularization (CNV) on FA, so it may mislead youin terms of assessing response to therapy. To date, therehave been no studies comparing FA with OCT todetermine the best way to follow patients after anti-VEFG therapy, but my impression is that OCT is moreuseful for guiding therapy decisions once therapy hasbeen initiated. Dr Puliafito, you have been instrumentalin the development of OCT. Tell us what you look for onOCT scans in wet AMD patients.

Dr Puliafito: OCT is now the core diagnostic technologyfor management of wet AMD. Reading an OCT involvesthe inspection of various spaces. We look at thesubretinal space. We look under the pigment epitheliallayer. We look very closely for cystic changes within theretina. Those are the 3 primary structural end points inwhich we are interested. (Figure 4)

Dr Kaiser: Spectral domain (SD) OCT providessubstantially more data than prior time domain (TD)OCT platforms, but this huge amount of data can oftenbe difficult to interpret. What scan patterns and analysisalgorithms do you use for your AMD patients? How canwe get the most out of this new technology?

Dr Puliafito: The increased dataset that we get from SD-OCT, in particular the multiple sections that we canobtain, substantially improves the specificity of ourdiagnostic ability. Optimally, we review the entire set ofsections. The manufacturer’s review station provides amuch more dynamic impression of the overall scandata. This increased dataset is tremendously helpful indetermining if the macula is dry or not dry. Lookingforward, OCT is going to get even better.

Dr Kaiser: Is there a role for other imaging modalities,such as wide field angiography or autofluorescence, inwet AMD?

Dr Puliafito: Wide field angiography may have a role inpatients who have eccentric CNV.

Dr Dugel: There is definitely a role for autofluorescence,which can be very helpful in distinguishing AMD fromother macular diseases, such as the various maculardystrophies.

Impact of Lesion Morphology andLocation on Choice of TherapyDr Kaiser: Dr Martin, in the past much was made oflesion morphology, for example, classic versus occult.Should we still be classifying AMD lesions as minimallyclassic, predominantly classic, or occult with no classic?

Dr Martin: No. Lesion type was an importantconsideration when we relied on photodynamic therapy(PDT). But anti-VEGF therapy is so much more potent thatit appears to overwhelm whatever differences in responseexisted on the basis of lesion morphology. In MARINA,ANCHOR, HARBOR, and CATT, the therapeutic responseappeared to be about the same, no matter what lesion typewas present at the initiation of therapy.

Dr Kaiser: Dr Dugel, does the location of the lesion havean effect on your management choice?

Dr Dugel: Lesion location matters in the sense thatthose rare patients with an extrafoveal classic lesion canbe very effectively treated with thermal laserphotocoagulation.

Dr Kaiser: I agree that there are still the rare well-defined extrafoveal and peripapillary lesions thatrespond well to laser therapy. For the most part, the anti-VEGF trials evaluated mainly subfoveal lesions. Incontrast, the CATT trial1 differed in terms of inclusioncriteria regarding lesion location. Dr Martin, can youexplain the rationale for this methodological difference?

Dr Martin: Previous studies required the CNV to beunder the geometric center of the fovea. In clinicalpractice, however, many clinicians use anti-VEGFtherapy for juxtafoveal and extrafoveal lesions as well. In addition, almost all retinal angiomatous proliferation(RAP) lesions have a hot spot that is juxtafoveal, but alsohave a PED or fluid that involves the center of the fovea.By design then, all previous studies have excluded RAPlesions because they required CNV under the center. Wethought these patients were very important because theymake up 10% to 20% of the population we see with wet

4

Figure 4. OCT identifies VEGF-induced exudation.

Figure Courtesy of Carmen A. Puliafito, MD


AMD, and the questions of relative efficacy ofranibizumab and bevacizumab* are just as important for these patients as for any other.

So in CATT, we did not require the CNV to be under thefovea. However, the center was required to be involved bysome aspect of wet disease, such as PED, subretinalfluid, blood, or the CNV itself. We also lowered the visualacuity requirement to 20/25, and if I had it to do over, Iwould have eliminated a lower boundary altogether.Previous studies did not allow patients who were betterthan 20/40 to participate, and yet in clinical practice,patients with these very good levels of vision and CNVare usually treated because of the relatively poor naturalhistory if not treated. The CATT entry criteria allowed usto enroll a much more representative sample of what weactually treat in clinical practice than did previous trials.

Counseling the Patient Regarding TherapyDr Kaiser: Let’s assume that the treatment-naïve patienthas now been fully evaluated, the diagnosis is wet AMD,and treatment is indicated. How do you counsel patientsregarding the course of treatment and follow-up regimen?

Dr Dugel: The first thing I tell my patients is that this isa chronic disease, very much like diabetes. It is a diseasefor a lifetime. It is fundamentally important thatpatients understand this from the start. The secondthing I tell them is that current therapies can help usmanage, but not cure, the disease. The third point Imake is that there is substantial new research ongoing,and that I am convinced that we will soon havetherapies that are better than those we have today.Regarding follow-up, I tell my patients that we will seethem monthly until their lesion is dry. Once we’veachieved this therapeutic goal, I tell them that the datasupport continuous monthly therapy for the absolutebest results, but that such a regimen may be tooburdensome for them. At that point, patients will haveinput on whether we continue monthly therapy orattempt to transition to a treat-and-extend approach.

Dr Ho: I agree that it is fundamentally important thatwe distinguish between treatment and cure. Patients’perception of AMD therapy has changed considerably.Before anti-VEGF therapy, there were treatments, butthey merely slowed the decline of vision rather thanstabilized or improved vision. Patients did not alwaysview these historic therapies as meaningful treatment.Modern anti-VEGF therapy offers stability to the vastmajority of patients, and significant visual improvementsin up to one-third of them. There is often an expectationof improvement, and because two-thirds of patients

treated with bevacizumab or ranibizumab do notexperience improvement,1-3 we have to manage theseexpectations up front.

Dr Kaiser: Are there any other counseling pearls?

Dr Ho: I routinely show my patients their imagingstudies. They are very useful for patient education. I usethe images to help illustrate the disease process.

New Data From Clinical Trials

CATT

Dr Kaiser: In the past year, the results of several largerandomized clinical trials concerning the treatment ofwet AMD were reported. We are fortunate to have keypersonnel from each of those studies on the panel.Beginning with Dr Martin, let’s review the rationalebehind and findings from the CATT study.

Dr Martin: Our first look at the ranibizumab MARINAdata was in July 2005 at the American Society of RetinaSpecialists annual meeting in Montreal, Canada. We wereall incredibly impressed with this paradigm-changingdrug. On the same day, a case report describing the use ofintravitreal bevacizumab in a patient with neovascularAMD detailed a remarkable therapeutic effect that lookedsimilar to what was being described for ranibizumab.Many clinicians went home and began usingbevacizumab as a surrogate for ranibizumab because itwas available for off-label use, had a target specificitysimilar to that of ranibizumab, and was inexpensive.

By the time ranibizumab was approved by the US Foodand Drug Administration (FDA), bevacizumab hadbecome the standard of care for the treatment ofneovascular AMD, despite the lack of any randomizedclinical trial data confirming its efficacy. In addition, therewas uncertainty about how bevacizumab, or for thatmatter ranibizumab, should be dosed. When we beganusing bevacizumab, little was known about its safety.Therefore, most retina specialists administered it on anas-needed (PRN) basis as opposed to the fixed monthlydosing that was employed in MARINA and ANCHOR.What we learned was that there were some patients whocould achieve an excellent visual result with less frequentdosing. Once ranibizumab was FDA approved, PRNdosing was adopted for it too; a treatment algorithm hadnever been studied in a large clinical trial. So by the endof 2006, the vast majority of patients (>95%) were beingtreated with either a drug or a treatment regimen thathad never been validated in a randomized clinical trial.

CATT was designed as a head-to-head comparison ofmonthly treatment or PRN treatment of eitherranibizumab or bevacizumab.1 At 1 year, ranibizumab

5

*off-label use for intravitreal injection


and bevacizumab produced equivalent, nearly identical,visual results when each drug was given at the samedosing regimen. PRN dosing of either drug alsoproduced an excellent visual outcome, but resulted in,on average, 2 letters less than monthly treatment.Patients on PRN dosing received 4 to 5 fewer injectionsover 1 year than their monthly counterparts, but patientswho were assigned to bevacizumab PRN received amean of 0.8 more injections than did ranibizumab PRNpatients. Structural outcomes were also evaluated.Ranibizumab appeared to dry the macula significantlymore effectively than did bevacizumab, with moreranibizumab-treated eyes dry at the 12-month markversus bevacizumab-treated eyes. The minority of eyesin either group were completely dry at 1 year, however;the eyes that were still wet had a small amount of fluid(mean of 10 microns). (Figure 5)

From an adverse event standpoint, there were no majordifferences in death, myocardial infarction, or strokebetween the groups. However, total serious adverseevents (SAEs) were higher in the bevacizumab groupthan in the ranibizumab group (24% vs 19%, P=.04).Most of these events were hospitalizations, and theimportance of this information is not clear. At a meanage of 79, patients in CATT were admitted to thehospital for many different reasons. In the more than 10years of study on intravenous bevacizumab in whichpatients receive 500 times greater doses than were givenin our study, the vast majority of reasons forhospitalization has never been associated with the useof anti-VEGF drugs. Most of the imbalance in SAEswere in those events unrelated to anti-VEGF therapy. Inaddition, the highest rate of SAEs was in the group thatreceived the least amount of drug.

There are several possible explanations for this finding.It could be a chance finding. It could be attributable to

differences in the risk profiles ofsubjects at baseline—for instance,the bevacizumab group was, onaverage, 1 year older than theranibizumab group. Or, it could bethat the increased risk may be realand related to the treatment itself.We hope that this safety finding atyear 1 will be clarified in year 2 ofCATT and in the other 5 ongoingtrials in Europe comparingranibizumab and bevacizumab.

Dr Ho: There are theoretical reasonswhy the differences in SAEs could bereal. Bevacizumab has a longer

serum half-life than ranibizumab has. It is notunreasonable to hypothesize that a drug with a longersystemic half-life could potentially have more serioussystemic safety events.

Dr Puliafito: Of the commercially available anti-VEGFagents, bevacizumab has a longer intravitreal half-lifethan either ranibizumab or the newest agent, aflibercept(VEGF Trap-Eye).4 However, ranibizumab has a higherbinding affinity than bevacizumab, and aflibercept hasthe highest binding affinity of all agents.5 The relativeimportance of intravitreal half-life and binding affinity isnot known. Our initial clinical results with aflibercept,however, indicate that having a high affinity maypresent a significant clinical advantage in eyes withchronic subretinal fluid and macular edema even whenwell treated with other agents.

Dr Martin: I very much look forward to the additionalsystemic VEGF data from IVAN. But the puzzle here isthat if the risk is real and we think the imbalance isrelated to the half-life and the presence of an Fcfragment on bevacizumab, why don’t we see the sameimbalance in SAEs with aflibercept? It, too, has a longerserum half-life than ranibizumab,6 has an Fc fragment,but has an even higher binding affinity for VEGF thandoes bevacizumab. By this logic, one would think there would have been an even bigger problem inVIEW1/VIEW2 and yet there was not. The whole thing doesn’t make sense.

Dr Kaiser: An increase in SAE rates from 2% to 3%represents a relative increase of 50%. The CATT studywas not powered to discover a 50% relative increase inSAE rates. To discover such an increase, a study mayneed more than 10,000 patients. To achieve suchnumbers, there have been 2 recent reports based on theMedicare claims database, both evaluating systemicsafety of anti-VEGF therapy in AMD. It would behelpful to review those findings in the context of theCATT findings.

6

Figure 5. Mean change in the visual acuity score during the first yearof follow-up.1 Reprinted with permission.


Dr Dugel: The paper by Gower and colleagues waspresented at the 2011 The Association for Research inVision and Ophthalmology (ARVO) meeting (Gower EWet al. ARVO E-Abstract 6644, 2011). The researchersevaluated nearly 78,000 Medicare beneficiaries withneovascular AMD. They found an 11% higher risk ofoverall mortality and a 57% higher risk of hemorrhagicstroke in patients treated with bevacizumab comparedwith those treated with ranibizumab. Both of thesefindings were statistically significant. However, it isworth noting that the stroke rate in the bevacizumabgroup was approximately 4%, which is the normalbackground rate for people this age, while the stroke ratein the ranibizumab group was approximately 2.6%.Unless we believe that ranibizumab is protective ofstroke, it is more likely that the reported values representa statistical chance finding.

The paper by Curtis and colleagues evaluated differences in adverse events between anti-VEGF therapy and PDT ina 5% sample of the Medicare database.7 Overall, there wasno difference between these 2 groups in the safetyoutcomes investigated. However, death rates differedamong the treatment groups: death occurred in 4.1% ofPDT patients, 4.1% of ranibizumab patients, 4.4% ofbevacizumab patients, and in 4.8% of pegaptanibpatients (P=.001). These results can be misleading, assome patients may have received more than 1 anti-VEGFagent throughout the course of treatment. When the datawere reanalyzed to include only those patients whoconsistently received the same drug throughouttreatment, the death incidence rates were statisticallyequivalent (4.7% for ranibizumab vs 4.3% forbevacizumab). Curtis concluded, and I agree, that there is no statistical safety difference between these 2 drugs.This conclusion was recently borne out in a major reviewof safety with all the anti-VEGF agents for AMD, in whichit was noted that all were safe and had similar safetyprofiles overall.8

Dr Kaiser: Despite methodological problems, both thesereports demonstrated the same thing in contrast to thesafety results of the CATT study. Do we think there isany systemic risk to the anti-VEGF drug class?

Dr Dugel: I am concerned about the occurrence of strokein patients with AMD. There is a higher incidence ofstroke in patients with AMD compared with thosewithout AMD.9-11 Also, the SAILOR trial suggested thatprior stroke patients are at particular risk of havinganother stroke following anti-VEGF therapy for AMD.12

In these patients, I may consider the 0.3-mg dose, whichhad a better safety profile in this subset of patients withvery little efficacy cost.12

Dr Kaiser: SAILOR identified prior stroke, cardiacarrhythmias, and a history of congestive heart failure as risk factors for stroke while receiving anti-VEGFtherapy.12 Aside from these, is there any other patientprofile or genetic factors that would influence yourchoice of anti-VEGF agents?

Dr Martin: We have collected DNA from all the CATTpatients and hope to have some information pertainingto this situation in the future. Also, the DAWN study(presented at the American Academy of Ophthalmologymeeting, October 2011, San Francisco, California, byIanchuley I et al) sought to explore the relationshipbetween patient profile and anti-VEGF therapy. DAWN isa substudy to HORIZON, which, in turn, was the long-term extension study of MARINA, ANCHOR, andFOCUS patients. DAWN sought to explain differentialresponse to ranibizumab therapy based on genotype. Infact, there was a particular allele that accounted for anearly 2-fold difference in visual gains depending onwhich allele the patient had. It is challenging to put thisobservation into clinical practice at this time, but futurework may provide insight and guidance into theselection of therapy based on genotype.

Dr Kaiser: Before we move on to the other importantclinical trials from this past year, what do you think wecan look forward to in the second year of CATT?

Dr Dugel: The switch from TD-OCT to SD-OCT willprovide us with a better representation of treatmentefficacy. We will likely see more fluid, and the questionwill be: How aggressive should we be in eliminating thisresidual fluid? I’m also interested to see if the PRNgroups maintain vision through the second year.

Dr Ho: I am curious to know whether the statisticallysignificant difference between systemic serious adverseevents in year 1 will hold up through the second year ornot. My prediction is that they will not hold up and thatthe rates of SAEs will equalize.

Dr Kaiser: I, like Dr Dugel, am eager to see how themonthly groups do in the second year when they arerandomized to remain monthly or to switch to PRNtherapy.

HARBOR

Dr Kaiser: There is no question that monthly therapyprovides the best chance for visual gains, but thisregimen imposes a huge burden on patients, theirfamilies, physicians, and the health care system. CATTindicated that PRN ranibizumab was equal to monthlytherapy with monthly follow-up and aggressive PRNtreatment guidelines. CATT-like PRN therapy reduces

7


the number of injections, but not the burden of visits.Some physicians have postulated that increasing thedose of ranibizumab, or even performing injectionsevery 2 weeks, could improve outcomes. Dr Ho, pleasedescribe the rationale and findings of the HARBOR trial.

Dr Ho: HARBOR (presented at the American Academyof Ophthalmology meeting, October 2011, Orlando,Florida, by Ho AC and Busbee BG et al) was a Phase IVcommitment by Genentech to the FDA to evaluatedifferent doses and dosing regimens of ranibizumab.The HARBOR study enrolled 4 groups: the standard 0.5mg monthly, a higher dose of 2 mg monthly, and eachof those 2 doses in a PRN schedule, with PRN definedas 3 loading doses up front and then as-needed based onretreatment criteria that differed from prior studiesbecause of the use of SD-OCT to guide retreatment.HARBOR confirmed that monthly dosing with 0.5 mgremains the optimal dosing regimen for ranibizumab.There was no added benefit to the higher dose, perhapsbecause 0.5 mg is at the top of the dose-response curve.

Dr Kaiser: It is nice to know that the 0.5-mg dose wealready have appears to be the most effective, butHARBOR also showed us that in those rare cases inwhich we might need a higher dose or every-2-weeksdosing, it may be safe. I hope to see additional analysisfrom HARBOR since it is the first study to use SD-OCT.It will be interesting to see if there is a differential OCTresponse in the monthly versus PRN groups.

Dr Ho: That is an excellent point, that the HARBORstudy safety findings revealed no new safety concernsfor any dose investigated, specifically that the safetyprofile of 0.5-mg and 2.0-mg dosing was similar; this isimportant in light of prior ranibizumab trials thatsuggested possible dose-response safety concerns. Asthe only large neovascular AMD clinical trial to date thatemployed only SD-OCT imaging, it was not a completesurprise that the rates for “dry” OCT images at 1 year inHARBOR were on the order of only 6% to 12%, muchlower than in other trials. We need to analyze theseHARBOR SD-OCT results to determine what OCTparameters are visually meaningful, to help guide us in

8

Anti-VEGF Agents: Similar Effects,Distinct Mechanisms

The 4 available anti-VEGF therapies forneovascular AMD share the common goal ofsuppressing VEGF activity. They all accomplishthis goal by binding to the VEGF molecule andblocking its interaction with the VEGF receptors.Each molecule has distinct features thatdifferentiate it from the others in this class.

• Pegaptanib is an aptamer, which is a singlestrand of RNA or DNA (RNA in the case ofpegaptanib) that folds up in such a way that itsshape meshes with the VEGF molecule like a lockand key. There are several isoforms of VEGF, allof which are active in the angiogenesis process.Pegaptanib selectively inhibits only the VEGF-165 isoform of VEGF, which may explain therelatively lower efficacy of this drug comparedwith others in the class.

• Bevacizumab is a full-length antibody that binds all isoforms of the VEGF-A family. It wasdeveloped as a systemic antineoplastic therapybut has been used off-label for neovascular AMD since 2005, first systemically and thenintravitreally.

• Ranibizumab is an antibody fragment adaptedfrom bevacizumab. Like its parent molecule,ranibizumab binds all isoforms of the VEGF-Afamily.

• Aflibercept, also known as VEGF Trap-Eye, is arecombinant protein in which the bindingdomains of VEGF receptors 1 and 2 have beencombined with the Fc portion of IgG. Themolecule has a very high binding affinity for allVEGF-A isoforms as well as for the relatedmolecules placental growth factor-1 and factor-2and VEGF-B.5

The 0.5-mg dose of ranibizumab appears tobe the most effective, but HARBOR alsoshowed us that in those rare cases in whichwe might need a higher dose or every-2-weeksdosing, it may be safe.


treatment decisions. Year 2 HARBOR data areforthcoming in the fall of 2012, and I am lookingforward to the results.

VIEW 1 and VIEW 2

Dr Kaiser: The other comparison study that reportedlast year was the VIEW study with aflibercept versusranibizumab.

Dr Ho: VIEW 1 (Nguyen QD. ARVO E-abstract 3073,2011) enrolled North American subjects and VIEW 2(Schmidt-Erfurth U. ARVO E-abstract 1650, 2011)enrolled international subjects with treatment-naïveneovascular AMD. Both trials randomized subjects to 4arms: 0.5 mg monthly ranibizumab, 0.5 mg monthlyaflibercept, 2 mg monthly aflibercept, and 2 mgaflibercept every 2 months. This dosing regimen wasused for the first 12 months. For the second 12 monthsof the study, patients were examined monthly, buttreated quarterly, unless they met pre-specifiedretreatment criteria, which triggered treatment earlierthan quarterly. The 12-month integrated analysis pooledthe data from both studies and demonstrated that whenthese 2 drugs were each administered monthly, theirefficacy was similar. However, considering the 2 studiesseparately, VIEW 1 found that 2-mg monthly afliberceptwas more efficacious than monthly ranibizumab, whileVIEW 2 found just the opposite.

This difference in results may be related in part todifferences in the 2 study samples. VIEW 1 wascomposed of predominantly white subjects, while VIEW2 had a more ethnically diverse sample population.Also, dosing aflibercept every 2 months seemed to be asefficacious as either drug dosed monthly. Overall,subjects in all arms gained, on average, 8 to 10 letters(Figure 6), and the proportion gaining 3 or more lines ofacuity was in the 30% to 35% range. Finally, no newsafety concerns were identified for anti-VEGF therapiesin the VIEW 1 and VIEW 2 studies.

9

0

2

4

6

8

10

12

Mea

n #

of l

ette

rs g

ain

ed

Aflibercept 0.5mgq4 wk

Aflibercept 2mgq4 wk

Aflibercept 2mgq8 wk

Ranibizumab 0.5mgq4 wk

VIEW 1

VIEW 2

Figure 6. 1-year VIEW 1 and VIEW 2 results.

VIEW 1 and VIEW 2 Year 2 Results13

DESIGN: In year 2 of the VIEW studies,participants continued to receive the same drugand dose to which they were randomized in year 1,but all 4 treatment arms changed to a PRN dosinginterval. Participants were evaluated monthly, andtreated no more often than once monthly and noless often than every 3 months, based onretreatment criteria.

EFFICACY: All 4 groups suffered modest loss ofbest-corrected visual acuity in year 2 compared tothe end of year 1, with mean losses ranging from0.8 to 1.7 letters. As in year 1, approximately one-third of patients in all 4 groups maintained gainsof 3 lines or more. Central retinal thicknessimprovements seen in year 1 were maintainedthrough year 2 in all 4 groups as well.

SAFETY: Both aflibercept and ranibizumabdemonstrated favorable safety profiles through year2, with similar incidences of serious ocular adverseevents among groups. As in year 1, the mostcommon adverse events were typically associatedwith the injection, the underlying disease process,or the aging process.

TREATMENT BURDEN: Through 2 years,participants in the aflibercept 2 mg every-4-weeksgroup received an average of 16 injections, of which4.2 occurred during the year 2 PRN dosing phase.In the aflibercept 2 mg every-8-weeks group, thecorresponding numbers were 11.2 and 4.1injections, and in the ranibizumab group, 16.5and 4.7 injections.


Dr Kaiser: The 2-mg dose of aflibercept received FDAapproval last month, so now we have an additionaltherapy in our anti-VEGF armamentarium. In whichpatients would you consider switching from yourcurrent anti-VEGF therapy to aflibercept?

Dr Puliafito: There are 2 categories of patients in whom Iam using aflibercept therapy. The first group consists ofthose patients who have required monthly treatment withtheir current therapy for a long period of time and wholose ground whenever we try to extend the dosinginterval. These patients seem to consume anti-VEGFdrugs at a high rate. The second group is made up ofthose patients who still have anatomic changes consistentwith wet AMD—including persistent subretinal fluidand/or persistent PED—after many months ofconventional anti-VEGF therapy. Herein, an importantissue arises in clinical practice. What is the definition oftreatment failure, and what is the best way to managepatients who fail therapy with bevacizumab orranibizumab?

Dr Kaiser: It is worth reiterating that with SD-OCT we are going to see residual fluid in many eyes that areresponding well to therapy. The idea that most patientswill have a dry OCT even with 1 year of monthly therapywas challenged by the CATT study. So, it is important toemphasize that the presence of residual fluid does notnecessarily indicate treatment failure. Perhaps thesepatients would benefit from an alternate therapy such asaflibercept, but it is important to know that we lack dataon its benefit in eyes that have failed ranibizumab orbevacizumab therapy. Over the next few months we will see how aflibercept therapy works in these difficult patients.

Dr Dugel: Another component of failure is often found inthe patient who does not come back as often as requiredfor reevaluation and retreatment. A treatment thatsignificantly reduces the number of injections needed peryear would be valuable in my practice, because it wouldreduce the treatment burden in many patients. It wouldsave a lot of injections and a lot of visits.

The Evolving Therapeutic RegimenDr Kaiser: So far I have heard that in this groupaflibercept has a place as second-line therapy in patientswho have failed ranibizumab or bevacizumab therapy. Isthere a role for aflibercept as first-line therapy? Assumea newly diagnosed, treatment-naïve patient presents to

your office. What is your treatment strategy now thataflibercept is available?

Dr. Martin: After many years of good experience withbevacizumab and ranibizumab, I am likely to start withthese drugs first. Since the CATT results becameavailable, I use much more bevacizumab thanranibizumab. It is inexpensive and effective. I willoccasionally start with ranibizumab if, after ourdiscussion, that is the patient’s preference. I lookforward to gaining experience with aflibercept and amcertain that I will use it more in the future. I canimagine using it in patients who require monthlytherapy and who would like to reduce their treatmentburden, or in patients who fail to achieve a dry maculawith bevacizumab.

Dr Puliafito: I agree that for treatment-naïve patients with no other concerns, bevacizumab is the appropriatefirst-line therapy. Patients who clearly cannot maintain amonthly visit schedule are good candidates for aflibercepttherapy. There is a substantial pool of patients, however,who have not responded well to conventional therapy and still have potential to respond to effective therapy. These patients are also appropriate candidates foraflibercept therapy.

Dr Ho: To summarize, there does not appear to be adistinctive difference in efficacy among these 3 drugs,and I am comfortable starting treatment-naïve patientswith any one. Initially, only a handful of retinaspecialists—primarily those involved in the VIEWtrials—have had significant experience with aflibercept,but the number is growing as we have witnessed thesuccessful launch of this new treatment option. Theremay be some first-line indications, particularly inpatients who struggle with monthly follow-up, but forthe most part, aflibercept is likely to be used primarily asa second-line drug until clinicians become more familiarwith it. Having more treatment options is better for us aswell as better for patients because some patients mayrespond better to one agent than to another.

Dr Martin: On balance, ranibizumab given every 2months might have done just as well as aflibercept every2 months. That was not an arm of the VIEW studies.Neither ranibizumab nor bevacizumab dosed every 2months has ever been studied in a clinical trial.

Dr Dugel: The assumption that aflibercept can reduceth e burden of follow-up should be carefully examined.Keep in mind that in both VIEW 1 and VIEW 2, allpatients were seen every month, not every 2 months.The label for this drug states that after the 3-doseloading phase, patients can be reevaluated every 2months. But we cannot be certain that there will be nodifferences in outcomes with follow-up that is monthlyversus follow-up every other month.

10

The presence of residual fluid with SD-OCTdoes not necessarily indicate treatment failure.


Dr Martin: That is a very fair point. In VIEW1 and VIEW 2 there were no treatment decisions being made inthe months when sham injections were given. In the realworld, we make treatment decisions every time we see thepatient. Seeing the patient monthly increases theprobability of observing a relapse event earlier. Seeing thepatient only every 2 months reduces the opportunities todetect a relapse. And also, with a 2-month follow-upschedule, the consequences of a missed visit—andtherefore a 4-month window between evaluations—become more significant.

Dr Kaiser: Whether to see patients every month or every2 months when using aflibercept is an importantclinical question. I suspect that until retina specialistsget comfortable with the typical clinical response toaflibercept therapy, they will continue to follow patientsmonthly. They won’t necessarily retreat on a monthlybasis, but I believe they will continue to evaluatemonthly until they can appreciate the duration of effectfor themselves.

Dr Martin: It will not surprise me to see cliniciansbegin to use aflibercept monthly and then transition to atreat-and-extend regimen. This is likely how I willinitially incorporate aflibercept into my practice.

Dr Kaiser: I agree fully and use this regimen myself. Dr Martin, please describe what you mean by a treat-and-extend regimen.

Dr Martin: Treat-and-extend begins with monthlytreatment until the macula is dry. Then the follow-upinterval is extended to 6 weeks, 8 weeks, 10 weeks, andso on, treating at each visit to maintain a dry macula. Ifthere is disease relapse (usually fluid or blood), say at 10weeks, then the inter-visit interval would be shortenedagain. Depending on the severity of the relapse, thepatient would be seen again at 8 weeks (2 weeks lessthan the previous maximum time between visits) or ona monthly basis until dry again. This algorithm is, ofcourse, different from PRN dosing, in which patientsare followed monthly but only retreated if there isevidence of recurrence of fluid.

Dr Ho: The treat-and-extend regimen accommodatesthe reality of treatment burden. It is my treatmentpattern no matter which anti-VEGF agent I use.

Dr Dugel: The PRN regimen does not reduce treatmentburden. You must still see the patient on a monthlybasis. Treat-and-extend does reduce the treatmentburden by reducing the frequency of visits. Both treat-and-extend and PRN dosing reduce the number ofinjections, which is likely to reduce the rate ofcatastrophic events such as endophthalmitis.

Combination Therapy Dr Kaiser: We now have several distinct monotherapytreatment modalities for managing neovascular AMD.Assuming a typical AMD lesion without evidence ofPCV, is there any role for combination therapy andwhich treatments might you combine?

Dr Dugel: Ultimately, combination therapy will be animportant part of disease management. Our currentapproach is tremendously better than what we’ve had inthe past, but still far short of the ideal. Combinationtherapy may help us achieve better outcomes, but just asimportantly, it may help us reduce treatment burden.Currently, I am unconvinced that there are any potentialcombinations of available drugs that have any data tosupport their use for wet AMD. It is an area of greatunmet need.

Dr Kaiser: So are you saying there is currently no rolefor combination therapy?

Dr Dugel: There is 1 clinical scenario at present inwhich I would consider combination therapy. This iswhen the patient informs me ahead of time that he orshe does not wish to return for ongoing evaluation andtherapy. In that setting, we are faced with the choice ofsimply surrendering to the natural history of the diseaseor offering a treatment that, while not ideal, combinesthe best possible efficacy with the best possible durationgiven the limitations of no follow-up. In my thinking,the patient described would be one in whom I wouldcombine anti-VEGF therapy with PDT. That would bethe only time that I would use combination therapy withthe currently available treatments.

Dr Ho: Why do not you use this approach morefrequently to reduce treatment burden?

Dr Dugel: Because most of the time patients don’tannounce their intention to stop coming back. They juststop coming without giving me the opportunity to usethis strategy.

Dr Ho: What is the rationale for this combination inpatients who do not intend to come back?

Dr Kaiser: Two studies—DENALI14 and MONTBLANC15—evaluated the combination of ranibizumabwith verteporfin PDT. The results have been presented,but not yet published. In these studies, subjects receivedPDT at baseline, as well as ranibizumab at baseline, andat months 1 and 2. Thereafter, retreatments with eithermodality were on a PRN basis. We can draw somesupport for Dr Dugel’s approach from these studiesbecause approximately 30% of patients required no PRNretreatment with either modality during the 12 months

11


of the study. These results suggest that in some patientswho elect not to continue treatment or follow-up,perhaps the best we can do is to offer them a treatmentthat will afford an approximately 30% chance forstability over the ensuing year. If the patient is adamantabout not returning, this certainly is a reasonable courseof action.

The studies also showed that the combination therapywas safe, and no evidence of acute severe vision loss thathas been described with PDT monotherapy in largerlesions was reported.

Dr Ho: The Phase II RADICAL study (presented at the American Academy of Ophthalmology RetinaSubspecialty Day meeting, October 2009, SanFrancisco, California, by Ho AC) also suggested thatcombination therapy—in this case ranibizumab, low-fluence PDT, and dexamethasone—producescomparable 12-month results with fewer retreatmentsthan does ranibizumab alone. So there is convergingevidence that combination therapy may reduce thetreatment burden, as Dr Dugel noted. But we probablyhaven’t found the ideal combination regimen yet.

Dr Kaiser: We should point out the obvious exception—patients with PCV. The EVEREST study showed thatcombination therapy with ranibizumab and PDT wassuperior to PDT and ranibizumab-alone in causingcomplete polyp regression and improving visual acuity.Thus, in patients with PCV, my treatment of choice isstandard fluence PDT combined with anti-VEGF therapy.

The FutureDr Kaiser: What breakthroughs can we expect in thenear future in terms of therapy for neovascular AMD?

Dr Dugel: Monotherapy with anti-VEGF therapy is soeffective that new therapies will be hard pressed tooutperform the established efficacy threshold. Studies ofcombination therapies will clarify the regimens that offerthe best in terms of optimizing efficacy and treatmentburden. One aspect of clinical management that we needto address is identifying the correct patients for each newregimen that emerges. I suspect the algorithm will startwith anti-VEGF monotherapy for treatment-naïve patients,this being the clinical standard today. Those who do welland can bear the treatment burden will continue withmonotherapy. Those who do not enjoy the efficacy benefitwe expect from this regimen, or who cannot bear theassociated treatment burden, may be candidates foremerging combination therapies.

In terms of novel treatments, there are a few potentialtherapies that may emerge soon. One is radiation,which may be a useful adjunct to anti-VEGF therapy.This therapy recently failed to meet its primary endpoint in a 2-year trial combined with ranibizumabtherapy in treatment-naïve patients (presented at theAngiogenesis, Exudation and Degeneration meeting,February 2012, Coral Gables, Florida, by Dugel P et al).But radiation may find application in other subsets ofpatients, such as those who fail to respond adequately toprimary anti-VEGF therapy. Another novel treatment isplatelet-derived growth factor (PDGF) inhibition. Anti-PDGF therapy is very promising and may have a role asprimary therapy.

Dr Kaiser: What is the status of sustained-releasetherapies to reduce treatment burden?

Dr Ho: Reducing treatment burden via sustained-release therapy is a huge unmet need. There are severaltechnologies to be introduced relatively soon that mayreduce the treatment burden for patients requiringfrequent anti-VEGF injections, and these technologiesmay even raise the bar in terms of efficacy.

Dr Kaiser: What is the status of gene therapy?

Dr Dugel: I tend to think of this concept as a drugdelivery issue, with the virus that delivers the genebeing the delivery device. There is a study ongoing, butit is early and there are no results to discuss yet.

Dr Kaiser: Any other thoughts on what the future holds?

Dr Puliafito: The average patient in my practice nowsees me more often than he or she sees a primary carephysician. Retina specialists have taken a front-line rolein disease management with an increasingly growingsegment of the population. But I think we are simply ina holding pattern, waiting for technology to catch up toreality. Neovascular AMD will inevitably and necessarilyevolve into a disease managed by surgical implantationof a sustained-release drug delivery device.

12


References1. CATT Research Group, Martin DF, Maguire MG, Ying GS,Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab andbevacizumab for neovascular age-related maculardegeneration. N Engl J Med. 2011;364(20):1897-1908.

2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR StudyGroup. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.

3. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA StudyGroup. Ranibizumab for neovascular age-related maculardegeneration. N Engl J Med. 2006;355(14):1419-1431.

4. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ.Pharmacokinetics of intravitreal ranibizumab (Lucentis).Ophthalmology. 2007;114(12):2179-2182.

5. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokineticrationale for dosing every 2 weeks versus 4 weeks withintravitreal ranibizumab, bevacizumab, and aflibercept(vascular endothelial growth factor Trap-Eye). Retina. 2012;32(3):434-457.

6. Eylea [package insert]. Tarrytown, NY: RegeneronPharmaceuticals, Inc; 2011.

7. Curtis LH, Hammill BG, Schulman KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding, and strokeassociated with therapies for age-related macular degeneration.Arch Ophthalmol. 2010;128(10):1273-1279.

8. van der Reis MI, La Heij EC, De Jong-Hesse Y, Ringens PJ,Hendrikse F, Schouten JS. A systematic review of the adverseevents of intravitreal anti-vascular endothelial growth factorinjections. Retina. 2011;31(8):1449-1469.

9. Wieberdink RG, Ho L, Ikram MK, et al. Age-related maculardegeneration and the risk of stroke: the Rotterdam study.Stroke. 2011;42(8):2138-2142.

10. Wong TY, Klein R, Sun C, et al; Atherosclerosis Risk inCommunities Study. Age-related macular degeneration andrisk for stroke. Ann Intern Med. 2006;145(2):98-106.

11. Liao D, Mo J, Duan Y, et al. Is age-related maculardegeneration associated with stroke among elderly Americans?Open Ophthalmol J. 2008;2:37-42.

12. Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T,Rubio RG. A Phase IIIb study to evaluate the safety ofranibizumab in subjects with neovascular age-related maculardegeneration. Ophthalmology. 2009;116(9):1731-1739.

13. Heier JS. Intravitreal aflibercept for AMD: 2-year results.Retina Today.March 2012:49-51. http://bmctoday.net/retinatoday/2012/03/article.asp?f=intravitreal-aflibercept-for-amd-2-year-results. Accessed March 20, 2012.

14. 12-Month results from DENALI study evaluating verteporfinPDT (Visudyne®) combination therapy [press release].Vancouver, BC, Canada; QLT Inc: June 15, 2010.http://www.qltinc.com/newsCenter/2010/100615.htm.Accessed February 8, 2012.

15. QLT announces 12-month results from Novartis sponsoredMONT BLANC study evaluating standard-fluence Visudyne®

combination therapy [press release]. Vancouver, BC, Canada;QLT Inc: June 15, 2009. http://www.qltinc.com/newsCenter/2009/090615.htm. Accessed February 8, 2012.

13

ANCHOR=Anti-VEGF Antibody for the Treatment ofPredominantly Classic Choroidal Neovascularization inAge-Related Macular Degeneration

CATT=Comparison of AMD Treatment Trial

DAWN=Genetic Substudy of HORIZON DENALI=[US and Canada] 24-month randomized, double-masked, multicenter trial in patients with subfovealchoroidal neovascularization secondary to wet AMD(all lesion types)

EVEREST=[Asia] multicenter, double-masked,indocyanine green angiography-guided randomizedcontrolled trial with an angiographic treatment outcomedesigned to assess the effect of verteporfin PDT alone orin combination with ranibizumab compared withranibizumab alone in patients with symptomaticmacular polypoidal choroidal vasculopathy

FOCUS=RhuFab V2 Ocular Treatment Combining theUse of Visudyne® to Evaluate Safety

HARBOR=Study of Ranibizumab AdministeredMonthly or on an As-Needed Basis in Patients WithSubfoveal Neovascular Age-Related MacularDegeneration

HORIZON=Extension Study to Evaluate the Safety andTolerability of Ranibizumab in Subjects With ChoroidalNeovascularization Secondary to AMD or MacularEdema Secondary to RVO

IVAN=Inhibit VEGF in Age-related ChoroidalNeovascularization

MARINA=Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment ofNeovascular Age-Related Macular Degeneration

MONT BLANC=[Europe] Randomized, double-masked,multicenter trial to compare the efficacy and safety ofsame-day verteporfin PDT and intravitreal ranibizumabcombination treatment versus ranibizumabmonotherapy in neovascular AMD

RADICAL=Reduced Fluence Visudyne Anti-VEGF-Dexamethasone in Combination for AMD Lesions

SAILOR=Safety Assessment of Intravitreal Lucentis®

for Age-Related Macular Degeneration

VIEW 1=[North America] VEGF Trap-Eye Investigationof Efficacy and Safety in Wet AMD

VIEW 2=[International] VEGF Trap-Eye Investigationof Efficacy and Safety in Wet AMD


1. Which of the following is/are false regarding the useof optical coherence tomography (OCT) in theevaluation of neovascular AMD?

a. TD-OCT offers higher resolution than SD-OCTb. Eyes that appeared fluid-free with TD-OCT mayshow residual fluid with SD-OCT

c. Both A and B are false

2. Which of the following is/are commonly used tests inthe evaluation of a newly diagnosed patient withneovascular AMD?

a. OCTb. Fluorescein angiographyc. Both A and B

3. Which of the following correctly describes themolecular structure of the anti-VEGF molecules?

a. Pegaptanib is an antibody fragmentb. Bevacizumab is an antibodyc. Aflibercept is an aptamer

4. Which of the following was not a finding in CATT?a. When each was dosed monthly, ranibizumab and bevacizumab produced comparable visualacuity outcomes

b. When each was dosed PRN, ranibizumab and bevacizumab produced comparable visualacuity outcomes

c. Monthly therapy was clearly superior to PRNtherapy with each drug

5. Which of the following is/are a valid conclusionregarding the VIEW studies of aflibercept?

a. Both View 1 and View 2 demonstrated thatmonthly aflibercept was more effective thanmonthly ranibizumab

b. Aflibercept dosed every 2 months was as effective as either aflibercept or ranibizumabdosed every month

c. Both A and B are true

6. Which of the following most accurately describes thesafety of anti-VEGF therapy?

a. Patients with AMD have fewer strokes overallthan patients without AMD

b. Anti-VEGF therapy clearly increases the risk of stroke

c. Neither A nor B is true

7. Which of the following most accurately describes theburden of therapy associated with anti-VEGFtreatment for neovascular AMD?

a. The need for monthly evaluation and therapy isextremely costly to the health care system

b. Risks of catastrophic complications such asendophthalmitis are cumulative with eachadditional injection


8. Which of the following is/are indications forswitching to an alternate therapy?

a. Stability with monthly injections, but loss ofacuity when the dosing interval is extended

b. Persistent subretinal fluid despite multiplemonthly injections of current therapy

c. Both A and B

9. Which of the following is a reasonable approach tothe neovascular AMD patient who desires todiscontinue follow-up?

a. Inject a double dose of anti-VEGF therapy onthe last visit

b. Combine anti-VEGF therapy with PDT toextend the therapeutic benefit

c. Neither A nor B is a reasonable approach

Which of the following is/are true regardingcombination therapy?

a. Combination therapy produces superior visualacuity outcomes to monotherapy

b. Combination therapy can often increase thedosing interval


14

CME POST TEST Advances in the Treatment of Wet Age-Related Macular Degeneration

To obtain AMA PRA Category 1 Credit™ for this activity, you must complete the CME Post Test by writing thebest answer to each question in the Answer Box located on the Activity Evaluation/Credit Request form on thefollowing page.

10.


To receive AMA PRA Category 1 Credit™, you must complete this Evaluation form and the Post Test. Record your answers to the Post Test in the Answer Boxlocated below. Mail or Fax this completed page to The New York Eye and Ear Infirmary–ICME, 310 East 14th Street, New York, NY 10003 (Fax: 212-353-5703).Your comments help us to determine the extent to which this educational activity has met its stated objectives, assess future educational needs, and create timelyand pertinent future activities. Please provide all the requested information below. This ensures that your certificate is filled out correctly and is mailed to the properaddress. It also enables us to contact you about future CME activities. Please print clearly or type. Illegible submissions cannot be processed.

PARTICIPANT INFORMATION (Please Print) � Home � Office

Last Name _____________________________________________________________________ First Name ________________________________________

Specialty ____________________________________________ Degree � MD � DO � PharmD � RPh � NP � RN � PA � Other ____________

Institution _________________________________________________________________________________________________________________________

Street Address ____________________________________________________________________________________________________________________

City ________________________________________ State _____________________ ZIP Code ____________________ Country ______________________

Email ______________________________________ Phone ______________________________________ Fax _____________________________________

Please note: We do not sell or share e-mail addresses. They are used strictly for conducting post-activity follow-up surveys that are required by theAccreditation Council for Continuing Medical Education (ACCME).

Learner Disclosure: To ensure compliance with the US Centers for Medicare and Medicaid Services regarding gifts to physicians, The New York Eye and EarInfirmary Institute for CME requires that you disclose whether or not you have any financial, referral and/or other relationship with our institution. CME certificatescannot be awarded unless you answer this question. For additional information, please call NYEE ICME at 212-979-4383. Thank you.� Yes � No I and/or my family member have a financial relationship with The New York Eye and Ear Infirmary and/or refer Medicare/Medicaid patients to it.� I certify that I have participated in the entire activity and claim 2.0 AMA PRA Category 1 Credits™.

Signature Required __________________________________________________________________ Date Completed ______________________________

OUTCOMES MEASUREMENT

� Yes � No Did you perceive any commercial bias in any part of this activity? IMPORTANT! If you answered “Yes,” we urge you to be specific about where the bias occurred so we can address the perceived bias with the contributor and/or in the subject matter in future activities.

_________________________________________________________________________________________________________________________________Circle the number that best reflects your opinion on the degree to which the following learning objectives were met:5 = Strongly Agree 4 = Agree 3 = Neutral 2 = Disagree 1 = Strongly Disagree

After successfully completing this activity, I have improved my ability to: • Demonstrate the implications of the CATT results for monthly and PRN dosing and monitoring

of currently used anti-VEGF agents in various subsets of patients 5 4 3 2 1 • Compare and contrast the anti-VEGF agents with respect to mechanism of action and binding affinities 5 4 3 2 1 • Discuss the results of the latest clinical trials and how anti-VEGF and other therapies

may be used in patients with wet AMD 5 4 3 2 1 • Discuss the advantages and drawbacks of various treatments and combinations in their

ability to reduce treatment burden and safety risks 5 4 3 2 1 • Employ current best practice use of OCT in guiding treatment 5 4 3 2 1 • Apply results from the latest clinical trials to AMD patient case scenarios 5 4 3 2 1

1. Please list one or more things, if any, you learned from participating in this educational activity that you did not already know. ____________________________

_________________________________________________________________________________________________________________________________

2. As a result of the knowledge gained in this educational activity, how likely are you to implement changes in your practice? 4 3 2 14=definitely will implement changes 3=likely will implement changes 2=likely will not implement any changes 1=definitely will not make any changesPlease describe the change(s) you plan to make:

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________3. Related to what you learned in this activity, what barriers to implementing these changes or achieving better patient outcomes do you face?__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________4. Please check the Core Competencies (as defined by the Accreditation Council for Graduate Medical Education) that were enhanced for you throughparticipation in this activity. � Patient Care � Practice-Based Learning and Improvement � Professionalism

� Medical Knowledge � Interpersonal and Communication Skills � Systems-Based Practice

5. What other topics would you like to see covered in future CME programs? ___________________________________________________________________________

_________________________________________________________________________________________________________________________________

ADDITIONAL COMMENTS __________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

ACTIVITY EVALUATION/CREDIT REQUEST

Advances in the Treatment of Wet Age-Related Macular Degeneration Proceedings From a Roundtable Discussion

1 2 3 4 5 6 7 8 9 10

POST TEST ANSWER BOX

Original Release: May 15, 2012 I Last Review: May 1, 2012 I Expiration: May 31, 2013


Proceedings From a Roundtable Discussion

Advances in the Treatment of

Wet Age-Related Macular Degeneration


advances in the treatment of wet age-related …journals.lww.com/retinajournal/documents/may...

Documents