Clinical Consultations ’

This continuing medical education activity is supportedthrough an unrestricted educational grant from

Genentech, Inc.

Jointly sponsored by The New York Eye and Ear Infirmary and MedEdicus LLC.

Distributed with

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This educational activity consists of a supplement and ten (10) studyquestions. The participant should, in order, read the learning objectivescontained at the beginning of this supplement, read the supplement, answerall questions in the post test, and complete the Activity Evaluation/CreditRequest form. To receive credit for this activity, please follow the instructionsprovided on the post test and Activity Evaluation/Credit Request form. Thiseducational activity should take a maximum of 2.0 hours to complete.

This continuing medical education (CME) activity captures content from aseries of regional CME meetings held in the summer and fall of 2013.

The treatment of wet age-related macular degeneration (AMD) has rapidlyevolved with the use of anti-vascular endothelial growth factor (VEGF)therapy. Today, treatment of wet AMD is turning toward individualizingtherapy. This CME program was developed specifically to address thequestions being asked by retina specialists throughout the United States whotreat patients with wet AMD. This monograph reflects the current evidence-based understanding of the issues with expert approaches for optimizingpatient outcomes where evidence is not yet available.

This educational activity is intended for retina specialists, retina fellows, andcomprehensive ophthalmologists caring for patients with wet AMD.

Upon completion of this activity, participants will be better able to:• Evaluate the current evidence on efficacy, safety, and dosing regimens of the anti-vascular endothelial growth factor agents used to treat wet AMD• Select a treatment strategy for a variety of patients with wet AMD thatmaintains visual acuity and long-term safety, as well as meets patientpreferences

This activity has been planned and implemented in accordance with theEssential Areas and Policies of the Accreditation Council for ContinuingMedical Education through the joint sponsorship of The New York Eye andEar Infirmary and MedEdicus LLC. The New York Eye and Ear Infirmary isaccredited by the ACCME to provide continuing medical education forphysicians.

In July 2013, the Accreditation Council for Continuing MedicalEducation (ACCME) awarded The New York Eye and EarInfirmary Institute for Continuing Medical Education“Accreditation with Commendation,” for six years as a provider ofcontinuing medical education for physicians, the highestaccreditation status awarded by the ACCME.

The New York Eye and Ear Infirmary designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claimonly the credit commensurate with the extent of their participation in the activity.

This continuing medical education activity is supported through anunrestricted educational grant from Genentech, Inc.

It is the policy of The New York Eye and Ear Infirmary that the faculty andanyone in a position to control activity content disclose any real or apparentconflicts of interest relating to the topics of this educational activity, and alsodisclose discussions of unlabeled/unapproved uses of drugs or devices duringtheir presentation(s). The New York Eye and Ear Infirmary has establishedpolicies in place that will identify and resolve all conflicts of interest prior tothis educational activity. Full disclosure of faculty/planners and theircommercial relationships, if any, follows.

2

, —Co-ChairClinical Associate Professor of Ophthalmology

Doheny Eye Institute, Keck School of MedicineUniversity of Southern CaliforniaLos Angeles, CaliforniaManaging PartnerRetinal Consultants of Arizona, LtdPhoenix, Arizona

, —Co-ChairDirector, Retina ServiceWills Eye HospitalProfessor of OphthalmologyThomas Jefferson UniversityPhiladelphia, Pennsylvania

, Clinical Professor of OphthalmologyKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, CaliforniaSenior PartnerRetina-Vitreous Associates Medical GroupBeverly Hills, California

, , Vitreoretinal SpecialistTexas Retina AssociatesT. Boone Pickens Senior Scientist andDirector, Macular Degeneration Molecular Laboratory

Retina Foundation of the SouthwestDallas, Texas

, DirectorNew England Eye CenterProfessor and ChairDepartment of OphthalmologyTufts University School of MedicineBoston, Massachusetts

David Boyer, MD, had a financial agreement or affiliation during the past yearwith the following commercial interests in the form of Consultant/AdvisoryBoard: Aerpio Therapeutics; Alcon; Allegro Ophthalmics, LLC; Allergan, Inc;Bausch + Lomb Incorporated; Bayer; Genentech, Inc; GlaxoSmithKline; Merck& Co, Inc; Neurotech Pharmaceuticals; Novartis; Ora, Inc; Pfizer Inc; QLT Inc;and Regeneron Pharmaceuticals, Inc; Fees for promotional, advertising or non-CME services received directly from commercial interest or their Agents (eg,Speakers Bureaus): Allergan, Inc; and Genentech, Inc; Ownership Interest:Allegro Ophthalmics, LLC.

Karl Csaky, MD, PhD, had a financial agreement or affiliation during the pastyear with the following commercial interests in the form of Consultant/Advisory Board: Acucela Inc; Genentech, Inc; GlaxoSmithKline; Merck & Co,Inc; Novartis; Ophthotech; Pfizer Inc; QLT Inc; Roche USA; and SantenPharmaceutical Co, Ltd; Contracted Research: Genentech, Inc; Fees forpromotional, advertising or non-CME services received directly from commercialinterest or their Agents (eg, Speakers Bureaus): Genentech, Inc; OwnershipInterest: Ophthotech.

Pravin Dugel, MD, had a financial agreement or affiliation during the pastyear with the following commercial interests in the form of Consultant/Advisory Board: Abbott Medical Optics; Alcon, Inc; Alimera Sciences;Allergan, Inc; ArcticDX; Digisight Technologies; Genentech, Inc; LuxBiosciences, Inc; MacuSight, Inc; NeoVista, Inc; Ora, Inc; Ophthotech,Regeneron Pharmaceuticals, Inc; and ThromboGenics NV; OwnershipInterest: ArcticDX; MacuSight, Inc; NeoVista, Inc; Ophthotech; and DigiSightTechnologies.

Jay Duker, MD, had a financial agreement or affiliation during the past yearwith the following commercial interests in the form of Consultant/AdvisoryBoard: EMD Serono, Inc; Novartis Pharmaceuticals Corporation; Optos; QLTPhototherapeutics, Inc; and ThromboGenics NV; Contracted Research: CarlZeiss Meditec, Inc; and Optovue, Inc; Ownership Interest: EyeNetra; HemeraBiosciences, Inc; Ophthotech; and Paloma Pharmaceuticals, Inc.

Carl Regillo, MD, had a financial agreement or affiliation during the past yearwith the following commercial interests in the form of Consultant/AdvisoryBoard: Genentech, Inc; GlaxoSmithKline; and Regeneron Pharmaceuticals,Inc; Contracted Research: Genentech, Inc; GlaxoSmithKline; and RegeneronPharmaceuticals, Inc; Fees for promotional, advertising or non-CME servicesreceived directly from commercial interest or their Agents (eg, Speakers Bureaus):Genentech, Inc; and Regeneron Pharmaceuticals, Inc.

John Sorenson, MD, has no relevant commercial relationships to disclose.

Tony Realini, MD, MPH, had a financial agreement or affiliation during the past year with the following commerecial interests in the form ofConsultant/Advisory Board: Alcon, Inc; Sensimed; and SucampoPharmaceuticals, Inc; Contracted Research: Alcon, Inc; Fees for promotional,advertising or non-CME services received directly from commerical interest ortheir Agents (eg, Speakers Bureaus): Alcon, Inc; and Lumenis Ltd.

Cynthia Tornallyay, RD, MBA, CCMEP; Kimberly Corbin, CCMEP; BarbaraAubel; and Vivian Fransen, MPA, have no relevant commercial relationshipsto disclose.

The contributing physicians listed above have attested to the following:1) that the relationships/affiliations noted will not bias or otherwise influencetheir involvement in this activity;

2) that practice recommendations given relevant to the companies withwhom they have relationships/affiliations will be supported by the bestavailable evidence or, absent evidence, will be consistent with generallyaccepted medical practice; and

3) that all reasonable clinical alternatives will be discussed when makingpractice recommendations.

- This activity includes off-label discussion of bevacizumab for ophthalmic use.Please refer to the official prescribing information for discussion of approvedindications, contraindications, and warnings.

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The New York Eye and Ear Infirmary Privacy & Confidentiality PoliciesCME policies: http://www.nyee.edu/cme-enduring.html Hospital policies: http://www.nyee.edu/website-privacy.html

CME Provider Contact InformationFor questions about this activity, call 212-979-4383.

™To obtain AMA PRA Category 1 Credit™ for this activity, read the material inits entirety and consult referenced sources as necessary. Complete theevaluation form along with the post test answer box within this supplement.Remove the Activity Evaluation/Credit Request page from the printedsupplement or print the Activity Evaluation/Credit Request page from theDigital Edition. Return via mail to Kim Corbin, Director, ICME, The NewYork Eye and Ear Infirmary, 310 East 14th Street, New York, NY 10003 or faxto (212) 353-5703. Your certificate will be mailed to the address you provideon the evaluation form. Please allow 3 weeks for Activity Evaluation/CreditRequest forms to be processed. There are no fees for participating in andreceiving CME credit for this activity.

Alternatively, we offer instant certificate processing and support Green CME. Please take this post test and evaluation online by going tohttp://tinyurl.com/TopQuestionsWetAMD. Upon passing, you will receiveyour certificate immediately. You must score 70% or higher to receive creditfor this activity, and may take the test up to 2 times. Upon registering andsuccessfully completing the post test, your certificate will be made availableonline and you can print it or file it.

The views and opinions expressed in this educational activity are those of thefaculty and do not necessarily represent the views of The New York Eye andEar Infirmary, MedEdicus LLC, Genentech, Inc., or Retinal Physician.

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This CME activity is copyrighted to MedEdicus LLC ©2013. All rights reserved.

IntroductionThe treatment of neovascular age-related macular

degeneration (AMD) has rapidly evolved with the use of

anti-vascular endothelial growth factor (VEGF) therapy. In

2013, anti-VEGF therapy is firmly established as the

primary method of preserving vision for patients with wet

AMD. Clinicians rely on data from relevant clinical trials

for guidelines on who and how to treat wet AMD but such

guidelines apply to only a narrow range of patients and

often cannot be used in “real-world” situations. Novel

approaches by clinicians can provide effective long-term

management of wet AMD with varying degrees of evidence-

based data. As with any evolving management strategies,

questions arise as treatment strategies are refined over time.

This continuing medical education program was designed

specifically to address the top questions that retina specialists

who treat patients with wet AMD across the United States

are asking. The answers reflect the current evidence-based

and/or consensus understanding of the issues relevant to

managing patients with wet AMD in real-world settings.

The primary goal of this educational activity is to provide

insight into the intricacies of clinical care in a setting where

all of the information needed to optimize patient outcomes

is not yet available.

Question 1.How do the anti-VEGF agents compare with eachother in terms of efficacy, duration, safety, and cost?

There are 4 inhibitors of VEGF currently available in the USmarketplace. Aflibercept (Eylea®, Regeneron) is a VEGF trapmolecule that is FDA-approved for neovascular AMD.Bevacizumab (Avastin®, Genentech) is an antibody that is notapproved by the US Food and Drug Administration (FDA) forAMD therapy but is widely used off-label for this purpose.Ranibizumab (Lucentis®, Genentech) is an antibody fragmentthat is FDA-approved for the treatment of neovascular AMD andother retinal disorders. These 3 agents are pan-VEGF inhibitors:They block the effects of all isoforms of VEGF, of which there areseveral. The fourth agent is pegaptanib (Macugen®, Valeant), anucleic acid-based aptamer that selectively inhibits only 1isoform of VEGF (VEGF165). In practical terms, pegaptanib isnot commonly used because of its clinical inferiority to the pan-VEGF inhibitors so it has no significant role in the currenttreatment approach to neovascular AMD.

To date, no data exist that compare all 3 anti-VEGF agents in asingle, contemporaneous, head-to-head trial. However, manystudies have compared various pairings of these agents (Table 1).

To assess the relative efficacy, safety, and duration of action ofthese agents, cross-study comparisons are generally required.However, limitations exist with cross-study comparisons. Thestudy populations are often different based on various eligibilitycriteria. In addition, dosing regimens typically vary from studyto study, the interpretation of optical coherence tomography(OCT) images can be disparate, and clinical endpoints may alsobe different for each study. Despite these limitations, usefulinsights can be gained from carefully reviewing the major trialsof anti-VEGF agents for neovascular AMD.

How Anti-VEGF Agents Compare on EfficacyThe first major study to compare bevacizumab and ranibizumabwas the Comparison of AMD Treatments Trials (CATT),1,2 whichwas designed with 4 arms: administration of bevacizumabmonthly or as needed, and administration of ranibizumabmonthly or as needed. Patients in the as-needed dosing groupsreceived a single treatment at enrollment and were then followedmonthly; only those patients in which visual acuity worsened orhad evidence of active neovascularization on clinical exam, OCT,or fluorescein angiography were treated subsequently. The mainoutcome measure was the mean change in best-corrected visualacuity (BCVA) at 1 year. At the end of the first year, bevacizumabwas deemed noninferior to ranibizumab when dosed monthly,while as-needed dosing of bevacizumab was not found to benoninferior to either agent dosed monthly. This is an important

4

Study Treatment Arms

CATT1,2 Ranibizumab 0.5 mg monthlyRanibizumab 0.5 mg as neededBevacizumab 1.25 mg monthlyBevacizumab 1.25 mg as needed

IVAN3 Ranibizumab 0.5 mg monthlyRanibizumab 0.5 mg as needed*Bevacizumab 1.25 mg monthlyBevacizumab 1.25 mg as needed*

GEFAL4 Ranibizumab 0.5 mg as needed*Bevacizumab 1.25 mg as needed*

VIEW5 Ranibizumab 0.5 mg monthlyAflibercept 0.5 mg monthlyAflibercept 2.0 mg monthlyAflibercept 2.0 mg every other month*

HARBOR6 Ranibizumab 0.5 mg monthlyRanibizumab 0.5 mg as needed*Ranibizumab 2.0 mg monthlyRanibizumab 2.0 mg as needed*

*after 3 monthly loading doses

CATT=Comparison of AMD Treatments Trials; IVAN=Inhibit VEGF in Age-relatedChoroidal Neovascularization; GEFAL=Groupe d’Evaluation Français Avastin versusLucentis; VIEW=VEGF Trap-Eye Investigation of Efficacy and Safety in Wet AMD;HARBOR=Study of Ranibizumab Administered Monthly or on an As-Needed Basisin Patients With Subfoveal Neovascular Age-Related Macular Degeneration

Table 1. Major Head-to-Head Anti-VEGF Trials in AMD

point and has been confirmed consistently in other large trials.No matter what anti-VEGF agent is studied, monthly dosingprovides the best BCVA outcomes. The as-needed dosing groupsrequired 7 to 8 injections (compared to 12 injections in themonthly treated groups) in the first year of CATT, with slightlymore treatments needed in the bevacizumab as-needed dosinggroup than the ranibizumab as-needed dosing group. Thisunexpected finding established that these 2 agents have similarduration of action. Previously, it was a commonly held belief thatbevacizumab lasted longer than ranibizumab, due to its longerhalf-life, but this was not evident in CATT based on the numberof treatments in the as-needed dosing groups.

In year 2 of CATT, those patients on monthly dosing during thefirst year were randomly assigned to remain on monthly dosingor move to as-needed dosing. Those patients maintained onmonthly dosing for the full 2 years had the best outcomes,establishing that the as-needed dosing regimen was inferior tothe monthly dosing regimen with both agents (Figure 1).2

Interestingly, those who switched from monthly to as-neededdosing for year 2 finished the year with BCVA measurescomparable to those who had been receiving as-needed dosingfrom the start. These data reinforce the point that monthlydosing may lead to best outcomes over the first 2 years from avisual acuity perspective, and there may be a slight visual acuitycost to reducing the frequency of injections to less than monthlydosing with bevacizumab and ranibizumab. Another importantconclusion from these observations is that no matter how longclinicians treat patients with AMD on a monthly basis, there isno permanent structural change regarding the effect of the anti-VEGF agent on the choroidal vascular membrane that isconferred to ease the treatment burden.

Although as-needed dosing may be statistically slightly inferior, itmay be an attractive option in clinical practice. The actualoutcome difference between the monthly and as-needed dosingarms in CATT was only an average of 2 Early Treatment DiabeticRetinopathy Study (ETDRS) letters. These 2 letters represented astatistically significant difference between the groups, but the

clinical significance of 2 letters is more difficult to assess.It may merely be a “smudge in the glasses.” In some ormost patients, it may be reasonable to give up those 2 letters in exchange for a reduced treatment burden,with fewer visits, fewer injections, and a reduced risk ofcomplications. This is a discussion that clinicians andtheir patients must have on an individualized basis.However, it must be pointed out that the differencebetween monthly and as-needed dosing was an averageof 2 letters overall; the real difference per patient may bemore or less than 2 letters.

The Inhibit VEGF in Age-related ChoroidalNeovascularization (IVAN) study, conducted in theUnited Kingdom, was the first international versionof CATT with the treatment groups defined in thesame way as CATT. Only a few differences were madein the study design for IVAN; the most notable

change was the as-needed groups received 3 monthly loadingdoses of bevacizumab or ranibizumab and then were reloadedwith every episode of recurrence.3 The IVAN results confirmedthe CATT results in both years. Bevacizumab was not found tobe noninferior to ranibizumab, and the discontinuous (as-needed dosing) arms were not noninferior to the monthlyarms. Furthermore, results from the Groupe d’EvaluationFrançais Avastin versus Lucentis (GEFAL) study—which wasconducted in France and followed the study design of bothCATT and IVAN—confirmed through the first year similarfindings that these 2 larger studies have shown.4

The VEGF Trap-Eye Investigation of Efficacy and Safety in WetAMD (VIEW 1) and VIEW 2 studies compared the outcomes ofpatients who received ranibizumab with the outcomes ofpatients who received aflibercept.5 The VIEW studies wereregistration trials for aflibercept and had 4 arms: aflibercept, 0.5. mg or 2.0 mg, monthly, aflibercept, 2.0 mg, every othermonth (after 3 monthly loading doses), or ranibizumabmonthly. The first year followed this fixed-dose regimen; in thesecond year all study arms required capped as-needed dosing,with 1 injection given every 3 months and additionalretreatment given during the intervening months based on OCTand vision criteria. In year 1 of VIEW, the 4 groups had nearlyidentical visual acuity gains ranging from 8.3 to 9.3 letters in thepooled VIEW 1 and VIEW 2 data set.

How Anti-VEGF Agents Compare on ActivityNo study has demonstrated a definitive difference in efficacy ordurability between these 3 anti-VEGF agents, despite previoustheoretical studies. For example, in vitro studies andpharmacokinetic modeling suggest that aflibercept has moreanti-VEGF activity than ranibizumab or bevacizumab.6 Anotherstudy suggests that the amount of fluid on OCT is a surrogatefor VEGF levels.7 If true, then the variable “drying effect of the 3 agents” suggests that aflibercept has more anti-VEGF activitythan ranibizumab, which, in turn, has more anti-VEGF activity

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Ranibizumab MonthlyBevacizumab MonthlyRanibizumab as NeededBevacizumab as Needed

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(145, 135, 285, 270) (134, 129, 264, 251)4 12 24 36 52

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Adapted from CATT Research Group et al, 2012.2

than bevacizumab.1,2,5 These theoretical assertionsregarding ultimate visual acuity outcomes have notbeen supported by large clinical trials. None of thecomparative studies has demonstrated better visionwith any of the 3 agents.

How Anti-VEGF Agents Compareon Duration of ActionCATT, IVAN, and GEFAL compared the outcomes ofpatients who received bevacizumab with the outcomesof patients who received ranibizumab, which reachedconsistent results on efficacy. There were no apparentdifferences in duration of action of these drugs inthese studies. VIEW 1 and 2 compared aflibercept toranibizumab. Interestingly, some study arms hadsubstantially different outcomes between VIEW 1 andVIEW 2, varying by as much as 40%. Given that thesepatients met the same eligibility criteria, received thesame treatment, and were followed with the sameevaluation schedule, this finding underscores howvariable neovascular AMD can be and whyindividualized patient care is recommended by thevast majority of US retinal specialists. In year 2, therewas a small diminution of visual acuity with thetransition to as-needed dosing, but all 4 groups stilldemonstrated remarkably similar outcomes (Figure2).8 The mean number of injections in year 2 was onlyslightly less in the aflibercept arms compared to theranibizumab arm (but both arms were still between 4 and 5 injections during the year). In other words,there was a level playing field for a head-to-headcomparison in year 2 of VIEW between ranibizumab andaflibercept. Yet, neither efficacy nor durability comparisonsshowed any significant differences, although trends favoredaflibercept in duration of action.

As previously noted, limitations exist with cross-studycomparisons. However, given the available data without thebenefit of head-to-head comparisons of all anti-VEGF agents,these agents appear to have a similar duration of action inpractice for treating neovascular AMD (Figure 3).

How Anti-VEGF Agents Compare on SafetyIn general, these anti-VEGF agents are viewed as safe. However,safety concerns include various ocular issues and systemic issues.

With respect to ocular safety concerns, questions about both theinjection process and the specific agent that is injected have beenraised. To date, there have been no reports of ocular safety issuesconclusively and exclusively attributable to the anti-VEGFactions of any of these agents. Some injection-related concernsinclude endophthalmitis, traumatic cataract, and retinaldetachment, although the risk of these problems has decreasedin the years since intravitreal injections became commonplace in

the vitreoretinal practice, mostly due to both experience and therefinement of protocols. However, there remains no standardprotocol for intravitreal injection technique—the use of a lidspeculum, mask, and even sterile gloves differs among clinicians.One interesting theory regarding endophthalmitis involves oralflora. Another issue that has arisen in recent times is thepotential risk of contamination associated with aliquotingbevacizumab from the vial used for systemic cancer therapy intosingle-dose syringes for intraocular injection (see sidebar onPreventing Endophthalmitis).

The development and progression of underlying dry maculardegeneration in the form of worsening geographic atrophy hasbeen observed in some studies and seems to be associated withfrequent injections and anti-VEGF activity in which thesurrogate marker is “complete” drying of the macula.2 It isunclear if this process is the same as the geographic atrophy seenin the dry form of AMD. Atrophy has been seen in associationwith all of the anti-VEGF agents. Analysis of some data hassuggested atrophy occurs more often when patients receive highor frequent anti-VEGF dosing,2-4 but keep in mind that these arethe patients who tend to be the driest. More recently, atrophy hasalso been seen in patients with low exposure to anti-VEGFagents in other studies.9 Its frequency in eyes with dry AMDsuggests that it may be part of the natural history of eyes that

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Figure 2. Two-year mean change in visual acuity outcomes of the VIEW studies.8

Adapted from Schmidt-Erfurth et al, 2013.8

Figure 3. Comparison of number of doses in as-needed dosing arms of major anti-VEGF agents in (not head-to-head) trials for AMD.

RBZ=ranibizumab; BVZ= bevacizumab; AFL=aflibercept

achieve dryness rather than being caused by exposure to anti-VEGF agents. Anti-VEGF therapy may address theneovascular component but not the non-neovascularcomponent of this disease, and this progressive atrophy is mostcommonly associated with long-term vision loss in AMD,according to the SEVEN-UP study,9 which was a 7-year study ofoutcomes in ranibizumab-treated patients in the Anti-VEGFAntibody for the Treatment of Predominantly Classic ChoroidalNeovascularization in AMD (ANCHOR) trial, the MinimallyClassic/Occult Trial of the Anti-VEGF Antibody Ranibizumab inthe Treatment of Neovascular AMD (MARINA) trial, and theOpen-Label Extension Trial of Ranibizumab for ChoroidalNeovascularization Secondary to Age-Related MacularDegeneration (HORIZON). Further study is necessary to clarifythis concern, particularly since anti-VEGF therapy is now beingused for patients with diabetic macular edema who are youngerthan those we typically see with wet AMD and may have agreater exposure to these agents over their lifetime.

Elevations in intraocular pressure (IOP) are recognized as anuncommon but potentially serious consequence of long-termintravitreal anti-VEGF therapy. The cause of these IOPelevations remains unknown. Short-term IOP elevations can beattributed to the volume expansion associated with theinjection. Long-term IOP elevations have also been reported andmay be due to aggregates of molecules within the formulationand/or contamination from the syringes in which the drug isstored, among other possible causes.10 These IOP elevations aremore common in people with preexisting glaucoma, and the riskalso increases with a greater number of injections.8

Systemic safety is an additional consideration with these anti-VEGF agents. Patients with AMD are typically older thanpatients with diabetic macular edema (DME) and often haveserious comorbidities. Patients with DME being younger mayrequire longer courses of therapy with anti-VEGF agents.Therefore, the systemic safety profiles are important.Characterizing the relative safety of these medications is difficultfor several reasons: (1) none of the studies have been poweredsufficiently to establish systemic risk, (2) no head-to-head safetytrials with all 3 anti-VEGF agents have been conducted, and (3)the sample size required to compare the rates of uncommonevents in such head-to-head safety trials is prohibitively highand consequently they are unlikely to be performed.

Nonetheless, the systemic safety profiles of the 3 pan-VEGFinhibitors may be an important differentiator of these agents. Variations in safety profiles may potentially be due to structuraldifferences among the different agents. The 2 larger molecules(aflibercept and bevacizumab) have the Fc component, unlikeranibizumab. Does the Fc component matter? Animal studieshave shown that molecules containing the Fc component dotend to remain in the systemic circulation longer. This findinghas been recently confirmed in humans. Human data onpatients with wet AMD and retinal vein occlusion showed thatplasma-free VEGF was lowered below the lowest level of

quantification for bevacizumab and aflibercept.11 In the IVANstudy, bevacizumab was associated with significantly moresystemic VEGF suppression than ranibizumab.12 Whether or notthis is a clinically relevant observation is unknown. In CATT,there were more serious systemic safety events in thebevacizumab groups than in the ranibizumab groups in bothyear 1 and year 2.1,2 When this same trend was seen in the firstyear of the IVAN study,3 the IVAN data safety monitoringcommittee elected to inform all patients in the IVAN study ofthis potential risk and have them re-sign their consent forms ifthey wished to remain in the study.

Aflibercept’s systemic safety compared to ranibizumab wasassessed in the VIEW studies, and the safety profiles were notedto be similar.7 Recently, the European equivalent of the FDAissued a report based on additional analysis of the raw data from VIEW and found some interesting trends.13 Their analysisstratified patients by age and looked separately atcerebrovascular events, such as strokes, and cardiovascularevents, such as myocardial infarctions. The age stratification was conducted specifically to look at older people, who tend tohave more comorbidities and generally frailer health. Theseresearchers found that patients aged 85 years or older had ahigher risk of cerebrovascular events in the aflibercept-treatedgroups and a higher rate of cardiovascular events in theranibizumab-treated group than patients under 85 years of age during the first year of VIEW. Data at the end of year 2pertaining to patients 85 years and older showed acardiovascular event rate of 10.3% in ranibizumab-treatedpatients versus 7.4% in aflibercept-treated patients. Thecerebrovascular event rate in this age group at the end of year 2was 9.5% for those treated with aflibercept versus 3.4% for thosetreated with ranibizumab.

This apparent increased risk for cerebrovascular events inpatients who are 85 years or older and who had a previoushistory of a cerebrovascular or cardiovascular event is notunique to aflibercept. In ranibizumab studies, patients with aprior history of stroke had a higher risk of stroke and deathwhile receiving ranibizumab than patients who had no historyof stroke.14 Similarly, a prior history of diabetes, hypertension,hyperlipidemia, or cardiac arrhythmias increased the risk ofboth strokes and cardiovascular events in patients whoparticipated in the ranibizumab trials.14

These safety signals are seen consistently across studies for allanti-VEGF agents, and likely point to a real phenomenon. There may be a slightly increased risk of cerebrovascular orcardiovascular events with these anti-VEGF agents, particularlyin vulnerable or high-risk patients such as those described.Fortunately, the increased risk is small and does not generallyoutweigh the benefits of these agents in recovering andmaintaining vision for patients with neovascular AMD. Mostpatients with neovascular AMD would opt for treatment andaccept the small risk rather than not receive anti-VEGF therapyand lose their sight from this disease. The risk of stroke or

7

cardiovascular events should not alter the decision to offer anti-VEGF therapy, but it might alter which anti-VEGF agent ischosen for these potentially at-risk patients. The specific case ofapproaching therapy in a patient who has had a prior stroke isdiscussed later in this monograph.

How Anti-VEGF Agents Compare on CostSignificant cost differences exist between these anti-VEGFagents, with the cost of bevacizumab therapy approximately 40 times less than therapy with ranibizumab or aflibercept. Infact, ranibizumab accounted for almost 10% of the total USMedicare Part B drug budget in 2010.2

Question 2. What are the roles of laser photocoagulation orphotodynamic therapy (PDT) today?

Laser photocoagulation was the sole intervention for patientswith neovascular AMD for many years, and numerous studiesdemonstrated that, despite its destructive and negative impacton visual acuity, laser photocoagulation led to better patientoutcomes than the untreated natural history of the disease. Inthe modern era of anti-VEGF agents, there is little room left forlaser photocoagulation, which may still have a role in raresituations for patients who present with a well-defined andentirely extrafoveal choroidal neovascular membrane.

PDT with verteporfin bridged the gap betweenphotocoagulation and the development of anti-VEGF therapy asa reasonable intervention for smaller, predominantly classiclesions, but has since largely fallen out of favor. The MONTBLANC study, a double-masked, multicenter trial in Europe, wasconducted to determine whether or not PDT combined withranibizumab could reduce the anti-VEGF treatment burden ofranibizumab alone by decreasing the frequency of requiredinjections.15 Patients with new-onset neovascular AMD wererandomly assigned either to ranibizumab as needed or PDT plusranibizumab as needed. By the end of 12 months, both groupsrequired the same number of as-needed ranibizumab injections(about 5 injections), and the ranibizumab monotherapy grouphad better visual acuity outcomes than the group treated withPDF plus ranibizumab as needed.

PDT may be of value in patients with polypoidal choroidalvasculopathy (PCV). In the EVEREST study, patients with PCVwere randomized to receive either PDT with verteporfin,ranibizumab, 0.5 mg, or the combination of bothinterventions.16 At month 6, PDT alone or combined withranibizumab was found to be superior to ranibizumabmonotherapy in achieving complete polyp regression (71.4%and 77.8% vs 28.6%, respectively; P=.01).

Another potential role of PDT is for patients who are refractoryto therapy with anti-VEGF agents. If patients fail to achievedrying of the macula with anti-VEGF agents, adding PDT maystabilize some of these eyes by reducing the anti-VEGFtreatment burden. As such, PDT is usually reserved for eyes witha relatively poor prognosis. A recent study based in southern

California evaluated this approach in 26 eyes with persistentsubretinal or intraretinal fluid despite 3 or more anti-VEGFinjections.17 Researchers found significant improvements invisual acuity 1 and 3 months after rescue PDT (P=0.01),reductions in central subfield retinal thickness at 1, 3, and 6 months (P≤.0003), and an increase in the proportion of fluid-free eyes from 0.5% to 41% (P=.00001)—all whileincreasing the interval between required anti-VEGF injectionsfrom 1.6 to 2.7 months (P=.002).

Question 3.What is the role of imaging, and how does it guideclinical decision-making in caring for patients withneovascular AMD?

OCT remains the primary imaging modality for neovascularAMD in terms of monitoring the effect of therapy. Virtually everymajor study has used OCT-based treatment criteria, and most ofthese studies have used time-domain OCT. To date, only theStudy of Ranibizumab Administered Monthly or on an As-Needed Basis in Patients With Subfoveal Neovascular AMD(HARBOR) has evaluated outcomes of as-needed therapy guidedby spectral-domain OCT.12 Certainly more retinal detail can beseen on spectral-domain OCT than time-domain OCT. It isunclear what the clinical significance is of seeing additionaldetails such as small pockets of fluid. Some patients have residualfluid, especially subretinal and subretinal pigment epithelium, onspectral-domain OCT but have good and stable visual acuity.Treating them to dryness might be unnecessary and impossible;attempting to do so might represent unnecessary overtreatment.It is sometimes difficult to know when to stop treating the testresults and focus on treating the patient.

Fluorescein angiography was once the only imaging modality for the diagnosis of AMD. It remains useful in establishing thediagnosis of neovascular AMD. In terms of following the responseto anti-VEGF treatment, its role is more limited. Angiography canhelp distinguish between neovascular AMD and masqueradesyndromes such as central serous chorioretinopathy orpseudovitelliform macular dystrophies. These entities should beconsidered whenever there is little or no response to initial anti-VEGF therapy. Angiography can also be helpful for patients withAMD who show a little fluid on OCT images but still have goodvisual acuity—it can help the clinician decide if the lesion isactively leaking or not. Similarly, angiography can reveal leakagein eyes with dry OCT images but declining visual acuity.

Indocyanine green angiography is less often used thanfluorescein angiography in the clinical management of patientswith AMD. Its primary role is in identifying PCV, and its routineuse on all new patients with neovascular AMD remainscontroversial. It is also useful in helping to differentiateneovascular AMD from central serous chorioretinopathy.

Question 4.Do angiographic lesion classification and locationmatter anymore with anti-VEGF therapy?

Before the advent of anti-VEGF therapy, fluoresceinangiography was routinely used to determine the lesion’s size,

8

location, and angiographic subtype (predominantly orminimally classic or occult). These characteristics mattered inthe era of photocoagulation and PDT because different lesiontypes responded differently to the various treatments available.

In ANCHOR, the majority of patients had predominantly classiclesions whereas in MARINA, they were typically minimallyclassic or occult.18,19 Outcomes in these 2 studies werecomparable, supporting the finding that lesion subtype is notimportant from the standpoint of anti-VEGF therapy. Both ofthese studies did show, however, that baseline lesion size was apredictor of outcomes, and HARBOR also showed that the areaof leakage was predictive of acuity outcomes.12

Question 5. How often should the patient with neovascularAMD be retreated? When initiating therapy, should the dosing schedule be on a monthly, as-needed, or treat-and-extend basis?

There is little or no significant difference in visual outcomes ofpatients with neovascular AMD between monthly and as-neededdosing schedules in the first year of treatment, according to the

major clinical studies, as long as these patients weremonitored on a monthly basis. Patient outcomes inCATT, IVAN, and HARBOR (Figure 4)demonstrated that good visual acuity results can beachieved using as-needed therapy with a mean of 7 to 8 injections in the first year.1,3,12 Interestingly,in as-needed dosing studies published to date inwhich the mean number of treatments of anti-VEGF therapy dropped below 5.5 injections inyear 1, such as the Study to Evaluate Ranibizumabin Subjects With Choroidal NeovascularizationSecondary to Age-Related Macular Degeneration(SAILOR),14 the visual acuity results did tend to besuboptimal. Data from large claims databasessuggest that clinicians are undertreating patientswith wet AMD in clinical practice, with an averageof 4 to 6 injections in the first year and far fewer inthe subsequent years (Table 2).20,21

The SEVEN-UP study was an extension of the MARINA,ANCHOR, and HORIZON studies and looked at patientstreated with anti-VEGF therapy for a mean of 7.3 years,including an average follow-up period of 3.4 years since thecompletion of HORIZON.9 In that 3.4-year period, an average of6.8 injections was given to each eye—2 injections per year. Notsurprisingly, only 37% of the patients maintained visual acuity≥20/70, and 23% of the patients had visual acuity ≥20/40 at thecompletion of SEVEN-UP. Another reason for this decline invisual acuity was the high incidence of atrophy seen with long-term follow-up.

The best approach proven to maximize long-term visual acuityis frequent, fixed-interval continuous therapy. While thisapproach—such as treatment with monthly bevacizumab orranibizumab or every 2 months with aflibercept—is backed upwith results from large clinical trials, it represents an enormoustreatment burden for both patients and clinical practices,leading to overtreatment for some patients with AMD. Inpractice, clinicians favor individualized therapy with either as-needed treatment as previously described or a variable,continuous approach called the “treat-and-extend” approach.The latest practice pattern surveys indicated the treat-and-extend style of anti-VEGF therapy is now what the majority ofretinal specialists favor. One reason for the shift away from as-needed dosing regimens is that the results in year 2 of CATTand IVAN did not show the as-needed dosing arms performed aswell as the monthly treatment arms. By the end of year 2 in thesestudies, the as-needed dosing arms with bevacizumab andranibizumab were not statistically noninferior to monthlytreatment arms.

The treat-and-extend approach maintains continuous therapy—patients receive an injection at every visit regardless of theirstructural or functional status—but is variable in terms of timebetween visits. Typically, a patient with AMD who remainsstable on monthly therapy may be extended to a 6-week

9

Figure 4. Two-year outcomes of the HARBOR study.12 Adapted from Busbee et al, 2013.12

Number of annual injections

Year 1 Year 2 Year 3

SAILOR14 (Cohort 1) 4.9 N/A N/A

SAILOR14 (Cohort 2) 3.6 N/A N/A

Lad et al 5.3 1.9 1.6

Holekamp et al (bevacizumab) 4.6 N/A N/A

Holekamp et al (ranibizumab) 5.9 N/A N/A

SAILOR=Study to Evaluate Ranibizumab in Subjects With ChoroidalNeovascularization Secondary to Age-Related Macular Degeneration; SAILORCohort 1: OCT-guided retreatment; SAILOR Cohort 2: Physician-determinedretreatment

Table 2. Underutilization of Anti-VEGF Agents in Studies With As-Needed Dosing

12

10

8

6

4

2

00 1 2 43 65 7 8 9 10 11 12 13 14

Evaluation Interval (Month)

Mean Change in BCVA (letters)

Mean #Rx as needed Yr 1 & 20.5 mg: 7.7 & 5.62.0 mg: 6.9 & 4.3

Mea

n Ch

ange

in B

CVA

(let

ters

)

15 16 17 18 19 20 21 22 23 24

Month 12 Month 24 ∆M12 to M240.5 mg monthly +10.1 +9.1 –1.00.5 mg as needed +8.2 +7.9 –0.32.0 mg monthly +9.2 +8.0 –0.32.0 mg as needed +8.6 +7.6 –1.0

The last-obervation-carried-forward (LOCF) method was used to impute missing data.

follow-up schedule and treated on return visits. If still stable atthat 6-week visit, the next visit may be pushed to 8 weeks, againwith treatment at the 8-week visit regardless of the patient’sprogress. In this way, many patients can be treated and extendedto visits sometimes as far apart as every 10 or 12 weeks. Onaverage, most patients with AMD make office visits every 6 to 8weeks in the maintenance phase of therapy in year 1 and year 2of treatment.

At this time, there is no level 1 evidence comparing the treat-and-extend style of therapy to either fixed, continuous (eg,monthly) or as-needed regimens. However, several compellingretrospective studies have found good visual outcomes over thecourse of about 1 year or so of treatment. Retinal specialists atthe Wills Eye Hospital conducted a retrospective analysis ofpatients treated with either ranibizumab or bevacizumab andfollowed on a treat-and-extend regimen for a mean of 1.5 years.22,23 The mean number of injections in the first year wasin 7 to 8 injections to gain an average of 2.0 to 2.5 lines, and 96%to 98% of these eyes experienced a loss <3 lines while 32% to33% of these eyes experienced a gain of ≥3 lines. These valuesare entirely consistent with outcomes reported in clinical trialswith monthly therapy for patients with AMD and were notdifferent between the 2 anti-VEGF agents studied.

A second study evaluated the treat-and-extend approach withranibizumab in a prospective fashion. In this study, 45 patientsreceived 3 monthly loading doses, after which the follow-up wasincreased or reduced by 2 weeks based on clinical examinationand OCT findings.24 At 12 months, mean visual acuity gainswere 1.3 lines, with 95% of these eyes losing <3 lines and 26% ofthese eyes gaining ≥3 lines, which are outcomes consistent withmonthly therapy in major trials.

A third study compared outcomes using the treat-and-extend (a total of 38 eyes) versus as-needed dosing (a total of 52 eyes)approaches.25 At year 1, the eyes that received the treat-and-extend regimen had received a mean of 7.8 injections and hadgained an average of 10.8 letters; the eyes in the as-neededdosing group had received an average of 5.2 injections and hadgained 2.3 letters.

Several larger, prospective trials are now under way to evaluatethe treat-and-extend approach. Some of the studies also includeas-needed dosing groups and are designed to assess the potentialbenefits of spectral-domain OCT in improving outcomes withas-needed dosing as suggested by HARBOR findings. Until these data become available, the guiding principle is to achievethe best possible visual acuity outcomes using the least possible treatment.

It is also interesting to consider the patient’s perspective whendetermining treatment frequency. A recent survey of 150 patients with AMD who had received an average of about 12 injections over a 2.5-year period revealed that patients do notmind the process.26 Almost 90% of these patients said theywould agree to lifetime monthly therapy if that was necessary topreserve their vision. As noted, clinicians are probably

undertreating patients with AMD and likely tend to minimizethe injection rate because they think these patients want as fewinjections as possible. This is only half true—patients with AMDwant as few injections as possible to achieve excellent outcomes.This finding supports the following underlying philosophy: Giveonly as many injections as are necessary to optimize outcomes,but be sure to give enough.

Question 6. If using an as-needed dosing treatment approachwith an anti-VEGF agent, does the patient with AMD have tobe seen monthly?

The major studies that included as-needed dosing treatmentarms required monthly evaluations, and even under thoseoptimal circumstances the visual outcomes in the as-neededdosing groups consistently fell below those in the monthlydosing arms. It seems clear that keeping the macula dry is betterthan letting it become wet and then drying it out over and over.It is likely that if the patient on an as-needed dosing regimen isseen less than monthly, the visual acuity outcomes will beinferior, as indicated in the findings from SAILOR.

Question 7. How many recurrences of fluid can be tolerated bypatients with AMD before a change in therapy is warranted?

In general, smaller or less frequent recurrences are bettertolerated than larger or more frequent recurrences. Cliniciansneed to make every effort to minimize the frequency andmagnitude of recurrences because, in the long run, there may beincomplete recovery and vision loss with many recurrences overtime. A more continuous style of therapy—either fixed andfrequent or variable such as with the treat-and-extendapproach—may be preferred over an as-needed dosing regimenwhen recurrences with the as-needed dosing approach are frequent.

In various head-to-head trials, these 3 anti-VEGF agents—bevacizumab, ranibizumab, and aflibercept—have been found tobe similar in efficacy, on average. But within individuals, there isthe possibility of differential responses, although the proportionof patients who would have a significantly different response tovarious anti-VEGF agents is likely to be low.27

Furthermore, issues such as tolerance or tachyphylaxis, in whichthe chronic use of 1 agent may limit future response to thatagent but not to other agents, may apply in certain patients withAMD, which may be the basis for the differences seen in switchstudies. One study that evaluated 26 patients with AMDswitched either from treatment with bevacizumab toranibizumab (10 patients) or from ranibizumab to bevacizumab(16 patients) found 81% of these patients demonstrated someimprovement.28 Similarly, in patients with inadequate responsesto treatment with either bevacizumab or ranibizumab and thenswitched to aflibercept (28 patients), 89% of these patients had ameaningful anatomic response within 1 month.29

The bottom line is that when treatment with anti-VEGF agentsfor patients with AMD fails to perform as expected, it isreasonable to try something different.

10

Question 8.Can anti-VEGF agents be given every 2 weeks, orcan the dose be doubled in patients who are inadequatelycontrolled on standard dosing administered monthly?

In patients who are suboptimal responders, have developedtolerance to anti-VEGF agents, or have refractory disease, it istempting to consider intensifying therapy by either increasingthe dosing or decreasing the frequency of injections. HARBORevaluated the relative efficacy of standard ranibizumab, 0.5 mg,dosing compared to a quadruple dose of ranibizumab, 2.0 mg.12

Both doses had monthly and as-needed (after 3 monthly loadingdoses) arms. There was no significant difference in the groupsreceiving monthly doses of ranibizumab, 0.5 mg, (mean 10.1letters gained at 12 months) or ranibizumab, 2.0 mg, (9.2 lettersgained). The as-needed dosing groups gained 8.2 to 8.6 letterson average. So there appears to be no advantage in giving higherdoses of anti-VEGF agents on average. However, this study didnot focus on patients inadequately controlled on monthlydosing, so there may be a benefit to administering higher ormore frequent doses in a specific subgroup of patients withrefractory or more aggressive disease.

Question 9. If a patient with AMD has had a recent stroke,should that affect the selection of anti-VEGF therapy?

Some safety signals have been raised regarding the risk of strokewith anti-VEGF therapy. In the VIEW studies, morecerebrovascular events (strokes and transient ischemic attacks[TIAs]) occurred in the aflibercept-treated groups than in theranibizumab-treated groups when looking at the vulnerablegroup of patients who are 85 years or older.13 In the head-to-head studies of bevacizumab versus ranibizumab, there weretrends toward higher rates of systemic serious adverse events inthe bevacizumab-treated groups that were not necessarilystroke-related.2,3 The bottom line is that clinicians have moreunanswered than answered questions regarding the risk ofstroke with anti-VEGF therapy. Is there a causal relationshipbetween anti-VEGF therapy and cerebrovascular events? Is therisk of cerebrovascular events different between these anti-VEGFagents? Are a prior stroke and a prior TIA considered equal riskfactors for subsequent stroke while using anti-VEGF therapy?Does it matter how recently the stroke occurred? Clinicianscannot answer these questions with scientific confidence.

However, these patients who have experienced cerebrovascularevents do exist in clinical practices, and clinicians have tomanage their care based on the best available evidence. Thesepatients warrant a cautious approach. First, there should be acandid discussion about the risk of cerebrovascular events,acknowledging all of the unknowns but involving the patient inthe decision-making process. Whether or not it is appropriate atthis time to have a conversation about strokes with all patientsbefore initiating anti-VEGF therapy is unresolved; sometimes itis better for patients to hear it from the retina specialist up frontthan to hear it later from their cardiologist, neurologist, or theirtechnology-savvy, Web-browsing children.

Once the decision is made to treat the patient’s AMD with anti-VEGF therapy—and these patients should be treatedbecause the risk of blindness is real and imminent while the riskof cerebrovascular events is relatively small—several adjustmentscan be made to the typical treatment regimen. The mostconservative interpretation of the available data suggests thatranibizumab may have the lowest cerebrovascular events rate, sothis might be the preferred agent for a patient with AMD at highrisk of cerebrovascular events. Regardless of the anti-VEGFagent chosen, an as-needed dosing or treat-and-extend approachmight be preferable to monthly therapy, particularly if both eyesrequire treatment. Likewise, if the disease is bilateral, treating 1 eye at a time would reduce the total systemic exposurecompared to simultaneous bilateral treatment. Ranibizumab isalso available in a 0.3 mg dose for DME (as opposed to thestandard 0.5 mg dose for AMD), and it is reasonable to considerusing the lower dose in patients at risk for stroke—in fact, therewas relatively little difference in efficacy outcomes in the phase 3trials that compared these doses for AMD.18,19 Smaller volumesof the other anti-VEGF agents can also be given by removing abit of the dose from the syringe before injecting.

For example, a patient with AMD who is currently receivingtreatment with anti-VEGF therapy may report having had astroke or TIA since his or her last visit. In this case, discussionwith the patient about the risk for stroke with anti-VEGFtherapy is warranted. Options might include transitioning toranibizumab or reducing the frequency of injections, either bytransitioning from monthly to a treat-and-extend approach or, ifalready using a treat-and-extend approach, extending thetreatment regimen further between injections.

Finally, in a patient who already has poor vision and is unlikelyto recover significant vision but still warrants treatment, PDTmight be a viable alternative to anti-VEGF therapy. Steroidscould also be considered but the efficacy results in small studieshave not been encouraging.

Question 10.Does a history of blindness from AMD in 1 eye alter your approach when the fellow eye needs treatment for AMD?

In theory, every eye is treated the best way possible, so thereshould technically be no difference in the management of thefellow eye. However, there is a psychological component for thepatient—and often for the clinician—as well as otherconsiderations. Monthly therapy would be the best approach topreserving vision in the second eye, although it comes withincreased risks and treatment burden compared to as-neededdosing or treat-and-extend regimens. The bottom line is thatclinicians must discuss the risks and benefits of anti-VEGFtherapy and allow the patient to be an active participant in thedecision-making process. Clinicians must individualizetreatment based on each patient’s needs.

11

12

Preventing EndophthalmitisEndophthalmitis is among the most dreaded complications of anti-VEGF therapy, and its risk is cumulative when patientshave ongoing therapy with multiple injections over time. Fortunately, refinements in injection protocols have greatlyreduced the rate of endophthalmitis in patients with AMD. Two important potential sources of endophthalmitis warrantfurther discussion.

Oral Flora

It is natural for the technician or nurse, while preparing the injection, to explain what is happening to the patient. Thepatient may then ask questions. Likewise, the physician may talk to the patient during the procedure. Is talking in the room arisk factor for endophthalmitis? As it turns out, bacteria common in the mouth are frequently found in isolates fromendophthalmitis after injections. Up to 90% of culture-positive endophthalmitis cases involve Gram positive organisms,30

and although the causative bacteria is usual Staphylococcus species, Streptococci are isolated in cultures and at rates that are 3-fold higher than in large series of anterior and posterior segment surgeries.31 Doshi and colleagues conducted anexploratory study in which 10 surgeons each recited a standardized 30-second script with a blood agar culture platepositioned 30 cm below their chin—in approximately the position of the surgical field during an intravitreal injection.32 Thesurgeons did this 4 times: once with no mask, once with a mask, once with no mask but the plates had been pretreated with5% povidone-iodine, and once with no mask, no plate treatment, and also no talking. After a 24-hour incubation period, theaverage number of colony-forming units (CFUs) seen on the plates were 8.6, 1.1, 0.1, and 2.4, respectively. Pretreating theplates prevented all colony growth except for 1 CFU on 1 of the 10 plates. In contrast, no mask and no pretreatment of theplates had the highest CFU rate. Importantly, wearing a mask or not talking significantly reduced the number of CFUs (1.1 and 2.4, respectively) compared to talking. These findings have been replicated in a second similar study.33

These observations raise the important point: Is it time for a standard protocol for intravitreal injection? Not everyone wearsa mask when injecting. Some, but not all, clinicians ban talking during the preparation and injection procedures. The needleis exposed while the drug is being drawn up and during the injection process—during these times it is susceptible tocontamination by oral flora. Oral flora can also directly contaminate the eye to be injected. Perhaps masks or no talkingrules should be incorporated into a standard protocol.

Compounding

Bevacizumab is approved for the treatment of various systemic neoplasms and is packaged in a systemic dose, available insmall bottles of 100 mg/4 mL or 400 mg/16 mL. The dose commonly used for the treatment of patients with neovascularAMD is 0.5 mg. Clearly, using a whole bottle for each injection would be a huge waste of this anti-VEGF agent—and wouldeliminate the cost savings associated with extracting multiple ocular doses from a single systemic dose bottle.

The process of extracting ocular doses from the systemic dose bottle (ie, aliquoting) is generally performed by compoundingpharmacies. Their role is to take the commercially available product and tailor it for use in ways that are not currentlyapproved by the FDA. The validity of this practice has been upheld several times by the US Supreme Court. The winningargument in that setting often pertains to the reformulation of a life-threatening drug available only in adult strength butneeded for a sick child.

The issue as it pertains to ophthalmology involves sterility. Recently, several reports of contamination arising at thecompound pharmacy have been associated with morbidity and mortality. Among the more dramatic reports was thecontamination of repackaged epidural steroids at a compounding pharmacy that left 64 people dead and 751 people withfungal infections in 20 states.34 Compounding pharmacies operate under relatively lax regulation and oversight. There is thepossibility that such a mass contamination and infection outbreak could occur in the ophthalmology setting as well.

The other issue pertaining to compounding involves access to drug. Under the strictest interpretation of US Supreme Courtrulings, each compounded drug should be individually prescribed for each patient. The current standard in ophthalmologypractices is to buy multiple doses and rotate the stock, using doses for patients on an as-needed basis. If this practice were tochange, per-patient compounding could significantly impact the facility with which we can offer treatment at the time itsneed is identified. To further complicate the issue, it could come to pass that clinicians would give patients a prescription forbevacizumab, 1.25 mg, have them obtain it through a compounding pharmacy, and bring it back to the clinician’s office foradministration.

This is a case of clinical practice evolving faster than regulatory practice. Clearly, clarification and standardization are neededto ensure optimal patient care and limit both financial and medicolegal liability.

13

1. How many clinical trials have compared all 3 pan-VEGFinhibitors as head-to-head trials?

a. 5

b. 3

c. 1

d. 0

2. The CATT study concluded all of the following except______at the 1-year primary endpoint:

a. Ranibizumab dosed monthly produced comparablevisual acuity outcomes to bevacizumab dosed monthly

b. Ranibizumab dosed as needed produced comparablevisual acuity outcomes to bevacizumab dosed as needed

c. Monthly therapy with either anti-VEGF agent producedcomparable visual acuity outcomes to as-needed dosingwith the same anti-VEGF agent

d. There were significantly more serious adverse eventswith bevacizumab compared to ranibizumab

3. The VIEW studies did not conclude that ___________:

a. Aflibercept, 2.0 mg, dosed monthly produced superiorvisual acuity outcomes to aflibercept dosed every other month

b. Aflibercept and ranibizumab demonstrated comparableefficacy

c. Aflibercept and ranibizumab demonstrated comparableoverall safety

d. The safety profiles of aflibercept and ranibizumab maybe different in vulnerable patients who are 85 years ofage or older

4. All of the following are potential ocular complications ofanti-VEGF therapy except:

a. Elevated intraocular pressure

b. Retinal pigment epithelial atrophy

c. Endophthalmitis

d. Diplopia

5. Which of the following statements is true regarding ocularimaging in AMD?

a. Time-domain OCT reveals more structural detail of theretina than spectral-domain OCT.

b. Fluorescein angiography can identify masqueradesyndromes such as central serous chorioretinopathy.

c. Indocyanine green is not useful for evaluating possiblepolypoidal choroidal vasculopathy.

d. Fluorescein angiography can identify evidence forchoroidal neovascular lesion leakage activity or growth.

6. Which of the following statements is false regarding thetreatment of neovascular AMD?

a. Data from multiple sources suggest that clinicians areundertreating the disease with anti-VEGF agents in practice.

b. Monthly therapy is proven to be the best approach foroptimizing visual acuity outcomes in patients with AMD.

c. A majority of patients would agree to lifelong monthlytherapy with an anti-VEGF agent to save their vision.

d. The risk of injection-related complications decreaseswith successive retreatments.

7. Evidence from clinical trials with as-needed dosing arms andfrom large claims databases demonstrates that the success ofanti-VEGF therapy for neovascular AMD drops significantlywhen the number of injections per year falls below:

a. 2

b. 3.5

c. 5.5

d. 7

8. The treat-and-extend dosing strategy for patients with AMDis best described as:

a. Evaluate monthly and treat if fluid is present or if acuity has dropped

b. Increase or decrease the interval between visits based onthe clinical course and treat at every visit

c. Evaluate monthly and treat monthly

d. Increase or decrease the interval between visits based onthe clinical course and treat only when needed

9. Which of the following is a reasonable approach to therapyfor a patient with AMD who has had a recent stroke?

a. Discuss the potential for an increased risk of stroke withanti-VEGF therapy

b. Consider as-needed dosing or a treat-and-extendapproach rather than monthly anti-VEGF therapy tominimize exposure

c. Consider using a lower dose of medication

d. All the above are reasonable

10. All of the following factors probably contribute to post-injection endophthalmitis except:

a. The location (inferior versus superior) on the globewhere the injection is given

b. Oral flora from talking during the procedure

c. Contamination during repackaging of bevacizumab

d. Failure to prep the eye with 5% povidone-iodine

Post Test

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1. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, FineSL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-relatedmacular degeneration. N Engl J Med. 2011;364(20):1897-1908.

2. Comparison of Age-related Macular Degeneration Treatments Trials (CATT)Research Group, Martin DF, Maguire MG, Fine SL, et al. Ranibizumab andbevacizumab for treatment of neovascular age-related macular degeneration:two-year results. Ophthalmology. 2012;119(7):1388-1398.

3. IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, et al.Ranibizumab versus bevacizumab to treat neovascular age-related maculardegeneration: one-year findings from the IVAN randomized trial.Ophthalmology. 2012;119(7):1399-1411.

4. Kodjikian L. Overview of the GEFAL Study. Presented at: The Association forResearch in Vision and Ophthalmology Annual Meeting; May 5-9, 2013; Seattle, WA.

5. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups.Intravitreal aflibercept (VEGF trap-eye) in wet age-related maculardegeneration. Ophthalmology. 2012;119(12):2537-2548.

6. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale fordosing every 2 weeks versus 4 weeks with intravitreal ranibizumab,bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye).Retina. 2012;32:434-457.

7. Hisatomi T. OCT predicts VEGF levels in human eyes. Invest Ophthalmol VisSci. 2013;54:5375.

8. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal afliberceptinjection for neovascular age-related macular degeneration: ninety-six-weekresults of the VIEW studies. Ophthalmology. 2013;120(9). doi:10.1016/j.ophtha.2013.08.011.

9. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K; SEVEN-UP StudyGroup. Seven-year outcomes in ranibizumab-treated patients in ANCHOR,MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP).Ophthalmology. 2013 May 3. [Epub ahead of print]

10. Kahook MY, Liu L, Ruzycki P, et al. High-molecular-weight aggregates inrepackaged bevacizumab. Retina. 2010;30(6):887-892.

11. Avery R. Visual acuity response as a function of the affinity and vitreous half-life of intravitreally administered anti-VEGF agents. Presented at:American Society of Retina Specialists 2012; Las Vegas, NV.

12. Busbee BG, Ho AC, Brown DM, et al; HARBOR Study Group. Twelve-monthefficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfovealneovascular age-related macular degeneration. Ophthalmology.2013;120(5):1046-1056.

13. European Medicines Agency. Assessment report [aflibercept]. Procedure No. EMEA/H/C/002392/. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Public_assessment_report/human/002392/WC500135744.pdf. Accessed June 27, 2013.

14. Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG. A PhaseIIIb study to evaluate the safety of ranibizumab in subjects with neovascularage-related macular degeneration. Ophthalmology. 2009;116(9):1731-1739.

15. Larsen M, Schmidt-Erfurth U, Lanzetta P, et al; MONT BLANC Study Group.Verteporfin plus ranibizumab for choroidal neovascularization in age-relatedmacular degeneration: twelve-month MONT BLANC study results.Ophthalmology. 2012;119(5): 992-1000.

16. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety ofverteporfin photodynamic therapy in combination with ranibizumab or aloneversus ranibizumab monotherapy in patients with symptomatic macularpolypoidal choroidal vasculopathy. Retina. 2012;32(8):1453-1464.

17. Tozer K, Roller AB, Chong LP, et al. Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growthfactor agents. Ophthalmology. 2013;120(10):2029-2034.

18. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumabfor neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.

19. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumabversus verteporfin for neovascular age-related macular degeneration. N Engl JMed. 2006;355(14):1432-1444.

20. Lad EM, Hammill BG, Qualls LG, Wang F, Cousins SW, Curtis LH. Treatmentpatterns in neovascular age-related macular degeneration between 2005-2010.Paper presented at: The Association for Research in Vision and OphthalmologyAnnual Meeting; May 5-9, 2013; Seattle, WA. Abstract 3819-B0129.

21. Holekamp NM, Yeh W-S, Chia YJ, Kiss S, Almony A, Kowalski J. Real-worldutilization of intravitreal antivascular endothelial growth factor agents inretinal diseases: A Claims Analysis from 2006 to 2011. Paper presented at:American Society of Retina Specialists Annual Meeting; August 25-29, 2012; Las Vegas, NV.

22. Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD.Bevacizumab for neovascular age-related macular degeneration using a treat-and-extend regimen: clinical and economic impact. Am J Ophthalmol.2012;153(3):468-473.e1.

23. Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treatand extend regimen using ranibizumab for neovascular age-related maculardegeneration: clinical and economic impact. Ophthalmology. 2010;117(11):2134-2140.

24. Oubraham H, Cohen SY, Samimi S, et al. Inject and extend dosing versusdosing as needed: a comparative retrospective study of ranibizumab inexudative age-related macular degeneration. Retina. 2011;31(1):26-30.

25. Toalster N, Russell M, Ng P. A 12-month prospective trial of inject and extendregimen for ranibizumab treatment of age-related macular degeneration.Retina. 2013;33(7):1351-1358.

26. Hassan TS, Luo CK, Willimas GA. Patient perceptions of the treatment regimenand expected outcomes of intravitreal anti-VEGF injections for wet age-relatedmacular degeneration. Paper presented at: American Society of RetinaSpecialists Annual Meeting; August 25-29, 2012; Las Vegas, NV.

27. Eghøj MS, Sørensen TL. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol.2012;96(1):21-23.

28. Gasperini JL, Fawzi AA, Khondkaryan A, et al. Bevacizumab and ranibizumabtachyphylaxis in the treatment of choroidal neovascularisation. Br JOphthalmol. 2012;96(1):14-20.

29. Cho H, Shah CP, Weber M, Heier JS. Aflibercept for exudative AMD withpersistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol. 2013;97(8):1032-1035.

30. Lyall DA, Tey A, Foot B, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond). 2012;26(12):1517-1526.

31. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection ofanti-vascular endothelial growth factor agents: causative organisms andpossible prevention strategies. Retina. 2011;31(4):654-661.

32. Doshi RR, Leng T, Fung AE. Reducing oral flora contamination of intravitrealinjections with face mask or silence. Retina. 2012;32(3):473-476.

33. Wen JC, McCannel CA, Mochon AB, Garner OB. Bacterial dispersal associatedwith speech in the setting of intravitreous injections. Arch Ophthalmol. 2011;129(12):1551-1554.

34. Lavole D. Victims in meningitis outbreak hope for criminal charges againstcompounding pharmacy. NBC News Digital. November 25, 2013.http://www.nbcnews.com/health/victims-meningitis-outbreak-hope-criminal-charges-against-compounding-pharmacy-2D1165341. Accessed December 2, 2013.

References

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 Box located 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). Alternatively, we offer instant certificate processing and support Green CME. Please take this post-test and evaluation online by going to

http://tinyurl.com/TopQuestionsWetAMD. Your comments help us to determine the extent to which this educational activity has met its stated objectives, assessfuture educational needs, and create timely and pertinent future activities. Please provide all the requested information below. This ensures that your certificate

is filled out correctly and is mailed to the proper address. 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 � retina specialist � comprehensive ophthalmologist � resident � Other (please specify):_____________________________________________

Degree � MD � DO � PharmD � RPh � NP � RN � PA � Other ___________

Institution _________________________________________________________________________________________________________________________

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E-mail ___________________________________________________________________________________________________________________________

Please note: We do not sell or share e-mail addresses. They are used strictly for conducting post-activity follow-up surveys to assess the impact of thiseducational activity on your practice.

Learner Disclosure: To ensure compliance with the US Centers for Medicare and Medicaid Services regarding gifts to physicians, The New York Eye and Ear Infirmary 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

1. �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.

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

2. 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

Upon completion of this activity, I am better able to:

• Evaluate the current evidence on efficacy, safety, and dosing regimens of the anti-vascular 5 4 3 2 1

endothelial growth factor (VEGF) agents used to treat wet AMD

• Select a treatment strategy for a variety of patients with wet AMD that maintains visual acuity 5 4 3 2 1

and long-term safety, as well as meets patient preferences

3. Number of years in practice: � ≤5 � 6-15 � 16-25 � Over 25

4. Number of patients seen per week with Wet AMD: � 0 � 1-5 � 6-10 � 11-25 � >25 � I don’t see patients at all

5. Average number of anti-VEGF treatments a typical patient in your practice with wet AMD CURRENTLY receives in his/her:

a. 1st year: � 0 � 1-2 � 3-4 � 5-6 � 7-8 � 9-10 � >10

� n/a (I refer my AMD patients requiring intravitreal injections to another doctor)

b. 2nd and subsequent years: � 0 � 1-2 � 3-4 � 5-6 � 7-8 � 9-10 � >10

� n/a (I refer my AMD patients requiring intravitreal injections to another doctor)

Activity Evaluation/Credit RequestClinical Consultations: Answering Today’s Top Questionson Managing Patients With Wet AMD

Original Release: January 2, 2014

Last Review: December 5, 2013

Expiration: January 31, 2015

Continued on next page

6. Having completed this activity, how do you PLAN TO CHANGE the number of anti-VEGF treatments you will give to a typical patient

in your practice with wet AMD:

a. In the 1st year: 1. Decrease significantly

2. Decrease somewhat

3. No change

4. Increase somewhat

5. Increase significantly

6. n/a (I refer my AMD patients requiring intravitreal injections to another doctor).

b. In the 2nd and subsequent years:1. Decrease significantly

2. Decrease somewhat

3. No change

4. Increase somewhat

5. Increase significantly

6. n/a (I refer my AMD patients requiring intravitreal injections to another doctor).

7. Based on your participation in this activity, please rate HOW YOUR LEVEL OF CONFIDENCE HAS CHANGED in your ability to individualize treatment in your

patients with wet AMD who:

5=Increased significantly, 4=Increased somewhat, 3=No change, 2=Decreased somewhat, 1=Decreased significantly; N/A= I do not see or treat these patients

a. Have recalcitrant fluid based on OCT 5 4 3 2 1 N/A

b. Have had a recent stroke or other cerebrovascular event 5 4 3 2 1 N/A

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

_________________________________________________________________________________________________________________________________

9. As a result of the knowledge gained in this educational activity, how likely are you to implement changes in your practice?

4=definitely will implement changes 3=likely will implement changes 2=likely will not implement any changes 1=definitely will not make any changes 4 3 2 1

Please describe the change(s) you plan to make: __________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

10. Related to what you learned in this activity, what barriers to implementing these changes or achieving better patient outcomes do you face?

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

11. Please check the Core Competencies (as defined by the Accreditation Council for Graduate Medical Education) that were enhanced for you through participation

in this activity. � Patient Care � Practice-Based Learning and Improvement � Professionalism

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

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

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

ADDITIONAL COMMENTS __________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________________________

1 2 3 4 5 6 7 8 9 10

POST TEST ANSWER BOX

Activity Evaluation/Credit RequestClinical Consultations: Answering Today’s Top Questionson Managing Patients With Wet AMD

Original Release: January 2, 2014

Last Review: December 5, 2013

Expiration: January 31, 2015