656 rp rvo 04 13.qxp:feature template©2013 allergan, inc., irvine, ca 92612 ... dr. kitchens is a...

April 2013

RetinalPHYSICIAN

A Comprehensive Approach toTreating Retinal Vein Occlusion

Experts discuss current thinking, including strategies for managing persistent disease.

ALSO INSIDE:• RVO and Macular Edema: Challenges and Opportunities •

• Combination Therapy for Difficult Cases •

656 RP RVO 04_13.qxp:Feature TEMPLATE 3/21/13 12:38 AM

*Branch or central retinal vein occlusion.

BECAUSE THERE ARE NO TIME-OUTS IN MACULAR EDEMA DUE TO RVO*

Indication and Usage

Retinal Vein Occlusion: OZURDEX® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Dosage and Administration

FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis.

Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.

IMPORTANT SAFETY INFORMATION

Contraindications

Ocular or Periocular Infections: OZURDEX® (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.

656 RP RVO 04_13_R1.qxd:Feature TEMPLATE 3/27/13 3:08 AM

• Every case of retinal vein occlusion (RVO) is different

• Every patient responds differently to therapy

• Every office visit is an opportunity to assess macular edema due to RVO and treat appropriate patients with OZURDEX®

Keep the Opportunity in Sight©2013 Allergan, Inc., Irvine, CA 92612 ® marks owned by Allergan, Inc. www.Ozurdex.com

APC64MK12 122961

IMPORTANT SAFETY INFORMATION (continued)

Contraindications (continued)

Advanced Glaucoma: OZURDEX® (dexamethasone intravitreal implant) is contraindicated in patients with advanced glaucoma.

Aphakic Eyes with Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in patients who have aphakic eyes with rupture of the posterior lens capsule.

ACIOL and Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in eyes with ACIOL (Anterior Chamber Intraocular Lens) and rupture of the posterior lens capsule.

Hypersensitivity: OZURDEX® is contraindicated in patients with known hypersensitivity to any components of this product.

Warnings and Precautions

Intravitreal Injection-related Effects: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection.

Potential Steroid-related Effects: Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.

Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Risk of Implant Migration: Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.

Adverse Reactions

The most common ocular adverse reactions reported by greater than 2% of patients in the first 6 months following injection of OZURDEX® for retinal vein occlusion and posterior segment uveitis include: intraocular pressure increased (25%), conjunctival hemorrhage (22%), eye pain (8%), conjunctival hyperemia (7%), ocular hypertension (5%), cataract (5%), vitreous detachment (2%), and headache (4%).

Increased IOP with OZURDEX® peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX® required surgical procedures for management of elevated IOP.

Please see Brief Summary of full Prescribing Information on adjacent page.

It may be time for OZURDEX®

(dexamethasone intravitreal implant) 0.7 mg


Brief Summary—Please see the OZURDEX® package insert for full Prescribing Information.INDICATIONS AND USAGERetinal Vein Occlusion: OZURDEX® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Posterior Segment Uveitis: OZURDEX® is indicated for the treatment of non-infectious uveitis affecting the posterior segment of the eye.CONTRAINDICATIONSOcular or Periocular Infections: OZURDEX® (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Advanced Glaucoma: OZURDEX® is contraindicated in patients with advanced glaucoma.Aphakic Eyes with Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in patients who have aphakic eyes with rupture of the posterior lens capsule.ACIOL and Rupture of the Posterior Lens Capsule: OZURDEX® is contraindicated in eyes with ACIOL (Anterior Chamber Intraocular Lens) and rupture of the posterior lens capsule.Hypersensitivity: OZURDEX® is contraindicated in patients with known hypersensitivity to any components of this product.WARNINGS AND PRECAUTIONSIntravitreal Injection-related Effects: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection [see Patient Counseling Information].Potential Steroid-related Effects: Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Risk of Implant Migration: Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.ADVERSE REACTIONSClinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.The following information is based on the combined clinical trial results from 3 initial, randomized, 6-month, sham-controlled studies (2 for retinal vein occlusion and 1 for posterior segment uveitis):Adverse Reactions Reported by Greater than 2% of Patients in the First Six Months

MedDRA Term OZURDEX® N=497 (%)

ShamN=498 (%)

Intraocular pressure increased 125 (25%) 10 (2%)Conjunctival hemorrhage 108 (22%) 79 (16%)Eye pain 40 (8%) 26 (5%)Conjunctival hyperemia 33 (7%) 27 (5%)Ocular hypertension 23 (5%) 3 (1%)

Adverse Reactions Reported by Greater than 2% of Patients in the First Six Months (continued)

MedDRA Term OZURDEX® N=497 (%)

ShamN=498 (%)

Cataract 24 (5%) 10 (2%)Vitreous detachment 12 (2%) 8 (2%)Headache 19 (4%) 12 (2%)

Increased IOP with OZURDEX® (dexamethasone intravitreal implant) peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX® required surgical procedures for management of elevated IOP.Following a second injection of OZURDEX® in cases where a second injection was indicated, the overall incidence of cataracts was higher after 1 year.USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Pregnancy Category C: Topical dexamethasone has been shown to be teratogenic in mice producing fetal resorptions and cleft palate. In the rabbit, dexamethasone produced fetal resorptions and multiple abnormalities involving the head, ears, limbs, palate, etc. Pregnant rhesus monkeys treated with dexamethasone sodium phosphate intramuscularly at 1 mg/kg/day every other day for 28 days or at 10 mg/kg/day once or every other day at 3 or 5 days between gestation days 23 and 49 had fetuses with minor cranial abnormalities. A 1 mg/kg/dose in pregnant rhesus monkeys would be approximately 85 times higher than an OZURDEX® injection in humans (assuming 60 kg body weight). There are no adequate and well-controlled studies in pregnant women. OZURDEX® (dexamethasone intravitreal implant) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use: Safety and effectiveness of OZURDEX® in pediatric patients have not been established.Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityNo adequate studies in animals have been conducted to determine whether OZURDEX® (dexamethasone intravitreal implant) has the potential for carcinogenesis.Although no adequate studies have been conducted to determine the mutagenic potential of OZURDEX®, dexamethasone has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test. PATIENT COUNSELING INFORMATIONIn the days following intravitreal injection of OZURDEX®, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patient should seek immediate care from an ophthalmologist. Patients may experience temporary visual blurring after receiving an intravitreal injection. They should not drive or use machines until this has resolved.©2012 Allergan, Inc., Irvine, CA 92612, U.S.A. ® marks owned by Allergan, Inc.Patented. See: www.allergan.com/products/patent_noticesMade in Ireland Based on 72212US14APC52EA12

OZURDEX®

(dexamethasone intravitreal implant) 0.7 mg


Editorial StaffEDITOR-IN-CHIEF, Retinal Physician: Peter K. Kaiser, MDEDITORIAL MANAGER, SPECIAL PROJECTS: Angela JacksonEDITOR, SPECIAL PROJECTS: Leslie GoldbergCONTRIBUTING EDITOR: Desiree Ifft

Design and ProductionPRODUCTION DIRECTOR: Sandra Kaden ART DIRECTOR: Claudette McClellan

Business StaffPRESIDENT: Thomas J. WilsonEXECUTIVE VICE PRESIDENT AND PUBLISHER: Douglas A. ParryASSOCIATE PUBLISHER: Dan MarshPROMOTIONAL EVENTS MANAGER: Michelle Kieffer

Editorial and Production Offices323 Norristown Road, Suite 200, Ambler, PA 19002Phone: (215) 646-8700

Copyright 2013, PentaVision, LLC. All Rights Reserved.

John W. Kitchens, MDDr. Kitchens is a vitreoretinal surgeon with RetinaAssociates of Kentucky in Lexington. The practice servespatients in seven locations throughout central and eastern Kentucky.

He is a consultant for Allergan, Optos, Synergetics andZeiss. He is a speakerand consultant for Genentech andRegeneron. His practice recieves research support fromGenentech and Regeneron.

Table of Contents

6RVO and Macular Edema:

Challenges and Opportunities

11Combination Therapy for

Difficult Cases

CASES16

Ozurdex/Grid Laser Combination Therapy for CRVO

17 & 18Anti-VEGF/Ozurdex

Combination Therapy for BRVO

Contributing Faculty

Michael A. Singer, MDDr. Singer is managing partner and director of clinicaltrials at Medical Center Ophthalmology Associates in San Antonio, Texas.

He is a consultant and lecturer for and has receivedresearch support from Allergan, Genentech andRegeneron. He has received research support fromAcucela, Eyegate, Optos and Thrombogenics; he is a consultant and lecturer for Bausch + Lomb and a consultant for Acucela, Quintiles, Santen and Thrombogenics.

Seenu M. Hariprasad, MDDr. Hariprasad is an associate professor, chief of theVitreoretinal Service and director of Clinical Research inthe Department of Ophthalmology and Visual Science atthe University of Chicago Medical Center.

He is a consultant/speaker for Alcon, Allergan, Bayer,Genentech, Ocular Therapeutix, OD-OS, Optos,Regeneron and Takeda.

Pravin U. Dugel, MDDr. Dugel is managing partner with Retinal Consultantsof Arizona, whose doctors serve patients in 26 communities throughout the state, and founder ofSpectra Eye Institute in Sun City. He is also a clinicalassociate professor at the University of SouthernCalifornia’s Keck School of Medicine.

He holds stock in and is a consultant for Arctic Dx,MacuSight, Neovista, Ophthotech and Digisight. He is aconsultant for Abbott, Acucela, Alcon, Allergan, Alimera Sciences, Genentech, LUX,ORA, Regeneron and Thrombogenics.


6

Seenu M. Hariprasad, MD: Retinal vein occlusion(RVO) is one of the most common causes of reducedvision due to retinal vascular disease.1 Unlike some ofthe other vitreoretinal conditions we encounter inour practices, RVO can affect both younger and olderpatients. Without timely treatment, macular edema,macular ischemia, neovascularization and otherpotential sequelae of RVO can lead to photoreceptorcell death, permanent cystoid and other structuralchanges and irreversible vision loss.

Fortunately, we have more options for treatingRVO-associated macular edema today than at anytime in the past. Treatments recently approved by theFDA for this indication include the VEGF inhibitorranibizumab (Lucentis, Genentech), the VEGF andplacental growth factor inhibitor aflibercept (Eylea,Regeneron Pharmaceuticals), and a dexamethasone-releasing intravitreal implant (Ozurdex, Allergan).These new treatments are enabling us to preservevision for many RVO patients who could not haveexpected such favorable results just 5 or 6 years ago.However, not every treatment is effective for everypatient, and whether one option is superior toanother or a combination of options is superior tomonotherapy have yet to be definitively determined.

Here, leading vitreoretinal specialists share theirinsights on these important issues. In particular, theydiscuss how they manage macular edema secondaryto RVO that is not responding adequately to initialtherapy.

One challenge we face in deciding how best tomanage patients is that we still lack a completeunderstanding of whether inflammation or VEGF isthe primary driver of macular edema associated with

RVO. Based on what is currently known, and yourexperience, what are your thoughts on this issue?Michael M. Singer, MD: Simplistically speaking, withRVO we have the original event and the body’sresponse to the event. A decrease in blood circulationand turbulent blood flow leading to thrombus forma-tion constitute the original compressive injury. Theresponse is capillary permeability, fluid backup andedema. Anti-VEGF agents and steroids can each beeffective treatments because they stop that secondaryswelling of blood vessels.John W. Kitchens, MD: It’s clear that VEGF is a majorplayer in most typical vein occlusions. We have seenoutstanding results from the BRAVO, CRUISE,GALILEO and COPERNICUS studies, all of whichevaluated anti-VEGF therapy for macular edema secondary to RVO. However, it appears that a subsetof cases have an inflammatory component. We seethese eyes in our practices. They may get 50% betterwith anti-VEGF injections, but they never get to thepoint of having the fluid-free, flat macula we want tosee on OCT. We also see mixed cases where VEGFseems to be the main driver but inflammation resultsin persistent leakage.Pravin U. Dugel, MD: It’s clear to most of us thatVEGF is a very important factor in all forms of macular edema but it’s not the only factor. In anycomplicated physiologic process such as angiogenesisor edema, hundreds, if not thousands, of chemical factors are involved. Also, we know from anti-VEGFmonotherapy studies in various diseases that perma-nent structural advantages are not necessarily conferred, even after months or years of treatment.We know in RVO, for instance, that when we stop

RVO and Macular Edema:Challenges and Opportunities

The likelihood of preserving vision increases with new treatment options.

656 RP RVO 04_13_R1.qxd:Feature TEMPLATE 3/21/13 9:33 PM

7

treatment, fluid has a propensity to return. All of thissuggests that more than VEGF is involved.

Preferences for First-Line TreatmentDr. Hariprasad: What is your preferred first-linetreatment for RVO?Dr. Kitchens: For most of my patients I start with ananti-VEGF agent, either ranibizumab, aflibercept orbevacizumab (Avastin, Genentech). The studies havebeen very convincing on their effectiveness. InBRAVO,2 61% of branch retinal vein occlusion(BRVO) patients treated monthly with the 0.5-mgdose of ranibizumab gained 15 or more letters inbest-corrected visual acuity (BCVA) from baseline to6 months compared with 29% who received sham. InCRUISE,3 those results for patients with central retinal vein occlusion (CRVO) were 48% vs. 17%.Similarly, in COPERNICUS,4 56% percent of CRVOpatients receiving aflibercept (2 mg) monthly gainedat least 15 letters of vision from baseline to 6 monthscompared with 12% in the sham group. InGALILEO,5 those results were 60% vs. 22%.

In my practice, I begin with 3 monthly anti-VEGFinjections before deciding whether it’s necessary toswitch directions and perhaps add a steroid or lasertreatment.Dr. Singer: Our primary goal is for patients toachieve the best vision possible, and based on the relevant clinical trials, I believe that monthly anti-VEGF injections are the best way to accomplish that.Dr. Hariprasad: I typically have a discussion with thepatient regarding the number of treatments that anti-VEGF vs. dexamethasone steroid will require in yearone. I also discuss side effects and cost. Dependingon our discussion, we pick either the dexamethasoneimplant, aflibercept or ranibizumab. I also explain tothe patient that it is very likely that he or she willreceive treatment with both classes of drugs duringthe course of therapy.Dr. Dugel: When the macula is involved, my first-lineapproach are anti-VEGF agents because they tend towork well and quickly.

A Closer Look at the RVO Clinical TrialsDr. Hariprasad: In terms of guiding first-line treatment for RVO, what do you consider importanttake-home points from the latest RVO clinical trials?Dr. Singer: The BRAVO and CRUISE studies ofranibizumab showed that achieving the best possiblevision in BRVO and CRVO requires monthly injec-tions. When injections were given at longer intervals

following monthly loading doses, about 20% of visualpotential was left on the table. The HORIZON exten-sion trial bore this out for CRVO in particular in thatthe visual gains and the reduction in OCT thicknessstarted to slip with prn dosing.6

Also interesting is that in COPERNICUS andGALILEO, aflibercept provided a very good responsein eyes with CRVO that were considered ischemic.While it would have been possible to excludeischemic eyes using diagnostic parameters similar tothose developed by Hayreh,7 that was not done inthese two trials. Therefore, a fairly significant numberof ischemic eyes were enrolled. For example, inGALILEO, 7% of eyes were nonperfused and 7% wereonly intermediately perfused. In COPERNICUS, 15%of eyes were nonperfused and 17% were intermedi-ately perfused, and they did very well on aflibercept.In contrast, ischemic eyes were screened out ofBRAVO and CRUISE for the most part, so we don’tknow their response to ranibizumab.

Applying that data to my practice, I am currentlyevaluating whether I can replicate the afliberceptresults in ischemic eyes. For non-ischemic eyes, withall else being equal, my first treatment choice is usually ranibizumab because I have more experiencewith it. Also, aflibercept is not yet FDA-approved forBRVO. I rarely use bevacizumab for RVO patients. Inmy experience, it is not effective enough. Soon I willbe presenting data from a study in my practice inwhich both CRVO and BRVO patients did better withranibizumab than with bevacizumab in terms ofedema reduction, and twice as many ranibizumabpatients had dry retinas within 2 weeks of initialinjection.

The GENEVA studies, which evaluated the use ofthe dexamethasone intravitreal implant vs. sham forCRVO and BRVO, represent another relevant clinicaltrial.8 The steroid implant improved BCVA in bothgroups of patients. Top-line data from the 12-monthresults included that 30% of patients had achieved again in BCVA of 15 or more letters compared withbaseline 60 days after implantation. Sixty days afterreceiving a second implant, 32% had achieved aBCVA gain of 15 or more letters from baseline.9 Thesteroid implant definitely has a place in the treatmentof RVO patients. It can work synergistically with ananti-VEGF agent, allowing us to attack the diseasefrom more than one angle. I personally tend to use itexclusively in combination with anti-VEGF therapy.Dr. Kitchens: BRAVO and CRUISE demonstrated how effective anti-VEGF agents can be against

656 RP RVO 04_13.qxp:Feature TEMPLATE 3/20/13 10:46 PM

8

RVO-associated macular edema. They set the standard for what we should expect from a treatment.They also showed that the disease responds quicklyto ranibizumab injections. Most eyes gain a line ormore of vision by the end of the first week therapy is initiated. The trials also reinforced that vein occlusion is a chronic disease, edema recurs and preserving vision requires repeat injections.

GALILEO AND COPERNICUS demonstrated thataflibercept is as effective as ranibizumab for macularedema secondary to RVO, so it’s nice that we have anadditional option. All of us have patients whorespond to one anti-VEGF agent but not another.

A main point I take from GENEVA is the dexam-ethasone implant has fewer side effects than intravit-real triamcinolone and we can expect it to have apositive effect for 3 or 4 months per insertion.8 In myexperience, it is a useful option for reducing the treat-ment burden in patients who would otherwise requiremonthly anti-VEGF injections and for patients whomay be refractory to all of the anti-VEGF agents.Dr. Dugel: One key point to glean from the RVO trials is whether the treatment is steroids or an anti-VEGF drug, the sooner we start treatment, the betterour results will be. This was evident in the RISE andRIDE studies of ranibizumab for diabetic macularedema (DME) as well. With delayed initiation oftreatment, we may see improvement but not to thesame extent as with earlier treatment. Also, what weconsider good vision is not necessarily good forpatients. We may measure 20/40, but that’s in thecontrolled, artificial setting of bright letters in a darkroom. Many patients feel debilitated at 20/40.

For these reasons, I tend to treat early and with alow threshold. I don’t hesitate to start treatment for apatient with 20/40 visual acuity or even for someonewho is 20/30 but has any level of macular edema. AsI said, when the macula is involved, my first-linetreatment is an anti-VEGF agent. In a minority ofcases, that is sufficient. However, in a significantnumber of cases, monotherapy is not sufficient so Isupplement with the dexamethasone implant. I treatthe vast majority of patients with both.

We should keep in mind, too, that we can’t cross-trial compare. We have a tendency to think thatbecause vision improved in one trial vs. another thatone drug is better than the other. A look at the shamgroups in the RVO trials is a good illustration of whywe should not compare results. The rate of ocularserious adverse events in the CRUISE sham groupwas 0.78%, while the rates in the COPERNICUS and

GALILEO sham groups were 13.51% and 8.45%,respectively. The rate of systemic adverse events was0.77% in the CRUISE sham group and 2.70% in theCOPERNICUS sham group. It’s clear from the shamgroup data that the patient populations in the trialswere quite different, which highlights why resultscan’t be directly compared across studies.

Variation in Patient Response to TreatmentDr. Hariprasad: At this time, we don’t have enoughknowledge or the tools to predict which treatmentwill be most effective for each patient. Some do verywell with an anti-VEGF agent but not steroids andvice versa. Also, some patients don’t respond as wellas others to initial anti-VEGF therapy. What might bethe reasons for this?Dr. Singer: One theory for why some patients don’trespond as well to initial treatment is that they mayhave significant ischemia, much of which may be inthe peripheral retina. We have only recently begun toconsider the potential effects of peripheral ischemia.We use Optos wide-field fluorescein angiography(FA) in our practice now and we are working on a protocol for determining how our treatments affectischemia. We’re finding that eyes with more edemaalso have more peripheral ischemia, and anti-VEGFinjections decrease both, essentially restoring circula-tion to some areas that were ischemic. However,when the treatment wears off, the peripheralischemia and the edema often recur.

Peter Campochiaro, MD, is conducting a studycalled RELATE, which is evaluating whether higherdoses of anti-VEGF agents could be more effective insome patients and whether laser treatment of periph-eral ischemia could reduce the need for injections.Based on his results thus far, he believes chronicedema prior to treatment and closed perifoveal capillaries in patients with BRVO may be predictorsof subpar final outcomes.Dr. Kitchens: Differences in response among patientsare multifactorial. Each presents with a differentdegree and duration of disease. An occlusion can beacute or 6 months old. BRVO can be quadrantic orhemiretinal. Macular ischemia may be present or not,and so on. For the clinician, it is a matter of quicklydetermining and effectively why a particular patientis not responding adequately to first-line treatment.Dr. Dugel: In my experience, the severity of an RVOpatient’s macular edema is a good indication ofwhether or not anti-VEGF monotherapy will be successful. I find that patients fall into three general


9

categories. One type presents with very little edemaand good visual acuity, although they may be both-ered by decreased vision. These are the patients forwhom anti-VEGF monotherapy is most likely to besufficient for controlling the disease process. They arethe minority, however, in my practice. A second typehas mild to moderate macular edema, which seems tomake the possibility of successful monotherapy lesslikely. I may try anti-VEGF monotherapy in thesepatients, but if edema reduction is not adequate aftera few monthly injections, I don’t hesitate to add thedexamethasone implant. I tell them from the start thatcombination therapy may be part of their treatmentplan. The third type of patient, the majority in mypractice, has diffuse, dense macular edema. Anti-VEGF monotherapy is rarely sufficient for suchpatients. Therefore, I recommend using a combinationof anti-VEGF and the steroid implant from the start.In these cases, I believe the severity of their edema\stems from a large inflammatory component at thecellular level, which anti-VEGF drugs do not address.

I will mention, too, that the dexamethasoneimplant is a much more attractive steroid option thanintravitreal triamcinolone. While triamcinolone wasour only option for quite some time and did confersome benefit, delivering steroid as a large bolus thatdissipates quickly is not an elegant strategy. Patientsoften had to deal with all of the side effects withoutmaximizing the benefits.Dr. Hariprasad: Near the end of last year, the FDAapproved ocriplasmin (Jetrea, Thrombogenics) forthe treatment of symptomatic vitreomacular adhesion(VMA). This is the first pharmacological agent to beapproved for this indication. Might this be of help intreating our RVO patients?Dr. Kitchens: One of our considerations is whethertraction such as VMA could be contributing to persis-tent macular edema. We know that in some cases, per-forming a vitrectomy and peeling the internal limitingmembrane provides long-term freedom from edema.We also know that surgery has not been shown to bevery effective in treating macular edema due to RVO.Ocriplasmin may release traction without the need fora vitrectomy. However, like a vitrectomy, ocriplasminmay change the pharmacokinetics of drugs in the eye.I don’t think we know for sure at this time whetherthe change will be positive or negative. Perhaps drugswill move more quickly out of the eye, creating a needfor more frequent anti-VEGF or steroid injections. Onthe other hand, liquefying the vitreous near the macula may facilitate delivery of drugs to that area.

Dr. Singer: Ocriplasmin will be a very valuable drug.In the clinical trial, complete release of VMAoccurred in nearly 25% of eyes by 28 days after injection.10 In addition, in 40% of eyes that had smallmacular holes, the holes completely closed. My practice was part of the clinical studies and havealready started using ocriplasmin in practice. Ourearly results are encouraging. I think the spectrum ofindications for which it will work best will be determined over time, although the number of RVOpatients who have traction or VMA is relatively small.

References1. Laouri M, Chen E, Looman M, Gallagher M. The burden

of disease of retinal vein occlusion: review of the litera-ture. Eye 2011;25(8):981-988.

2. Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N,Rundle AC, Murahashi WY, Rubio RG; BRAVOInvestigators. Ranibizumab for macular edema followingbranch retinal vein occlusion: six-month primary endpoint results of a phase III study. Ophthalmology2010;117(6):1102-1112.

3. Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY; CRUISEInvestigators. Ranibizumab for macular edema followingcentral retinal vein occlusion: six-month primary endpoint results of a phase III study. Ophthalmology2010;117(6):1124-1133.

4. Boyer D, Heier J, Brown DM, Clark WL, et al. Vascularendothelial growth factor trap-eye for macular edema secondary to central retinal vein occlusion: six-monthresults of the phase 3 COPERNICUS study. Ophthalmology2012;119(5):1024-1032.

5. Korobelnik JF. The 6-month (primary endpoint) results ofthe phase 3 GALILEO study: VEGF Trap-Eye in CRVO.Presentation at the annual meeting of the AmericanSociety of Retina Specialists, Aug. 22, 2011, Boston, Mass.

6. Heier JS, Campochiaro PA, Yau L, Li Z, Saroj N, RubioRG, Lai P. Ranibizumab for macular edema due to retinalvein occlusions: long-term follow-up in the HORIZONtrial. Ophthalmology 2012;119(4):802-809.

7. Hayreh SS. Central retinal vein occlusion. July 15, 2010lecture, University of Iowa Health Care, Ophthalmologyand Visual Sciences. Accessed Jan. 9, 2013. Available at:http://webeye.ophth.uiowa.edu/dept/CRVO/.

8. Haller JA, Bandello F, Belfort R Jr, et al., the OzurdexGENEVA Study Group. Randomized, sham-controlled trialof dexamethasone intravitreal implant in patients withmacular edema due to retinal vein occlusion.Ophthalmology 2010;117(6):1134-1146.

9. Haller JA, Bandello F, Belfort R Jr, et al., the OzurdexGENEVA Study Group. Dexamethasone intravitrealimplant in patients with macular edema related to branchor central retinal vein occlusion twelve-month studyresults. Ophthalmology 2011;118(12):2453-2460.

10. Stalmans P, Benz MS, Gandorfer A, et al., the MIVI-TRUSTStudy Group. Enzymatic vitreolysis with ocriplasmin forvitreomacular traction and macular holes. N Engl J Med2012;367:606-615.


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EDUCATION DIRECTORS Peter Kaiser, MDCole Eye Institute Cleveland Clinic. Cleveland, OH

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Dr. Hariprasad: The newest treatment options formacular edema secondary to retinal vein occlusion(RVO) have raised our expectations for how effectiveour interventions can be. At the same time, given thenature of the disease process, successful treatment israrely “one and done.” Furthermore, we all havepatients who don’t respond as robustly as we wouldlike to initial treatment. How do you define a non-responder or perhaps a suboptimal responder?Dr. Singer: When we see patients once a month, andthey return after an anti-VEGF injection with macular edema still present, we may assume theydidn’t have a response. I believe, especially with adisease like RVO that produces high levels of VEGF,that there is always some response, but it may be anincomplete response. I have been seeing manypatients every 2 weeks instead of every month toevaluate this further. If central macular thickness ismore than 350 microns (on Cirrus SD-OCT, CarlZeiss Meditec) 2 weeks after an injection, I definitelyconsider that an inadequate response. However, inmy experience, most patients have less fluid at 2 weeks after injection compared with before injection, but not all patients are dry (Cirrus SD-OCT less than 300 microns).Dr. Dugel: I consider a non-responder to be someonewho either gets worse or doesn’t get any better withtreatment. In my experience, it is unusual for apatient to get worse, but not unusual for a patient tohave little or no improvement. Anti-VEGF monother-apy typically stabilizes the situation quickly. I con-sider a suboptimal response to be one in whichmacular edema stabilizes but persists.

Dr. Kitchens: We really do not have good definitionsof non-responders and suboptimal responders. Arethey patients who get 50% better with injections butnever achieve total drying of the retina? Are theypatients whose edema recurs in 2 weeks rather than6? In the BRAVO trial of ranibizumab (Lucentis,Genentech) for macular edema secondary to branchretinal vein occlusion (BRVO), 25% of patientsrequired laser therapy. In that context, they would bethe non-responders or under-responders to anti-VEGF. For me in daily practice, an under-responderis someone whose macula is not 90% dry with SD-OCT compared to presentation despite at leastthree injections of an anti-VEGF agent.Dr. Hariprasad: In BRAVO, and the CRUISE trial ofranibizumab for central retinal vein occlusion(CRVO), significant fluid reduction and more than80% of the vision gains in a year were achieved bythe third or fourth injection. Based on that, residualfluid and minimal vision gain indicate a suboptimalresponse after four initial monthly injections. Thatsaid, some eyes will not improve to 20/40 regardlessof what we do. Therefore, it makes more sense tofocus on the macular anatomy on SD-OCT. If I don’tsee significant drying by the third or fourth anti-VEGF injection, I consider a different approach.

Managing Persistent Macular Edema Dr. Hariprasad: Once you identify a patient as a suboptimal responder to first-line anti-VEGF treatment, what are your next steps?Dr. Dugel: When patients have mild or moderatemacular edema, I start them on monthly anti-VEGF

Combination Therapy forDifficult Cases

Reducing the treatment burden is a key potential advantage.

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injections. After about the third injection, if I see adecrease in edema but not improvement in visualacuity, or if fluid persists, I don’t hesitate to use thedexamethasone implant (Ozurdex, Allergan). Insome cases, the implant resolves the edema. If not, I

continue to supplement with as-needed anti-VEGFinjections, an approach that has worked well for me.

When patients present with dense, diffuse macu-lar edema, I am fairly confident they will need morethan monotherapy to completely dry the retina, so I

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Role of Laser in RVO Begins to Evolve

Seenu M. Hariprasad, MD: Many of the ways we currently use laser treatment in retinal vein occlusion(RVO) are largely based on earlier trials, such as the Branch Vein Occlusion Study and the Central VeinOcclusion Study. For example, macular grid laser is a viable option for improving visual acuity compro-mised by persistent macular edema in branch but not central RVO. From the more recent SCORE trial,we know that grid laser is as effective as intravitreal triamcinolone for improving decreased vision dueto macular edema in BRVO, but with a more favorable complications profile.

Regarding panretinal photocoagulation (PRP) for RVO, an interesting new theory has emerged. Nowthat we have the ability to visualize the retinal periphery with ultra-widefield fluorescein angiography,we are learning that the extent of ischemia in the periphery can be significant even when the macula isnot ischemic. The theory, then, is perhaps we can treat the peripheral ischemia with PRP, thereby reduc-ing VEGF production and the inflammation and macular edema that follows.

How do you utilize laser treatment in RVO?John W. Kitchens, MD: If an RVO patient is developing neovascularization, particularly in the posteriorsegment, PRP is crucial for preventing neovascular glaucoma. I have tried to use PRP to reduce macularedema in BRVO and CRVO but haven’t achieved the results others have reported. That said, I do use it forBRVO patients who have extensive nonperfusion in an effort to reduce the injection burden, but I don’tcount on it to eliminate the need for injections. I also may use it when significant macular edema haspersisted after we have already tried anti-VEGF agents and steroids and the next step would be surgery.I tell patients it may reduce edema somewhat, but it’s not a cure.Michael M. Singer, MD: Even though we have more options than ever for treating macular edema asso-ciated with RVO, what we don’t have is a way to stop the cycle of ischemia. Therefore, rebound macularedema is the reality in the majority of cases. Our group and others have been working to determine if targeting PRP to only the peripheral ischemic areas of the retina can stop the cycle whilepreserving more peripheral vision.

We are conducting our own study involving BRVO and CRVO patients who were treated with anti-VEGF injections and/or the dexamethasone intravitreal implant.1 We used SD-OCT and wide-fieldangiography to determine when edema recurred and to quantify ischemic areas. Findings so far havebeen intriguing. These patients exhibit a great deal of variability in the extent of peripheral nonperfusion at baseline, and the differences seem to correlate with the extent of edema as well as thestructural and functional response to treatment. I am becoming more and more convinced that themain driver of edema is peripheral ischemia.Pravin U. Dugel, MD: In the absence of thick hemorrhage when it’s possible to use laser, it remains animportant tool in the armamentarium. As we know, it does lead to permanent structural changes so ifwe could harness those changes for good rather than bad by using them to turn off the VEGF engine,that would be a great role.Dr. Hariprasad: The jury is still out on whether decreasing the VEGF load with PRP laser in the periphery can reduce macular edema, but it makes a lot of sense. At the very least, eliminating theperipheral nonperfusion may serve to make our pharmacologic treatments more effective.


initiate combination treatment with an anti-VEGFagent and the dexamethasone implant. With theimplant in place, I see patients monthly for at least 3 months to monitor intraocular pressure. If the disease is status quo, i.e., little or no improvement ata visit, I supplement with an anti-VEGF injection.Most of the time, injection frequency drops signifi-cantly. Patients tend to reach a period of stability andthen I can see them less and less for anti-VEGF supplementation.

In my hands, the durability of the steroid implanthas been variable from patient to patient. I don’t havean explanation for that other than differences inpatient metabolism and severity of their disease.While the effects may last 5-6 months in somepatients, I’m seeing a duration of 3-4 months onaverage, which is the right amount of time for this

particular disease. The pharmacokinetics are suchthat the amount of drug released declines graduallyafter an initial bolus release. This drug egress profileis appropriate for RVO. I have many patients whohave received up to six steroid implants. I have noqualms about repeat insertions. The needle designhas been improved, making it more comfortable forpatients and easier for me.Dr. Singer: We are seeing in RVO, as we did withAMD, that some patients who don’t respond well toone anti-VEGF agent may respond to another. So Iwill switch to another one in some cases before con-sidering steroids. It has been nice to have anotherFDA-approved option with aflibercept (Eylea,Regeneron). That said, I believe I am quicker thanmost to introduce the dexamethasone implant. Idon’t have too great a concern about managingpatients who have a steroid response. In mostpatients who have an intraocular pressure response,it is almost always controllable with anti-glaucomatous drops. If IOP rises to more than 30 mmHg on drops, I have used selective laser trabeculoplasty to control it.

In studies we conducted in our practice to evaluatecombination therapy with an anti-VEGF agent and

the dexamethasone implant, we were able to keepretinas dry for 3.5 to 4 months and prolong the timebetween anti-VEGF injections.2 Furthermore, the tim-ing of the rebound edema was very predictable.

The two treatments appear to be synergistic.Moving away from monthly injections may not leadto vision as good as with monthly, but the best possi-ble vision is not every patient’s goal. Some are moreconcerned with cost of treatment or convenience.Dr. Kitchens: I, too, tend to work my way throughthe anti-VEGF agents if macular edema does notimprove or recurs quickly with the first choice.When I switch drugs, I see the patient back in a weekbecause I want to know whether I am dealing with anon-responder or an early recurrer. If I see someresponse, but macular edema is still present, I consider adding steroids or in BRVO perhaps laser.

One scenario I try very hard to avoid with RVOpatients is them losing faith in what we’re trying toaccomplish. If monthly injections are helping butare not keeping them dry for longer than a month,the visits can become too burdensome for them.They may question the importance of coming backso frequently. In my experience, they tend to havehigher expectations than patients with other condi-tions. They may be of working age or may not be asaccustomed to or accepting of living with a chronicdisease as our AMD or diabetic patients are. Whenthey regain some visual acuity they may think, well,I can see OK and my other eye is fine so I don’twant to keep going back for treatment. The dexam-ethasone implant can be a good way to gain theirconfidence because it can allow us to see them lessfrequently.

Finally, for suboptimally responding eyes, signifi-cant epiretinal membrane formation or vitreomaculartraction may mean surgery is the necessary path for-ward. If fluorescein angiography shows peripheralnonperfusion, I add panretinal photocoagulation(PRP) to the vitrectomy and membrane peeling. Ialso insert the dexamethasone implant and injectsub-Tenon’s triamcinolone. It is an aggressive

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I have also found the dexamethasone implant and an anti-VEGF agent to be a powerful combination for suboptimally responding eyes. — Seenu M. Hariprasad, MD


approach, but I want to do everything I can for thepatient at the time of surgery.Dr. Hariprasad: I have also found the dexametha-sone implant and an anti-VEGF agent to be a power-ful combination for suboptimally responding eyes. Ifthe macula isn’t significantly flatter and vision isn’tbetter by the patient’s third or fourth anti-VEGFinjection, I recommend we add the dexamethasoneimplant. As we discussed previously, in the BRAVOand CRUISE trials of ranibizumab in RVO, morethan 80% of the first year reduction in macularthickness and the gain in visual acuity occurred bythat point. Therefore, I don’t want to continue givinganti-VEGF injections alone if further vision gains arenot going to be accomplished.

Once I proceed with a dexamethasone implant, I continue to see patients monthly. If the retina is dry,I send them home for another month. If fluid is present on SD-OCT, I proceed with an anti-VEGF

injection. At 4 months, if the fluid has not resolved, Iinsert another dexamethasone implant and stay withthe same follow-up regimen. It is interesting to notethat in the GENEVA studies, approximately 21% ofBRVO patients and 17% of CRVO patients requiredonly one implant to keep the retina dry for the entireyear. Dry was defined as 20/20 visual acuity and retinal thickness of 250 microns or less on OCT.3

This durability is rarely seen with anti-VEGF thera-pies and is a feature more commonly seen with the dexamethasone implant.

Building on the Progress That Has Been MadeDr. Hariprasad: Keeping the macula fluid-free is ourmain goal, our best strategy for safeguarding vision,and I think we all strive for the additional goals ofgetting each patient to that point with the least burdensome treatment regimen and cost as possible.Dr. Singer: Yes, and we shouldn’t feel restricted to one

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Figure 1. In the BRAVO clinical trials of ranibizumab for the treatment of macular edema associated withretinal vein occlusion, 80% of the first-year gains in vision were seen by month 4.


drug or class of drug if we are not getting the desiredresponse. I believe using the entire arsenal available tous, much like oncologists do, provides our best chancefor success. Even though our current interventionsmay be prolonging the course of the disease process,they are preferable to the scarring and atrophy thatwould occur without them. Until we have a way to fixthe underlying problem of the occlusion, we shouldcontinue to explore ways to utilize anti-inflammatoryand anti-VEGF agents as well as laser treatments toour advantage against macular edema, hopefullybreaking the cycle of recurrence.Dr. Dugel: There are some studies under way thatmay shed more light on the challenges of RVO andmacular edema, but the number of treatment optionsto compare and the number of patients that would berequired for drawing solid conclusions are prohibi-tive. I don’t think we will have an obvious patientmanagement blueprint in the foreseeable future. We

will have to make our best clinical judgments basedon studies that are not comparable. In other words,we will continue to be doctors and researchers,studying the studies in order to understand what wecan and cannot extrapolate from the results.

References1. Tan CS, Singer M, Bell D, Sadda SR. Predictive value of the

area of peripheral retinal non-perfusion on treatmentresponse in branch and central retinal vein occlusion. Paperpresented during the annual meeting of the Association forResearch in Vision and Ophthalmology, May 7, 2012, FortLauderdale, Fla.

2. Singer MA, Bell DJ, Woods P, et al. Effect of combinationtherapy with bevacizumab and dexamethasone intravitrealimplant in patients with retinal vein occlusion. Retina 2012;32(7):1289-1294.

3. Haller JA, Bandello F, Belfort R Jr, et al., the OzurdexGENEVA Study Group. Randomized, sham-controlled trialof dexamethasone intravitreal implant in patients with mac-ular edema due to retinal vein occlusion. Ophthalmology2010;117(6):1134-1146.

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Figure 2. In the CRUISE clinical trials of ranibizumab for the treatment of macular edema associatedwith retinal vein occlusion, 80% of the first-year gains in vision were seen by month 4 as well.


A 49-year-old female reporting one day of vision loss OD presented to our retina service on 1/14/2011 seekingtreatment and a second opinion. The day before, at a different institution, she had been diagnosed with CRVO andadvised that one month of observation was the best course of action.

Fundus photography and fluorescein angiography showed CRVO OD with no neovascularization (Figure 1). OCTwas unable to accurately measure retinal thickness due to severe thickening. Thickness was approximately 1,200microns (Figure 2). Visual acuity was 20/400. Because of the patient’s young age, we ordered a hypercoagulabilitywork-up, which was positive for Protein S deficiency.

On the day the patient presented, we inserted dexamethasone intravitreal implant 0.7 mg (Ozurdex) OD. Threeweeks later, vision improved to 20/30 and we performed grid laser OD (Figure 3). For the next 3 months, the patientdid not require additional treatment. Three months after Ozurdex implantation and grid laser treatment (Figures 4and 5), her visual acuity was 20/30 and her IOP was 15 mmHg. One year follow-up revealed that no further treat-ments were necessary and her vision was stable at 20/30.

— Case provided by Seenu M. Hariprasad, MD

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Case 1. Ozurdex/Grid Laser Combination Therapy for CRVO


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We first treated this 93-year-old female patient for BRVO in June 2009. Throughout the course of her treatment,rebound macular edema has been problematic. After she was initially treated with four anti-VEGF injections, weimplanted Ozurdex. Since November 2009, she received numerous anti-VEGF injections and a total of five Ozurdeximplants. Each implant allowed her to go without additional treatment for 3 to 6 months. She was able to switch to aLucentis/Ozurdex combination in October 2010 and stayed dry until insurance issues prevented her from receivingcombination therapy. She now requires monthly Avastin injections. Figures 1 through 6 illustrate her SD-OCT results at select times. At the last of her visits shown here, August 2012, 3 years and 2 months after her first treatment, her visual acuity was 20/80 and she received an anti-VEGF injection.We have continued to follow and treat her as needed.

— Case provided by Michael M. Singer, MD

Case 2. Anti-VEGF/Ozurdex Combination Therapy for BRVO

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6


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We diagnosed BRVO in this 82-year-old female patient in June 2009. We treated her with three Avastin injections.Two weeks after the third injection, her visual acuity was 20/30-2 and her macular center point thickness accordingto SD-OCT was 318 microns and we implanted Ozurdex. Three months later, in January 2010, we gave an anti-VEGFinjection in an attempt to prolong her response to treatment. When her macular edema recurred 2 months after theinjection, we gave another anti-VEGF injection and followed it in 2 weeks with a second Ozurdex implant. With thesecond steroid implant in place, the patient did not require additional treatment for the next 15 months. Figures 1through 6 show her SD-OCT image results throughout this timeframe in her treatment.

— Case provided by Michael M. Singer, MD

Case 3. Anti-VEGF/Ozurdex Combination Therapy for BRVO

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6


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