new insights into the management of diabetic macular edemaretinatoday.com/pdfs/0109_supp.pdf ·...

Neil M. Bressler, MD, Program CoordinatorPresentations by:

Susan B. Bressler, MDMark S. Blumenkranz, MD

David M. Brown, MD

Supplement to

January/February 2009

New Insights Into

the Management of

DiabeticMacular Edema

and Related Conditions

Jointly sponsored by the Dulaney Foundation and Retina Today

New Insights Into

the Management of



Neil M. Bressler, MD, Program CoordinatorPresentations by:

Susan B. Bressler, MDMark S. Blumenkranz, MD

David M. Brown, MD

Highlights of a symposiumheld in New York City.


RT0109_DME-quark6-gp2.qxd 2/4/09 3:20 PM

STATEMENT OF NEEDAccording the National Institutes of Health, 7.8% of the US population, or

23.6 million people, have diabetes. The Centers for Disease Control andPrevention reports ophthalmic complications of diabetes are the leadingcause of blindness in adults aged 20 to 74 years. A common cause of visionloss in patients with diabetes is diabetic macular edema (DME). The preva-lence of DME among US diabetics approaches 30% in adults who have hadthe disease for 20 years or more.1 Although laser photocoagulation remainsthe gold standard therapy,2 clinicians continue to explore new treatments,including modifications to laser therapy and combinations of laser therapywith pharmacologic therapy. A 2008 survey by Retina Today shows that 55%of its readers are using combination or triple therapy for DME. A thoroughunderstanding of current management options as well as new and novelapproaches is critical for clinicians to effectively treat patients with DME andrelated conditions, such as central retinal vein occlusions (CRVOs).

1. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy: IV. Diabeticmacular edema. Ophthalmology. 1984;91:1464-1474.2. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema.Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796-1806.

TARGET AUDIENCERetina specialists and other ophthalmologists.

LEARNING OBJECTIVESUpon successfully completing this learning program, participants should

be able to:1. Discuss the prevalence and natural history of DME.2. Review the relevance of findings from the Diabetes Control and

Complications Trial (DCCT) and the Early Treatment Diabetic RetinopathyStudy (ETDRS).

3 Describe potential pharmacologic options for treating DME.4. Discuss the pathogenesis of CRVO.5. Describe current treatment options for CRVO, including systemic,

photocoagulation, pharmacologic, and surgical.

METHOD OF INSTRUCTIONParticipants should read the continuing medical education (CME) activity

in its entirety. After reviewing the material, please complete the self-assess-ment test, which consists of a series of multiple-choice questions. To answerthese questions online and receive real-time results, please visithttp://www.dulaneyfoundation.org and click “Online Courses.” Upon com-pleting the activity and achieving a passing score of over 70% on the self-assessment test, you may print out a CME credit letter awarding 2 AMA PRACategory 1 Credits.™ The estimated time to complete this activity is 2 hours.

ACCREDITATIONThis activity has been planned and implemented in accordance with the

Essential Areas and policies of the Accreditation Council for ContinuingMedical Education (ACCME) through the joint sponsorship of the DulaneyFoundation and Retina Today. The Dulaney Foundation is accredited by theACCME to provide continuing education for physicians. The DulaneyFoundation designates this educational activity for a maximum of 2 AMAPRA Category 1 Credits.™ Physicians should only claim credit commensuratewith the extent of their participation in the activity.

DISCLOSUREIn accordance with the disclosure policies of the Dulaney Foundation and

to conform with ACCME and the US Food and Drug Administration (FDA)guidelines, anyone in a position to affect the content of a CME activity isrequired to disclose to the activity’s participants: (1) the existence of any

financial interest or other relationships with the manufacturers of any com-mercial products/devices or providers of commercial services; and (2) identifi-cation of a commercial product/device that is unlabeled for use or an investi-gational use of a product/device not yet approved.

CONTENT VALIDATIONIn compliance with ACCME standards for commercial support and the

Dulaney Foundation’s policy and procedure for resolving conflicts of interest,this CME activity was peer-reviewed for clinical content validity to ensurethe activity’s materials are fair, balanced, and free of bias; the activity materi-als represent a standard of practice within the medical profession; and anystudies cited in the materials upon which recommendations are based arescientifically objective and conform to research principles generally acceptedby the scientific community.

FACULTY CREDENTIALSNeil M. Bressler, MD, is James P. Gills Professor of Ophthalmology, The

Wilmer Eye Institute, Johns Hopkins University in Baltimore. Participation byDr. Bressler in this activity does not constitute or imply endorsement by theJohns Hopkins University, the Johns Hopkins Hospital or the Johns HopkinsHealth System.

Susan B. Bressler, MD, is the Julia G. Levy, PhD, Professor of Ophthalmol-ogy at the Wilmer Eye Institute at the Johns Hopkins University School ofMedicine in Baltimore.

Mark S. Blumenkranz, MD, is Professor and Chair of Ophthalmology atStanford University School of Medicine, Stanford, CA.

David M. Brown, MD, is the Director of the Greater Houston RetinaResearch Center and practices at Vitreoretinal Consultants and TheMethodist Hospital in Houston, TX.

FACULTY/STAFF DISCLOSURE DECLARATIONSNeil M. Bressler, MD: Grants to investigators at The Johns Hopkins

University are negotiated and administered by the institution, which receivesthe grants, typically through the Office of Research Adminstration.Individual investigators who participate in the sponsored project(s) are notdirectly compensated by the sponsor, but may receive salary or other sup-port from the institution to support their effort on the project(s). Dr. NeilBressler is Principal Investigator for the following: Allergan, Inc., Bausch &Lomb, Inc. (B&L), Carl Zeiss Meditec, Inc., Genentech, Inc., Notal Vision,Othera Pharmaceuticals, Inc., QLT, Inc., Regeneron Pharmaceuticals, Inc.,Steba Biotech. Dr. Bressler’s spouse has been or is currently consultant for thefollowing: AstraZeneca, Genentech, Inc., Notal Vision, Pfizer, Inc.

Susan B. Bressler, MD: Grant/research support from B&L, Genentech, Inc.,Novartis Ophthalmics; investigator for Genentech, Inc.

Mark S. Blumenkranz, MD: Grant/research support from AlconLaboratories, Inc.; consultant for Allergan, Inc., Eli Lilly and Company,Genentech, Inc.; consultant and shareholder for MacuSight/OptiMedica.

David M. Brown, MD: Grant/research support from Alcon Laboratories,Inc., Allergan, Inc., Alimera Sciences, Eli Lilly and Company, Genentech, Inc.,Jerini AG, NeoVista, Inc., Neurotech, Novartis Ophthalmics, OtheraPharmaceuticals, Inc., Pfizer, Inc., Regeneron Pharmaceuticals, Inc., SirionTherapeutics, Inc.; consultant for Genentech, Inc., Novartis Ophthalmics,Regeneron Pharmaceuticals, Inc.

The following faculty members have indicated they will discuss off-label,experimental, and/or investigational use of drugs or devices:

Neil M. Bressler, MD: Ranibizumab, bevacizumab, triamcinolone.Susan B. Bressler, MD: Ranibizumab, bevacizumab, triamcinolone.David M. Brown, MD: Intravitreal steroids, bevacizumab.All those involved in the planning, editing, and peer review of this educa-

tional activity have indicated they have no financial relationships to disclose.

Jointly sponsored by the Dulaney Foundation and Retina Today.

Release date: February 2009. Expiration date: February 2010.

This continuing medical education activity is supported by unrestricted educational grants from Allergan, Inc., Carl Zeiss Meditec, Inc., Genentech, Inc., and OptiMedica Corporation.

2 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS


New Insights Into

the Management of




New Insights Into

the Management of




JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 3

4 Laser Therapy’s Role in Managing DMEBy Susan B. Bressler, MD

8 Exploring the Potential of Combination Therapiesfor DMEBy David M. Brown, MD

11 Potential Role of Vitrectomy for Treating DiabeticRetinopathyBy Mark S. Blumenkranz, MD

13 The Potential Role of Long-acting SteroidsBy Mark S. Blumenkranz, MD

15 Diabetes Control and Complications Trial: AnOphthalmologist’s UnderstandingBy Susan B. Bressler, MD

18 Treatment of Retinal Venous Occlusive DiseaseBy Mark S. Blumenkranz, MD

20 Considering Anti-VEGF Therapies for VeinOcclusionsBy David M. Brown, MD

Contents




Laser therapy has been part of our armamentariumfor treating diabetic macular edema (DME) since themid-1980s. Twenty-plus years later, the question is: Isthis a procedure we still want to be doing and doing

regularly, or are we ready to cast it aside in favor of pharma-cologic means for treating macular edema?

FOCAL/GRID LASER IN THE ETDRSI am using the term focal/grid laser photocoagulation to

refer to the technique that was evaluated in the EarlyTreatment Diabetic Retinopathy Study (ETDRS), a two-parttreatment performed at one sitting.1 For the focal compo-nent of the treatment, you first identify the focal leakagesites within the area of thickened retina, namely micro-aneurysms, and directly ablate them with light intensity andsmall spots of photocoagulation. For the grid component,you place a limited macular scatter pattern within the areasof edematous or thickened retina, being careful to placethese spots between spots that have already addressed thefocal leaks. The grid treatment generally corresponds toareas of leaking capillary beds on fluorescein angiography.

This is the treatment that we have been using for morethan 20 years. We call it modified now because we use alighter-intensity burn, and most clinicians use the 50-µmspot size.

LESSONS FROM THE ETDRSFrom the ETDRS, we learned that performing focal/grid

treatment reduced the risk of moderate vision loss—threeor more lines of acuity—as compared with no treatment.We also learned that, when monitored for 3 years, only15% of patients with clinically significant macular edema,center-involved or noncenter-involved, who receivedfocal/grid treatment experienced moderate vision loss.This was half as frequently as the eyes assigned to observa-tion. That summarizes the primary outcome of the ETDRS,which has led us to do focal/grid treatment for eyes withDME for the last 20 years.

We also learned in the ETDRS that eyes with less severe(not considered clinically significant) macular edema in the

treatment group had reduced rates of moderate vision lossas compared with eyes with equivalent degrees of macularedema in the observation group. We concluded, however,that it was probably reasonable to monitor eyes with lesserdegrees of macular edema, follow them until they devel-oped clinically significant edema, and then perform thefocal/grid treatment rather than intervene during earlierphases of macular edema.

At the end of the ETDRS, we were disappointed that,despite successful treatment and decreased retinal thicken-ing, only 17% of patients recovered three or more lines ofacuity relative to their entry levels of vision. That is why wehave been searching for better treatments. In addition tobeing able to stop vision loss over time, we would like to beable to restore vision in a greater proportion of patients.

TWENTY YEARS LATERAt the beginning of this decade, some isolated cases and

then small case series touted the benefits of intravitrealsteroid administration.2,3 After putting steroids into the vit-reous, several researchers observed that some eyes experi-enced a rapid reduction in retinal thickening, as confirmedby optical coherence tomography (OCT). Some of thosepatients also had an associated improvement in visual acu-ity as their edema improved. So with the presentation andpublication of those short-term, small case series, the retinacommunity began experimenting with intravitreal steroids.

In the 2005 Preferences and Trends survey conducted bythe American Society of Retina Specialists, more than 90%of the 370 respondents reported they were using intravitrealsteroids to manage patients with persistent DME. That setthe stage for a randomized clinical trial to compare our goldstandard treatment, focal/grid laser, with intravitreal ster-oids. The Diabetic Retinopathy Clinical Research Network(DRCR.net) recently completed and published results fromsuch a study.4

STUDY DESIGN, OBJECTIVE, ELIGIBILITYThe recently completed DRCR.net trial was a multicenter,

randomized clinical trial with three treatment arms: photo-

Laser photocoagulation remains the most effective treatment for diabetic macular edema.

BY SUSAN B. BRESSLER, MD

Laser Therapy’s Role inManaging DME



HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY

coagulation and two dosages (1 mg or 4 mg) of preserva-tive-free triamcinolone acetonide delivered intravitreally.The primary goal was to compare the efficacy and safety ofthe steroid vs laser therapy. We looked at two dosages of tri-amcinolone because we expected complications, such asglaucoma and cataract, and we wanted to find out if alower dosage would reduce the frequency of complicationswhile providing the same degree of efficacy. Follow-up visitswere quarterly for 3 years, and all patients were eligible forretreatment with the treatment assigned at entry as often asevery 4 months if edema persisted.

The primary outcome assessment was at the 2-year visit,and the major outcome variable was visual acuity, specifical-ly the average change in vision over time. The scientificobjective was mean change in visual acuity; the regulatoryobjective, as proposed by the US Food and Drug Admin-istration, was the proportion of patients with a decrease of≥15 letters. An important secondary measure was retinalthickening on OCT.

Patients were eligible to participate if they had type 1 ortype 2 diabetes. Every patient had DME with center invol-vement, which was confirmed on OCT with a central sub-field thickness reading of at least 250 µm. Best-correctedvisual acuity could not be better than 20/40 or worse than20/320. We studied 840 eyes (about 140 people had botheyes in the study) with about 250 people enrolled in each ofthe treatment arms. Follow up at the 2-year visit was nearly90%.

KEY STUDY RESULTSAt 2 years, individuals who had been assigned to laser, on

average, gained one letter of acuity on standardized eyecharts; whereas, those receiving the lower dose steroid, onaverage, lost two letters, and those receiving the higher dosesteroid, on average, lost three letters, which is equivalent to

half a line of vision. When you compare the distribution ofchanges in vision over time, the differences in outcomesalways favored laser treatment.

Looking at the median acuity, note that all three groupsbegan balanced—somewhere between 20/50 and 20/60(Snellen equivalent)—and 4 months into the study, thesteroid group showed improvement. Relative to the lasergroup, on average, vision in both steroid groups wasimproving, particularly patients receiving the higher-dosesteroid. A year later, however, visual acuity in the laser groupwas slowly improving, while visual acuity in the steroidgroups was declining from their initial upturn. The differ-ence between the groups became significant at month 16 infavor of laser, and that significant difference was maintainedthrough month 24. The laser-treated eyes had a slightimprovement overall relative to baseline, and the steroid-treated eyes had a slight diminution, so that there was a sig-nificant difference when comparing laser to either of thesteroid groups.

Considering that vision in the steroid-treated groupsimproved initially and then declined, you might wonder ifthese patients were developing cataracts from the repeatedintravitreal steroid injections. We took the presence ofcataract off the table by analyzing the data and confining ourreview to people who were pseudophakic when they joinedthe study or who had undergone cataract surgery at somepoint before the 2-year visit, or people for whom the retinasurgeon determined had minimal or no cataract at the 2-year visit. Even isolating the analysis to these individuals, thelaser-managed eyes did better over time than those receivingsteroids (Figure 1). Even if we look only at the relatively smallnumber of people who were pseudophakic at baseline—maybe one-sixth of the participants—if anything, the 2-yearoutcomes favored laser. So we cannot blame cataract forinterfering with the vision outcomes in the steroid group.

Figure 1. Researchers took cataract off the table in this analysis. Figure 2. Laser-treated eyes had most resorption by month 16.




What about central subfield thickness on OCT? Note thatthe three groups started balanced with central subfieldthickness measurements of about 400 µm. At 4 months, asanticipated, the steroid group rapidly acted like a reversesponge, drying up. The laser-treated eyes slowly demonstrat-ed further reductions in central subfield thickness, however,so that by month 16, they had the most edema resorption(Figure 2). This is a significant difference that persistedthrough 24 months, favoring the laser-treated eyes.

We saw few complications, such as retinal detachmentsor endophthalmitis, from intravitreal injections; however,four patients in the 4-mg dosage group needed filtrationsurgery to manage elevated IOPs. Roughly 30% of individu-als in this treatment group had IOP increases of 10 mm Hgor more during the study.

Investigators were encouraged to remove visually signifi-cant cataracts that developed during the study, and someolder patients in the laser group had cataract surgery duringthe 2 years. The rate of cataract surgery doubled in thelower-dose steroid group, and then doubled again with thehigher dose relative to the laser-treated eyes. In the 4-mg tri-amcinolone group, one-half of the initially phakic eyes need-ed cataract surgery during the 2 years while receiving, onaverage, three intravitreal steroid injections.

STUDY RESULTS PROMPT NEW QUESTIONThe visual acuity benefit at 4 months favored the higher-

dose steroid, which was consistent with results from thesmall case series reported earlier. By 1 year, however, therewas no advantage for the steroids, and by 2 years, there wasa clear-cut advantage for laser treatment in terms of visualoutcome and fewer adverse effects. The OCT findings paral-leled the visual acuity outcomes.

Twenty years after the ETDRS report, we have evidencethat focal/grid photocoagulation is very much here to stayand in our patients’ best interests. It is the most effective

means of managing DME, and looking forward, it mustremain the benchmark for any further clinical trials.

Given what we know now about the importance of pho-tocoagulation in managing eyes with DME, we need to ask:Should we forego the focal component of laser treatmentand the angiograms required to identify the focal sites ofleakage and just grid the posterior pole? The DRCR.netaddressed this question in a prospective randomized study.

DRCR.NET PILOT STUDYThis study of 263 patients compared the modified ETDRS

(mETDRS) focal/grid laser technique with a mild maculargrid (MMG), a technique in which burns were placedthroughout a zone within 3,000 µm of the fovea, about oneburn width apart, whether or not the retina was thickened.5

Figure 3 shows an eye that was treated with the mETDRSfocal/grid treatment. You can barely see the light intensityburns. In contrast, Figure 4 shows the MMG grid treatmentthat we explored. Treatment spots began about 500 µmfrom the foveal center and extended almost to the arcade,about 2 disc diameters in every direction, utilizing a lightintensity such that 6 weeks later, not much is visible in thefundus.

With 200 patients enrolled, we had excellent power todetect a minimum difference of 50 µm in central retinalthickening between these two laser modalities on OCT.There were 323 eyes randomized within this trial, about halfin each laser technique group. Follow up at the 12-monthvisit was 88%.

As Figure 5 shows, the differences in central subfieldthickness between groups are not statistically significant,but we see a trend toward thinner measurements in themETDRS laser technique group.

What about vision improvement? At follow-up visits at 3,8, and 12 months, a higher proportion of patients in themETDRS group are achieving moderate vision improve-

Figure 3. Eye treated with modified ETDRS focal/grid laser. Figure 4. Note the fundus 6 weeks post treatment.




ment. Similarly, for vision loss of three or more lines of acuityat 3.5 months and again at 12 months, a smaller proportionof those who are receiving focal/grid treatment are losingvision compared to those in the grid group (Figure 6).

The bottom line is: The MMG treatment appears to beless effective in reducing retinal thickening than themETDRS treatment, as confirmed by OCT. These resultssuggested that a much larger trial exploring grid photocoag-ulation is not necessary because it is unlikely we would findit superior to the more traditional focal/grid technique. Wesaw no data that suggested we should change the tech-nique we have been using.

We did recognize, however, that by 1 year, edema hadresolved in only 30% of subjects who had undergonemETDRS treatment. These outcomes support the need forus to continue to explore other treatments.

LASER PREVAILS AS SEARCH CONTINUESIs focal/grid treatment still indicated to treat DME? My

answer is an emphatic yes. By performing this procedure ineyes with clinically significant edema, particularly center-involved, we are reducing the risk of moderate vision lossover a 2-year period to about 20%. We now also recognizethere is more vision improvement than we thought previ-ously. Unfortunately, 20% of patients will decline, so wemust continue to search for more ways to treat them.

In this trial, we evaluated eyes that started at 20/40 orworse, so that every eye had the potential to recover 3 ormore lines of vision. In fact, one of three study eyes had twoor more lines of acuity improvement with focal/grid lasertreatment. That frequency of vision improvement is muchbetter than we formerly thought. So the bar for improvedoutcomes with new treatment modalities is somewhathigher than we formerly thought. Although there are other

potential therapies—intravitreal steroids, bevacizumab,ranibizumab—we need to remind ourselves that none ofthese agents has been shown to have a greater and moredurable effect than laser therapy for eyes with DME. ■

1. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macularedema. Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796-1806.2. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabeticmacular edema. Am J Ophthalmol. 2001;132:425-427.3. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macularedema. Ophthalmology. 2002;109:920-927.4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamci-nolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology.2008;115:1447-1449.5. Fong DS, Strauber SF, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network.Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laserphotocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480.

Figure 5. Note trend toward thinner measurements in mETDRS

group.

Figure 6. A smaller proportion of patients in the mETDRS

group are losing vision compared to those in the MMG group.




From the Early Treatment Diabetic Retinopathy Study(ETDRS), we know laser treatment is the primary andonly proven therapy for clinically significant macularedema.1 Laser therapy, performed according to the

ETDRS protocol, basically doubled the chances that apatient would not experience significant vision loss com-pared to observation. Less than 3% of eyes in the ETDRSgained 15 letters at 3 years, and many eyes started the studywith excellent visual acuity.

The Diabetic Retinopathy Clinical Research Network(DRCR.net) compared the modified ETDRS laser techniqueand the mild macular grid technique for diabetic macularedema (DME).2 That trial found that when patients with20/40 or worse vision received modified ETDRS focal laser,they had a 29% chance of a three-line gain and a 49% chanceof a two-line gain. Many researchers in pharmaceutical trialshad no idea laser was this good because they were compar-ing their results with historical ETDRS data in which mostpatients had visual acuity better than 20/40 and, thus, wereunlikely to be able to improve. Two illustrative cases follow.

CASE EXAMPLESFigures 1 and 2 show a patient before and after focal laser.

I have always said that for small areas of edema, focal/grid

laser works great. For large diffuse edema, laser has beensuggested as not being as effective, but there is no uniformdefinition of diffuse edema.3 In the DRCR.net study, patientswith very thickened DME were more likely to have resolu-tion of edema with laser than with intravitreal triamci-nolone. In addition, visual acuity outcomes were not superi-or with triamcinolone compared with focal/grid laser.

Figures 3 and 4 show a macula with a great deal of edema.I might have suspected that laser would not have helped,but this patient responded nicely to macular laser therapy.

What other treatment options do we have? Researchersalso have explored the potential of pharmacologic agents.

STEROIDS AND ANTI-VEGF AGENTSThe short-term benefit of intravitreal steroids is obvious,

but we often see problems, such as cataract; and endoph-thalmitis and glaucoma can develop over time. As theDRCR.net study showed, steroids win at month 4. By month12, they are equal to laser, and by month 16 and beyond,laser wins.4

We also have explored the use of anti-VEGF agents, suchas ranibizumab (Lucentis, Genentech, Inc.) and bevacizu-mab (Avastin, Genentech, Inc.). In the phase 2 Ranibizumabfor Edema of the Macula in Diabetes (READ) study, Nguyen

While laser monotherapy remains the gold standard,researchers continue to seek more efficacious treatments.

BY DAVID M. BROWN, MD

Exploring the Potential ofCombination Therapies for DME

Figure 1. Patient before focal laser treatment. Figure 2. Patient after focal laser treatment.




and colleagues showed a gain of one to two lines over 6 to12 months with continued ranibizumab injections.5 Is therea problem with attacking DME with a relatively short-actinganti-VEGF agent? The difference between the use of theseagents in age-related macular degeneration (AMD) is that inAMD, there is only minimal VEGF. In diabetes, VEGF is pres-ent in high concentrations and is produced continuously.You cannot keep using sponges to try to dry up a waterfall.So short-acting anti-VEGF agents may not be the answer forlong-term diabetes care.

NEXT STEP: COMBINING THERAPIES?We know that laser therapy works fairly well, and we see

short-term benefits from steroids or anti-VEGF agents, sowhy not combine them? The DRCR.net is studying thoseoptions in the Laser-Ranibizumab-Triamcinolone for DMEStudy. Patients with clinically significant DME are random-ized to four groups:

1. Focal/grid laser plus sham.2. Focal/grid laser plus ranibizumab.3. Ranibizumab alone, and then focal/grid laser if needed.4. Focal/grid laser plus triamcinolone.The primary efficacy outcome

is visual acuity. The secondary effi-cacy outcomes are the number ofinjections in the first year and thechange in retinal thickening ofcentral subfield and retinal vol-ume measured on optical coher-ence tomography (OCT).

The main safety outcomes are:injection-related (endophthalmi-tis, retinal detachment); oculardrug-related (inflammation,cataract, cataract surgery,increased IOP, glaucoma medica-tions, glaucoma surgery); and sys-

temic drug-related (cardiovascular events). Hopefully, thisand other well-designed studies will uncover additionaloptions.

EARLY EXPERIENCE: LASER WITH ANTI-VEGFAnti-VEGF therapy stops macular edema, but our current

agents provide only short-term VEGF blockade, thus limit-ing the utility of anti-VEGF therapy. What is the answer tothis dilemma?

If you want to stop your bathtub from overflowing, youturn off the spigot. Should we, in effect, turn off VEGF? Ibelieve we soon will determine the source of the VEGF,which will help us understand how to control it. I am notnecessarily advocating that we ablate it, but I would like tofind out what it is and either kill it pharmacologically ormake it healthier. Although it is not proven, I postulatethat it is possible that most of the VEGF that is causingmacular edema could be coming from ischemia in theperipheral retina.

Figure 5 shows an early phase angiogram (left) withlarge areas of capillary nonperfusion; the late phase is onthe right. Figure 6 shows diffuse central macular edema on

Figure 3. Before grid laser treatment. Figure 4. After grid laser treatment.

Figure 5. Early (left) and late-phase (right) angiogram. Note large areas of capillary non-

perfusion.

(Imag

e cou

rtesy

of D

avid

Boy

er, M

D.)

(Image courtesy of David Boyer, M

D.)




OCT. Figure 7 shows the laser treatment directed at themost ischemic areas. This patient also has proliferative dis-ease, but we are performing some panretinal (scatter)photocoagulation (PRP) to treat macular edema only.

This approach was proven to not work in the originalETDRS, but at that time, anti-VEGF agents were not avail-able, and we were unable to target our PRP to areas thatlooked angiographically compromised. So if we can de-crease the VEGF drive, we hypothesize that we may be ableto decrease the need for monthly or every 6-week anti-VEGF therapy. I think this needs further study.

We discovered early on that even with micropulsed pat-tern scan laser therapy delivered to targeted ischemic areas,we saw rebound edema. So we began to use targeted PRPfor areas of nonperfusion in combination with intravitrealbevacizumab and then ranibizumab. We often saw signifi-cant rebound edema, probably an inflammatory responseto the laser burns. In the end, we had to treat patients con-comitantly with a steroid.

Figure 8 shows the 6-month results with this patient afterwe treated the areas that looked the most ischemic withtargeted PRP and a concomitant triamcinolone injection.This case appears to be a success, but this technique needsto be validated before we can recommend it.

FURTHER STUDY NEEDEDTreatment of DME requires ongoing management of

patients’ underlying systemic conditions, and it begins withfocal/grid laser as applied in the DRCR Network studies. It isyet to be determined if combining some type of laser treat-ment with an intravitreal agent will be superior to ETDRSlaser alone. I encourage everyone who treats DME to con-sider supporting one or more of the DRCR.net trials to helpadvance the treatment of this common problem. ■

1. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macularedema. Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796-1806.2. Fong DS, Strauber SF, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Comparisonof the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagula-tion strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480.3. Browning DJ, Altaweel MM, Bressler NM, Bressler SB, Scott IU; Diabetic Retinopathy ClinicalResearch Network. Diabetic macular edema: What is focal and what is diffuse? Am J Ophthalmol.2008;146:649-655.4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamci-nolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology.2008;115:1447-1459.5. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus fordiabetic macular edema. Am J Ophthalmol. 2006;142:961-969.

Figure 6. Diffuse central macular edema on OCT.

Figure 7. Laser treatment directed at the most ischemic

areas.

Figure 8. Outcome after targeted PRP and concomitant

triamcinolone injection.



Vitrectomy is reported to be effective in resolvingmacular edema, but the data sets have been lim-ited, and the published studies to date have, forthe most part, not been well-controlled, prospec-

tive, randomized trials.1-4 An important question is: Whyshould vitrectomy work at all? One theory is that mechani-cal stress or stretch causes leakage. Another is that there is aphysiologic improvement in oxygenation in the vitreous,and a third is that intravitreal VEGF levels are reduced.5,6

EARLY STUDIESIn the 1992 paper that first described the potential bene-

fits of vitrectomy for macular edema, we reported on 10patients who were failures of prior photocoagulation.1 Wepostulated that an abnormally thickened hyaloid was exert-ing traction on the vitreoretinal interface and causing leak-age. Some of these eyes had epiretinal membranes, andapproximately 60% were judged to be successes.

Several years later, I reviewed my results on a secondcohort of 15 patients.7 Before surgery, none of these patientshad visual acuity better than 20/80, but after surgery, abouttwo-thirds of them had better than 20/80 vision. In fact,20% had better than 20/50, suggesting that vitrectomy washelping these patients.

Interestingly, these findings did presage some later under-standings. With monochromatic blue-light photography,one could see 2 x 2 disc diameter shiny, circular zones in themacula that corresponded to leakage in the later fluoresceinangiogram and which seemed distinct from a macularpucker (Figure 1). At that time, we described it without pos-tulating what it was. Now, we recognize it is the contractedinternal limiting membrane (ILM). Subsequently, we per-formed en face histologic examination after vitrectomy onpeeled membranes after placing them on a glass slide ratherthan embedding them in paraffin. The impact was to exam-ine them as we would with an ophthalmoscope as opposedto conventional histology, which is analogous to opticalcoherence tomography (OCT). We could see that these verymodestly hypocellular membranes were composed primari-ly of ILM of the retina (Figure 2).7

Another interesting finding was that many membranescontained very small vessels. These were, in effect, vascular-ized epiretinal membranes that were causing localized trac-tion. Now, we suspect that the ILM in DME is probablyimportant. Some vitreoretinal surgeons globally considervitrectomy a primary form of therapy that may precedefocal or grid photocoagulation in selected settings. Thisview, however, is not a standard of care in the United Statesand is considered controversial.

PROSPECTIVE COHORT STUDYData should drive best clinical practice, and the Diabetic

Retinopathy Clinical Research Network (DRCR.net) has pio-neered a host of studies on treatment of diabetic retinopa-thy. One is the Evaluation of Vitrectomy for Diabetic

Ongoing studies are examining this option.

BY MARK S. BLUMENKRANZ, MD

Potential Role of Vitrectomy forTreating Diabetic Retinopathy


Figure 2. Histopathologic observations: components include

thickened ILM and vascular ERMs.

Figure 1. Subsequent observations on surgical ophthalmo-

scopic features of DME: the importance of ILM abnormalities

and ERM.



Macular Edema Study.5 This study provides anopportunity to collect data prospectively, usingstandardized protocols to assess benefits andrisks. The results can be used to stimulate thedesign and execution of a prospective, random-ized clinical trial with Level 1 evidence, and it alsocan be used to help design other studies.

A series of patients, aged ≥18 years old, wereenrolled in one such study. Figure 3 summarizeseligibility criteria. Surgery was performed accord-ing to the investigator’s usual routine. About halfof the patients had small-gauge vitrectomy, andthe other half had standard 20-gauge surgery.About two-thirds of the patients had epiretinalmembranes removed. Clearly, the surgeons feltsome degree of traction was present, althoughnot in every patient. There are those who arguethat performing a vitrectomy alone, with or with-out ILM peeling, still helps DME.

This prospective, nonrandomized but con-trolled study showed no significant change inmean visual acuity from baseline to 3 months or to 6months. Although some patients improved, and morepatients improved at 6 months than at 3 months, somebecame worse. So the aggregate effect was that there wasno improvement in the mean visual acuity overall. It isunknown how these eyes would have fared if they had notreceived vitrectomy, so the proportion with improvementmay be better than no vitrectomy, and the proportionwith loss may be better than no vitrectomy. At the least,this information provides some guidance regarding expec-tations for patients considering this surgery for these cir-cumstances.

There was a benefit in the OCT-measured macularthickness. There was a considerable decrease in thicknessfrom about 500 µm to just under 300 µm. All factorsbeing equal, we would have assumed that if the meanmacular thickness decreased, the mean visual acuitywould improve, yet it did not. Cataract could have been afactor, or perhaps these maculas did not have reasonablepotential for visual improvement because of prior dam-age from diabetes.

When an epiretinal membrane is present, we know thattime-domain OCT in the autocalculation mode shows theretina to be thicker than it might really be. So the OCT cen-tral subfield thicknesses may not reflect as much reductionin retina thickness; much of the reduced thickness may havebeen from removing the epiretinal membranes.

WEIGHING BENEFITS/RISKSWhenever we judge the efficacy of a therapy, we must

take into account the positive benefits and subtract the

complications. The net of those two determines whether ornot treatment is beneficial. Many treatments are beneficialbut have unacceptably high risk, while others are not espe-cially beneficial but they have minimal risk. The treatingphysician and the patient must decide how to achieve thebest balance for the patient.

These data show the surgery was fairly successful in thesense that it was not likely to lead to serious adverseevents, but we also know that most patients older than40 years will develop a cataract after vitrectomy, and asmall percentage will experience a detachment or othercomplications.6

What these data show is that we do not know everythingwe need to know to make an informed judgment aboutwhether vitrectomy is or is not safe and effective for DME.They do suggest, however, that vitrectomy reduces macularthickness. So a conclusive recommendation remains anopen issue at this time, and there should be additional stud-ies looking at this. My hope is that within several years wewill have more information to guide us. ■

1. Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction andedema associated with posterior hyaloidal traction. Ophthalmology. 1992;99:753-759.2. Harbour JW, Smiddy WE, Flynn HW Jr, Rubsamen PE. Vitrectomy for diabetic macular edema associ-ated with a thickened and taut posterior hyaloid membrane. Am J Ophthalmol.1996;121:405-413.3. Tachi N, Ogino N. Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. Am JOphthalmol. 1996;122:258-260.4. Pendergast SD. Vitrectomy for diabetic macular edema associated with a taut premacular posteriorhyaloid. Curr Opin Ophthalmol. 1998;9:71-75.5. Stefánsson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol. 2006;51:364-380.6. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 andvascular endothelial growth factor are related to diabetic macular edema. Ophthalmology.2003;110:1690-1696.7. Blumenkranz MS. Paper presented at: Retinal Subspecialty Day; October 1991; Jules Stein EyeInstitute, Los Angeles, CA.

12 I SUPPLEMENT TO RETINA TODAY I JANUARY/EBRUARY 2009

Figure 3. The Evaluation of Vitrectomy for Diabetic Macular Edema Study

will collect data prospectively, using standardized protocols to assess

benefits and risks.




Dramatic advances are being made in theemerging field of retinal pharmacotherapy.1 Itis important to remember, however, that laserphotocoagulation remains the gold standard

of treatment for diabetic retinopathy2 until it can bedirectly compared to pharmacotherapy or alternativetreatments in well-controlled prospective, randomizedclinical trials.

Various studies of corticosteroids to treat diabeticmacular edema (DME) are under way. Some are beingconducted by the Diabetic Retinopathy ClinicalResearch Network.3-5 The following is a brief survey ofsome of the steroid implants under development forDME, known to the author of the time of the prepara-tion of this lecture.

FLUOCINOLONE ACETONIDEEarly data on a fluocinolone acetonide bioerodable

intravitreal implant (Retisert; Bausch & Lomb, Rochester,NY) suggested that steroids work but alsohighlighted that steroids can be dangerous.6

The study is being repeated using lowerdoses.

In the initial study, patients showed signifi-cant improvement, albeit with complications.If we consider only the reduction in macularthickening and the visual acuity at 6 months,the improvements are obvious. After that,however, the problems appear to overwhelmthe benefits with the longer-acting, high-dosesteroids. Fifty percent of the eyes had elevat-ed pressures, and approximately 40%required filtration surgery.

A small, nonbioerodable fluocinolone ace-tonide implant (Medidur; Alimera Sciences,Alpharetta, GA) is also under development. Itstays in the vitreous cavity and releases drugfor up to 2 years, according to the manufac-turer. Clinical trials are under way.

DEXAMETHASONEThe results were somewhat better with this bioerod-

able polymer implant, which contains the long-actingsteroid dexamethasone (Posurdex; Allergan, Inc., Irvine,CA) This was likely because less drug was being releasedand possibly because of differences in the inherentpotency of the active agent.

A phase 2 study showed a positive dose response rela-tionship for all groups combined (Figure 1).7 At day 90and day 180, there was a statistically significant increasein patients achieving 2 and 3 lines or more of visual acu-ity after receiving the steroid, compared with no treat-ment. These were patients who had previously failedlaser therapy. Angiograms graded by masked readersindicated that there was a 2-step reduction in leakagecompared with untreated controls (Figure 2).

This was the first randomized, prospective clinical trialthat used optical coherence tomography (OCT) as anendpoint. When used as a surrogate measure for

Researchers are investigating intravitreal implants.


The Potential Role ofLong-acting Steroids

Figure 1. Note positive dose response relationship for all groups combined.




improvement, as opposed to vision or fluoresceinangiography, OCT showed a fairly dramatic improve-ment that was also dose-related (Figure 3). Later obser-vations may be confounded by cataract or glaucoma,which impact visual acuity.7

TRIAMCINOLONE ACETONIDEDe Juan and colleagues have developed a nonbioerod-

able helical coil containing triamcinolone acetonide (I-vation, Surmodics, Eden Prairie, MN), which essentially

can be screwed into the eye and removed asneeded. A clinical trial is under way.8

AWAITING FURTHER STUDYOne oversimplification that we occasion-

ally use in teaching is that steroids for DMEare beneficial in the short term but less soin the long term. On the other hand, lasertherapy is less effective in the short termbut very good in the long term. Perhapscombining the two modalities will providethe optimum benefit of short-term pluslong-term efficacy while minimizing sideeffects. We await results from further stud-ies to make this determination.9

For now, as a monotherapy, intravitrealsteroids have not been shown to be superiorto focal/grid photocoagulation at improvingthe chance for vision gain, decreasing therisk of vision loss, or causing regression ofedema.3 This outcome is true whether theeye is pseudophakic at baseline, has hadprior macular laser for DME, has a verythickened retina, or relatively poor visualacuity.3 Whether combining these drugswith laser is shown to be superior tofocal/grid laser alone remains to be deter-mined. For now, the standard care for DMEremains focal/grid photocoagulation. ■

1. Blumenkranz MS. The current status of steroids in treating diabeticretinopathy. Retinal Physician. 2007;9:42-47.2. Early Treatment Diabetic Retinopathy Study Research Group.Treatment techniques and clinical guidelines for photocoagulation ofdiabetic macular edema. Early Treatment Diabetic Retinopathy StudyReport No. 2. Ophthalmology. 1987;94:761-774.3. Diabetic Retinopathy Clinical Research Network. A randomized trialcomparing intravitreal triamcinolone acetonide and focal/grid photoco-agulation for diabetic macular edema. Ophthalmology.2008;115:1447–1459.4. Chieh JJ, Roth DB, Liu M, et al. Intravitreal triamcinolone acetonidefor diabetic macular edema. Retina. 2005;25:828-834.5. Blumenkranz MS. Ongoing studies of intraocular sustained releasedrug delivery implants for macular edema. Retinal Physician. 2008;Jan.6. Pearson P, Levy B, Comstock T, and Fluocinolone Acetonide Implant

Study Group. Fluocinolone acetonide intravitreal implant to treat diabetic macular edema:3-Year results of a multicenter clinical trial. Invest Ophthalmol Vis Sci. 2006;47: E-Abstract5442.7. Kuppermann BD, Blumenkranz MS, Haller JA, Williams, GA et al. Randomized con-trolled study of an intravitreous dexamethasone drug delivery system in patients with per-sistent macular edema. Arch Ophthalmol. 2007;125:309-317.8. Dugel PU, Cantrill HL, Eliott D, et al. Clinical safety and preliminary efficacy of anintravitreal triamcinolone implant (I-vation TA) in DME. Poster presented at the Associationfor Research in Vision and Ophthalmology, May 6–10, 2007, Fort Lauderdale, FL. Abstract1413.9. Grover D, Li t, Chang C. Intravitreal steroids for macular edema in diabetes. CochraneDatabase of Systematic Reviews. 2008;23:CD005656.

Figure 2. Note 2-step reduction in leakage compared with controls.

Figure 3. OCT showed dose-related improvement.




The Diabetes Control and Complications Trial(DCCT), published in the early 1990s, is still rele-vant today because it relates the importance ofa patient’s systemic health to eye health and

confirms that controlling blood sugar is critical todecreasing disease progression, particularly eye disease.1

Before the DCCT, animal studies and observationalstudies linked elevations in blood glucose to severity ofdiabetic disease complications.2-7 It was the DCCT, how-ever, that strove to validate the glucose hypothesis bylooking directly at an intervention to control and lowerblood sugar and ask if it reduces the morbidity associat-ed with diabetes. Fortunately for ophthalmologists, eyedisease, because it is so readily classifiable, was the pri-

mary endpoint in the DCCT as investigators used oph-thalmic variables to monitor treatment efficacy.

STUDY DESIGN AND ELIGIBILITYThis study involved individuals who had type 1 dia-

betes. A total of 1,441 relatively young patients withouthypertension, significant kidney disease, or hypercholes-terolemia were about equally divided between 2cohorts. Within each cohort, subjects were randomlyassigned to intensive or conventional management oftheir glycemia.

The primary cohort joined the study with no retinopa-thy, and the question they served to address was: By insti-tuting tight control, could you decrease the development

With eye disease progression as its primary endpoint,this trial validates the importance of tight glycemic control.

BY SUSAN B. BRESSLER, MD

Diabetes Control andComplications Trial:An Ophthalmologist’sUnderstanding

Figure 2. Note positive effect of intensive therapy.Figure 1. Three steps was considered progression.




of diabetic eye disease? The secondary cohort joined thestudy with mild or moderate nonproliferative disease, andthe question they helped answer was: By instituting tightcontrol, could you slow the rate at which the eye diseasewould progress?

CONVENTIONAL VS INTENSIVE THERAPYIn the mid-1980s, the goal of conventional therapy was

to avoid symptoms of hyperglycemia or hypoglycemia.That meant using injections of insulin once or twice a day;daily self-monitoring of control, blood or urine testing;quarterly feedback of control, using glycosylated hemoglo-bin (HbA1c) levels; general information about the impor-tance of diet and exercise; and an office visit four times ayear. The annual price tag for that type of regimen in late-1980s dollars was about $1700.

In contrast, the goal of intensive treatment in the DCCTwas to keep blood glucose values as close to normal as pos-sible, 24/7. To do that, individuals could self-select use ofmultiple doses of insulin (MDI) per day, or they could usean external insulin pump. They were required to monitortheir glycemia levels by finger-stick blood determinations aminimum of four times a day. They received monthly feed-back of their HbA1c levels; they were supported monthlywith calls from nutritionists and nurse practitioners; andthey had monthly clinic visits. The annual cost to deliverthat type of care was two to three times more than con-ventional therapy: $4000 (MDI), $5800 (pump).

FOLLOW-UPSeven-field photographs were taken annually and read at

a masked reading center. Three steps of progression on theretinopathy scale (1 to 25 steps) was considered progres-sion (Figure 1).

Figure 2 shows how well the intensive treatment regimenworked to control blood sugar levels over 24 hours. Eventhough the intensive group was aiming for preprandialblood glucose concentrations between 70 and 120 mg/dL,they do not quite achieve it, but they are much lower andcloser to normoglycemia than the value of 231 ±55 mg/dLobtained in the conventional group.

Figure 3 shows the HbA1c profiles over the 10 years ofthe study. On average, HbA1c levels were 7% for the inten-sive therapy group and 9% for the conventional therapygroup with no overlap between the groups. So the intensiveregimen used in the DCCT was effective at decreasingglycemia.

Figure 4 shows the primary cohort and the proportion ofpeople who developed a sustained 3 step progression ineye disease, meaning these eyes enrolled without anyretinopathy and they progressed to mild non-proliferativedisease. Comparing conventional therapy to intensive thera-py, there was a five-fold reduction in progression of diabeticeye disease by intensive management. This is very clinicallyrelevant and obviously statistically significant. You can pre-vent development of mild disease with intensive control.

In the secondary cohort (Figure 5), by 10 years, there wasa three-fold reduction in progression of diabetic eye diseaseby intensive management.

Figure 6 shows another important endpoint: the need forphotocoagulation. Again, there was a three-fold reductionof rates at which these patients required laser treatment.

ADVERSE EVENTSWith tight glycemic control, the risk of a significant

hypoglycemic event increases, and there was a three-foldincrease in the incidence of hypoglycemia in the intensivetherapy group. Another adverse effect with intensive

Figure 4. Note a five-fold reduction in diabetic eye disease

progression by intensive management.

Figure 3. Glycemic control over 10 years.




therapy was an increase in body weight. With tight con-trol, patients are less prone to lose glucose in theirurine, rather they are forced to metabolize it, so there isgreater potential for weight increase. The intensivelymanaged individuals gained more weight gain, and thatcan be a real problem among young type 1 diabetics,particularly women.

CONCLUSIONS FROM THE DCCTThere is undeniable evidence from the DCCT that

tight glycemic control reduces the morbidity associatedwith diabetes. A general recommendation to everypatient with diabetes—as we extrapolate DCCT data toindividuals with type 2 diabetes, as well—is to maintainthe best control possible, safely within their sensitivitylevels to detect impending hypoglycemia, to try todecrease long-term organ damage. In the interest oftime, we did not review the DCCT data in depth, whichwould have emphasized that the benefits get wider andmore substantial over time. The DCCT provided posi-tive data monitoring participants over one decade.Imagine how these graphs might continue to separate ifparticipants were monitored for a second or thirddecade of tight control.

Additionally, benefits were seen over a range of oph-thalmic endpoints and over the gamut of retinopathy.What’s more, investigators looked at kidney disease, car-diovascular disease, and cognitive functioning, all ofwhich showed benefits with tight control.

POST-TRIAL OBSERVATIONAL STUDYAt the conclusion of the DCCT, most patients agreed

to further follow-up within an observational studycalled the Epidemiology of Diabetes Interventions and

Complications (EDIC) study.8 At entry into the EDICstudy, all patients were advised to aim for tight control,but they no longer received assistance through thestudy.

The patients originally assigned to conventionalmanagement tried to follow the instructions, and theirHbA1c levels fell to 8% over the 4-year period. Lackingtheir accustomed support, the patients who had beenin the intensive management group in the DCCT sawtheir HbA1c levels drift upward. So 4 years after theDCCT, HbA1c levels for both groups were equivalentat 8% in the EDIC study. Despite that, patients whohad been in the intensively managed group of theDCCT continued to show a reduction in disease pro-gression, even after they “slacked off” to a degree. Thisshows us that a big investment up front still pays divi-dends in the later years, even if control becomes lessstringent. ■

1. The Diabetes Control and Complications Trial Research Group: The effect of intensivetreatment of diabetes on the development and progression of long-term complications ininsulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.2. Engerman R, Bloodworth JM Jr, Nelson S. Relationship of microvascular disease in dia-betes to metabolic control. Diabetes. 1977;26:760-769.3. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during goodglycemic control. Diabetes. 1987;36:808-812.4. Cohen AJ, McGill PD, Rossetti RG, Guberski DL, Like AA. Glomerulopathy in sponta-neously diabetic rat: impact of glycemic control. Diabetes. 1987;36:944-951.5. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic studyof diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagno-sis is less than 30 years. Arch Ophthalmol. 1984;102:520-526.6. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Glycosylated hemoglobin predictsthe incidence and progression of diabetic retinopathy. JAMA. 1988;260:2864-2871.7. Chase HP, Jackson WE, Hoops SL, Cockerham RS, Archer PG, O’Brien D. Glucose con-trol and the renal and retinal complications of insulin-dependent diabetes. JAMA.1989;261:1155-1160.8. EDIC Research Group. Retinopathy and nephropathy in patients with Type 1 diabetesfour years after a trial of intensive therapy. N Engl J Med. 2000; 342:381-389.

Figure 6. Note three-fold reduction of rates at which inten-

sive management group required laser therapy.

Figure 5. Note three-fold reduction in progression of diabetic

eye disease in intensive management group.




In many ways, phenotypically if not genotypically,retinal venous occlusive disease shares certain fea-tures with diabetic retinopathy and is the secondmost common cause of macular edema.1 In terms

of prevalence, it is a major public health problem, withabout 130,000 cases per year in the United States, andmore than twice as many in other industrializednations.2

ROLE OF THROMBOSISThe traditional teaching is that venous thrombosis is

the cause of retinal venous occlusion, and there is sup-port for this statement from histopathologic studies aswell as intuitively.3 It is thought that the endotheliumbecomes damaged in response to hemodynamic stress.When the collagen under the endothelium is exposed,platelets adhere, and thrombi form, occluding thelumen.

What is also clear but has not been as well appreci-ated until the last 4 or 5 years, is that inflammationmay play a role in the etiology. Chan, Green, and col-leagues showed that in 29 eyes, inflammatory cellswere adjacent to the thrombus in about 48% of thecases.4

In terms of the natural history, the severity of theocclusion and the presenting visual acuity typicallydetermine final vision. The principal complications ofbranch retinal vein occlusion (BRVO) are macularedema, retinal capillary loss, and neovascularization.Although iris neovascularization rarely occurs withBRVO, it is common in central retinal vein occlusion(CRVO).

When evaluating the natural history of CRVO, it isimportant to pay attention to presenting visual acuity.Patients who present with 20/40 or better vision attheir initial visit tend to do well. About two-thirds ormore will retain 20/40 or better, whereas only a smallfraction of patients who present with poor vision,

20/200 or worse, have a good outcome.5 So itbehooves us to be aggressive with patients who pres-ent with poor vision and to be cautious with thosewho present with good vision.

EVOLUTION OF THERAPIESPreviously, therapies focused solely on complications,

principally macular edema and neovascularization.Newer therapies now focus on the primary process ofthe occlusion or the inflammation. Some of the seminalstudies on BRVO from the 1980s showed that laser pho-tocoagulation was an effective form of therapy.6 Patientswho had grid laser for macular edema were about twiceas likely to achieve two lines of vision improvement andtwice as likely to achieve 20/40 or better vision as thosewho received no treatment. Obviously, this study didnot look at macular edema treated by steroids, becausethat treatment did not exist at that time.

A significant complication of BRVO is the develop-ment of retinal neovascularization or vitreous hemor-

Focus has moved from complications to the primary process of the occlusion or theinflammation.


Treatment of Retinal VenousOcclusive Disease

Figure 1. Hemorrhage resolved and neovascularization

regressed after scatter laser photocoagulation was applied to

areas of capillary nonperfusion.




rhage. Patients who had neovascularization and thenreceived laser therapy had a reduced chance of bleedingcompared to the control patients.7

Interestingly, using the laser, you could reduce by halfthe number of patients who went on to develop neo-vascularization or vitreous hemorrhage, although thisdid not result in a difference in the final visual acuity.Although laser was not recommended in the commentsection of that article, many clinicians apply laser whenretinal neovascularization develops to reduce thechance of vitreous hemorrhage.8

Figure 1 shows a young patient whom I treated. Youcan see bleeding from an area of neovascularization.We applied scatter laser photocoagulation to areas ofcapillary nonperfusion, and the hemorrhage resolved,the neovascularization regressed, and patient hadgood visual acuity.

The Central Retinal Vein Occlusion Study (CVOS)Group found average visual acuity stayed about thesame in the laser group pre- and post-treatment, as itdid in the control group.9 There was no visual benefit,even though the macular edema did improve on fluo-rescein angiography. This is one of the first studies thatshowed a fundamental disconnect between vision andrelated surrogate measures, such as fluorescein angio-graphic macular edema or OCT thickness.

ANOMALIES EXISTWhenever you mine old, well-done studies, such as

the CVOS, you may find data anomalies. One mightassume intuitively that if laser works well for iris neovas-cularization, it would work even better if you treatedearlier. This was not the case. Eyes that had more than acertain amount of capillary nonperfusion on fluorescein

angiography and treated with scatter photocoagulationhad less iris or angle neovascularization than eyes nottreated with scatter laser. However, scatter laser did notreduce the risk of neovascular glaucoma in these eyescompared with eyes receiving scatter laser after iris orangle neovascularization developed.10 As a result, theconventional wisdom and the standard of care basedon this large trial is that we should not treat ischemicCRVOs without iris neovascularization with scatterphotocoagulation.

CONCLUSIONRetinal vein occlusion remains a common cause of

vision loss and macular edema that may benefit fromlaser photocoagulation in addition to newer pharma-cotherapies. ■

1. Central Vein Occlusion Study Group. Natural history and clinical management of centralretinal vein occlusion. Arch Ophthalmol. 1997;115:486-491.2. Klein R, Klein BE, Moss SE. Meuer SM. The epidemiology of retinal vein occlusion: theBeaver Dam Eye Study. Trans Am Ophthalmol Soc. 2008;98:133-141.3. Klein BA. Occlusion of the central retinal vein; clinical importance of certain histopatho-logic observations. Am J Ophthalmol. 1953;36:316-324.4. Green WR, Chan CC, Hutchins GM, Terry JM. Central retinal vein occlusion: a prospec-tive histopathologic study of 29 eyes in 28 cases. Trans Am Ophthalmol Soc.1981;79:371-422.5. Central Vein Occlusion Study Group. Central vein occlusion study of photocoagulationtherapy: baseline findings. Online J Curr Clin Trials. 1993;Oct 14:doc No. 95.6. Finkelstein D. Argon laser photocoagulation for macular edema in branch vein occlu-sion. Ophthalmology. 1986; 93:975-977.7. Branch Vein Occlusion Study Group: Argon laser scatter photocoagulation for preven-tion of neovascularization and vitreous hemorrhage in branch vein occlusion: a randomizedclinical trial. Arch Ophthalmol. 1986; 104:34-41.8. Jain A, Blumenkranz MS, Paulus Y, et al. Effect of pulse duration on size and characterof the lesion in retinal photocoagulation. Arch Ophthalmol. 2008;126:78-85.9. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation formacular edema in central vein occlusion. M report. Ophthalmology. 1995;102:1425-1433.10. The Central Vein Occlusion Study Group. A randomized clinical trial of early panretinalphotocoagulation for ischemic central vein occlusion. N report. Ophthalmology. 1995;102:1434-1444.




As we search for new therapies to treat retinalvein occlusions, it is important to recall whatwe know about the mechanisms that are inplay. An ischemic CRVO occurs when venous

thrombosis is closer to the optic nerve head and anteriorto most preexisting collateral veins, causing venous pres-sure to increase to the point where arterial flow is com-promised.1 Whether this occurs at the lamina cribrosa ormore posteriorly is inconsequential. What is important isthe location of the occlusion in relation to the naturallyoccurring collaterals. With a more posterior occlusionwithin the CRVO as it passes through the optic nerve,collateral veins allow limited flow, so there is still arterialpressure, creating a nonischemic CRVO. According toHayreh, the outlook is poor for ischemic CRVOs: 70%develop rubeosis; 50% develop neovascular glaucoma.2

DIFFERENTIATING CRVO FROM ISCHEMIC CRVOFor the Central Vein Occlusion Study (CVOS),3

researchers primarily used fluorescein angiography to dif-ferentiate ischemic from nonischemic CRVOs. They pre-ferred the term nonperfused because the nonperfusionon the angiogram does not differentiate if the retina isischemic or infarcted. The CVOS defined a nonperfusedcentral vein occlusion as one with at least 10 disc areas of

nonperfusion. Substantial hemorrhage often exists in aCRVO, so determining if areas on angiography are non-perfused can be difficult. If hemorrhage obscured theview, a CRVO was termed indeterminate. The CVOS diddetermine, however, that most indeterminate centralvein occlusions have a natural history similar to nonper-fused vein occlusions. In summary, angiography can beused to differentiate perfused from nonperfused centralvein occlusions, and if there is too much blood to makethis differentiation, the vein occlusion should be consid-ered nonperfused.

In natural history studies, Hayreh has shown that sev-eral prognostic tests are sensitive and specific identifiersfor ischemic CRVO (Figure 1).1 The CVOS found that ifone takes into account the visual acuity and extent ofhemorrhage, then additional data from pupil responsesto electroretinogram provide further prognostic informa-tion as to whether the eye will progress from nonperfu-sion to neovascularization.

Hayreh reported the cumulative risk of developing irisneovascularization, angle neovascularization, and neovas-cular glaucoma is highest during the first 90 days. After90 to 180 days, venous-venous collaterals often enlargeenough to decrease venous pressure, and improvementcan occur. By about 9 months, the curve is flat (Figure 2).

Studies reveal the relationship between VEGF and neovascularization.

BY DAVID M. BROWN, MD

Considering Anti-VEGFTherapies for Vein Occlusions

Figure 1. Prognostic tests for ischemic CRVO. Figure 2. Note cumulative risk is highest in first 90 days.




PROMISING INTERVENTIONSThe list of CRVO interventions is littered with good

intentions and bad results. Laser anastomosis has beenshown to work in case series, but usually an adequateanastomosis cannot be created.4 Radial optic neurotomyand optic nerve sheath fenestration have not beenshown convincingly to alter visual acuity outcomes or

progression to neovascularization in a way thatdiffers from the natural history. Ongoing studies,such as the Standard Care vs Corticosteroid forRetinal Vein Occlusion (SCORE) study,5 should tellus how steroid therapy compares with the naturalhistory. And thus far, intravitreal anti-VEGF thera-py has shown promising short-term results inuncontrolled studies.

Is there a rationale for using an anti-VEGFagent? Pe’er looked at neovascular glaucoma enu-cleation specimens going back to the 1920s andfound messenger RNA upregulation of VEGF.6 Inanother study, Boyd and colleagues performedanterior chamber taps in patients with neovascu-lar glaucoma before and after laser treatment.They found neovascularization occurred whenaqueous VEGF concentrations were 849 pg/mL to1569 pg/mL and regressed fully when they fellbelow 550 pg/mL.7

We also have good studies showing increasedVEGF in proliferative diabetic retinopathy andvein occlusions.8,9 These data confirm that VEGFcorrelates to neovascularization.

RAVE TRIALIn the ongoing Rubeosis Anti-VEGF (RAVE)

Trial for Ischemic CRVO,10 monthly intravitrealinjections of ranibizumab (Lucentis, Genentech,Inc.) were administered over 9 months. Opticalcoherence tomography, wide-field and conven-tional angiography, and Goldmann perimetrywere performed monthly. The goal was to pre-vent neovascular glaucoma and visual field lossrelated to panretinal photocoagulation, and tolearn more about nonperfused CRVO.

Preliminary analysis of the first 10 subjectssuggests that one went from marked retinalthickening to resolution of edema and even lossof normal retinal thickness (Figure 3). Despitethese large improvements in retinal thickening,most subjects had only slightly improved visualacuity, usually at very low (poor) levels (Figure4). Figure 5 shows best-corrected visual acuitychanges using the 20-minute ETDRS refraction:60% had a 4-line gain with monthly ranibizumab

to month 9. Although some of these follow-up visualacuities are only in the 20/100 to 20/200 range, visualacuity appears definitively better than the initial acuityand may have some value to the patient.

The next question was: What would happen whentreatment was stopped? Would regression of effect occurbecause the treatment had led to upregulation of VEGF?

Figure 3. RAVE Trial: Preliminary analysis of first 10 subjects.

Figure 5. Note vision gains with monthly ranibizumab injections.

Figure 4. Despite improved retinal thickening,VA improved only slightly.




In about two-thirds of the eyes, the swellingdid not return (Figure 6). In about one-third, theswelling returned immediately, and those sub-jects lost the visual acuity they had gained(Figure 7). Some of the gains from baseline tomonth 9 were lost by not treating from month 9to month 12 (Figure 8). Thus far, it appears muchof the edema in these cases is VEGF-driven and notnecessarily related only to venous pressure, becauseif you give enough anti-VEGF, the edema resolves,and you can prevent it if you keep giving anti-VEGF.

QUESTIONS REMAINQuestions remain on the management of non-

perfused CRVO. Why is there a disconnectbetween edema and neovascularization? Why dosome patients with or without edema get neovas-cularization?

We should have more definitive data in thenext year or so from trials that are currentlyrecruiting, such as SCORE, BRAVO (A Study ofthe Efficacy and Safety of Ranibizumab Injectionin Patients With Macular Edema Secondary toBranch Retinal Vein Occlusion), CRUISE (A Studyof the Efficacy and Safety of RanibizumabInjection in Patients With Macular EdemaSecondary to Central Retinal Vein Occlusion), andthe Branch Retinal Vein Occlusion or Central VeinOcclusion with Macular Edema Posurdex ImplantStudy, which should put us closer to answeringsome of these questions. ■

1. Hayreh SS, Klugman MR, Beri M, Kimura AE, Podhajsky P. Differentiation ofischemic from non-ischemic central retinal vein occlusion during the early acutephase. Graefes Arch Clin Exp Ophthalmol. 1990;228:201-217.2. Hayreh, SS; Rojas, P; Podhajsky, P; Montague, P; Woolson, RF. Ocular neovascu-larization with retinal vascular occlusion-III. Incidence of ocular neovascularizationwith retinal vein occlusion. Ophthalmology. 1983;90:488–506.3. The Central Vein Occlusion Study Group. A randomized clinical trial of early pan-retinal photocoagulation for ischemic central vein occlusion. The Central VeinOcclusion Study Group N report. Ophthalmology. 1995;102:1434–1444.4. Fekrat S, Goldberg MF, Finkelstein D. Laser-induced chorioretinal venous anasto-mosis for nonischemic central or branch retinal vein occlusion. Arch Ophthalmol.1998;116:43-52.5. Scott IU, Ip MS. It’s time for a clinical trial to investigate intravitreal triamcinolonefor macular edema due to retinal vein occlusion: the SCORE study. Arch Ophthalmol.2005;123:581-582.6. Pe’er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E. Vascular endothelialgrowth factor upregulation in human central retinal vein occlusion. Ophthalmology.1998;105;412-416.7. Boyd SR, Zachary I, Chakravarthy U, et al. Correlation of increased vascularendothelial growth factor with neovascularization and permeability in ischemic centralvein occlusion. Arch Ophthalmol. 2002;120:1644-1650.8. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocularfluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med.1994;331:1519-1520.9. Augustin AJ, Keller A, Koch F, Jurklies B, Dick B. Effect of retinal coagulation sta-tus on oxidative metabolite and VEGF in 208 patients with proliferative diabeticretinopathy. Klin Monatsbl Augenheilkd. 2001;218:89-94.10. Brown DM. Rubeosis anti-VEGF (RAVE) trial for ischemic CRVO: 1-year data.Paper presented at: 40th Annual Scientific Meeting of the Retina Society; September2007; Boston, MA.

Figure 6. Note response after treatment was stopped.

Figure 7. Note VA after treatment was stopped.

Figure 8. Some gains were lost by not treating from month 9 to

month 12.



1. When monitored for 3 years in theETDRS, what percentage of subjectswith clinically significant macularedema who received focal/grid treat-ment experienced moderate vision loss?a. <5%b. 15%c. 25%d. >30%

2. What percentage of 370 respondentsto the 2005 ASRS Preferences andTrends survey reported they were usingintravitreal steroids to manage patientswith persistent DME?a. >10%b. >30%c. >50%d. >90%

3. In the Diabetic Retinopathy ClinicalResearch Network (DRCR.net) trialcomparing photocoagulation and twodosages of intravitreal preservative-freetriamcinolone, at 2 years, what was thechange in visual acuity (on standard-ized eye charts) in the laser group ?a. +1 letterb. +2 lettersc. –2 lettersd. –3 letters

4. In the DRCR.net trial that comparedthe modified ETDRS laser techniquewith the mild macular grid techniquefor DME, in what percentage ofpatients receiving modified ETDRS lasertherapy did edema resolve after 1 year?a. 10%b. 30%c. 50%d. 90%

5. What is the primary efficacy out-come in the Laser-Ranibizumab-Triamcinolone for DME Study?a. Visual acuityb. Contrast sensitivityc. Number of injections in the first yeard. Change in retinal thickening

6. What was the change in mean visualacuity from baseline to 6 months in thecohort study from the Evaluation ofVitrectomy for Diabetic MacularEdema Study,?a. The majority of patients gained 3 letters.b. There was no significant change.c. The majority of patients lost 1 line.d. Results have not yet been reported.

7. Comparing conventional to intensivetherapy in the primary cohort of theDiabetes Control and ComplicationsTrial (DCCT), progression of diabeticeye disease in the intensive manage-ment group was reduced by how much?a. Two-foldb. Three-foldc. Five-foldd. About the same in both groups

8. In the Epidemiology of DiabetesInterventions and Complications(EDIC) study, subjects originallyassigned to conventional managementtried to follow the intensive manage-ment instructions. How did this groupfare after 4 years?a. Their HbA1c levels fell to 8%.b. Their HbA1c levels drifted upward.c. Their HbA1c levels remained the sameas they were in the DCCT.d. They continued to show a reduction indisease progression.

9. Which of the following complicationsrarely occurs with BRVO but is com-mon with CRVO?a. Macular edemab. Retinal capillary lossc. Iris neovascularizationd. Vitreous hemorrhage

10. According to Hayreh, when is therisk of developing iris neovasculariza-tion, angle neovascularization and neo-vascular glaucoma highest in ischemiccentral retinal vein occlusion?a. During the first 90 daysb. From 90 to 180 daysc. From 6 to 9 monthsd. After 9 months

11. After performing anterior chambertaps before and after laser treatment inpatients with neovascular glaucoma,Boyd and colleagues found neovascu-larization occurred when aqueousVEGF concentrations were at whatlevel?a. Below 550 pg/mLb. Between 849 pg/mL and 1569 pg/mLc. Above 1569 pg/mLd. The data were inconclusive

12. In the Rubeosis Anti-VEGF (RAVE)Trial for Ischemic CRVO, what percent-age of patients had a 4-line gain withmonthly ranibizumab to month 9?a. 30%b. 40%c. 50%d. 60%

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