Evaluating and Integrating New Evidence In The Treatment of RVO

ROUNDTABLE PARTICIPANTS
Julia A. Haller, MD,
served as Chair for this program and monograph. Dr. Haller is Ophthalmologistin- Chief of the Wills Eye Institute, and Professor and Chair of the Department of Ophthalmology of Jefferson Medical College of Thomas Jefferson University. She was educated at the Bryn Mawr School in Baltimore, Princeton University, and Harvard Medical School. After a surgical internship at Johns Hopkins Hospital and a fellowship in ocular pathology with Dr. Frederick A. Jakobiec at Manhattan Eye, Ear and Throat Hospital and Cornell Medical Center, she entered the residency program in ophthalmology at the Wilmer Eye Institute at Johns Hopkins. Following her subsequent retina fellowship at Johns Hopkins directed by Ronald G. Michels, MD, she became Wilmer's first female chief resident in 1986. She joined the Johns Hopkins faculty thereafter, became the inaugural Katharine Graham Professor of Ophthalmology in 2002, and was installed as the inaugural Robert Bond Welch, MD Professor of Ophthalmology in 2006. At Wilmer, she directed the retina fellowship program. She assumed leadership of the Wills Eye Institute in 2007. Dr. Haller has published over 250 peer-reviewed papers as well as 22 book chapters. She is immediate past president of the American Society of Retina Specialists, treasurer of the Retina Society, chairs the ASCRS Retina Subcommittee, and serves on the editorial boards of the journals RETINA, Retinal Physician, Ocular Surgery News, Ophthalmology Times, EyeWorld, and Evidence-Based Eye Care.

David M. Brown, MD,
is Clinical Associate Professor in the Department of Ophthalmology, The Methodist Hospital, Weill College of Medicine, Cornell University; and is in private practice at Retina Consultants of Houston in Houston, Texas. He is the director of clinical research at the Greater Houston Retina Research Center at The Methodist Hospital in Houston. Dr. Brown received his medical degree and completed his internship at Baylor College of Medicine; and he completed an ophthalmology residency and a fellowship in medical retina and vitreoretinal surgery at University of Iowa Hospitals and Clinics in Iowa City. Dr. Brown has published book chapters on disorders of the vitreous and retina, in addition to first author peerreviewed publications in the New England Journal of Medicine, RETINA, American Journal of Ophthalmology, Survey of Ophthalmology, Archives of Ophthalmology, Ophthalmology, and British Journal of Ophthalmology. He was the recipient of an American Academy of Ophthalmology Honor Award in 2000.

Jeffrey S. Heier, MD,
is Co-Director of the Ophthalmic Consultants of Boston/Tufts Retina Fellowship, Assistant Professor of Ophthalmology at Tufts School of Medicine, and a Clinical Instructor of Ophthalmology at Harvard Medical School. He is a leading retinal clinical researcher for new treatments in exudative and non-exudative macular degeneration, diabetic macular edema, venous occlusive disease, vitreoretinal surgical techniques and instrumentation, and diagnostic imaging of the retina. Dr. Heier received his medical degree from Boston University, and then served his transitional internship and ophthalmology residency at Fitzsimons Army Medical Center. He completed a vitreoretinal fellowship at Ophthalmic Consultants of Boston/Tufts University School of Medicine, where he is currently a partner. He lectures nationally and internationally on retinal research and innovative approaches to the treatment of retinal diseases, and has authored or coauthored numerous works in peer-reviewed journals.

Baruch D. Kuppermann, MD, PhD,
is Professor of Ophthalmology and Biomedical Engineering, Chief of the Retina Service and Vice-Chair of Clinical Research at the Gavin Herbert Eye Institute, Department of Ophthalmology at the University of California, Irvine. He received his medical degree at the University of Miami, Florida, and a PhD in neuroscience at the California Institute of Technology. Dr. Kuppermann interned at Los Angeles County/University of Southern California Medical Center, and was a resident in ophthalmology at the University of Southern California Doheny Eye Institute. He completed fellowships in retina and vitreous at both St. Joseph's Medical Center in Baltimore under Drs. Ronald Michels, Bert Glaser and Robert Murphy, and at the University of California, San Diego. Following those fellowships, he joined the UC Irvine faculty, where he has been since 1992, including serving as Acting Chairman of the Department of Ophthalmology (1995-1996) and Interim Chairman (1996-1998). His laboratory research focuses on assessing the toxicity of drugs on retinal cells in culture, including the assessment of the toxicity of various vital stains, steroids, and anti-VEGF compounds. Dr. Kuppermann is on the editorial boards of RETINA, Retina Today, Brazilian Archives of Ophthalmology, and Brazilian Journal of Ophthalmology.

Ingrid U. Scott, MD, MPH,
is Professor of Ophthalmology and Public Health Sciences, and Director of the Ophthalmology Residency Program, at Penn State Hershey Eye Center, Penn State College of Medicine. She earned her medical degree and master of public health (MPH) degree from Johns Hopkins University. She completed an ophthalmology residency, a fellowship in vitreoretinal surgery and diseases, and chief residency at Bascom Palmer Eye Institute, University of Miami, where she served on the faculty for many years. She has served as Vice-Chair of the Diabetic Retinopathy Clinical Research Network funded by the National Eye Institute (NEI), Co-Chair of the NEI-funded Standard Care vs COrticosteroid for REtinal Vein Occlusion (SCORE) Study, and Executive Committee member of the NEI-funded Age-Related Eye Disease 2 (AREDS2) Study. Dr. Scott has published over 220 peer-reviewed papers as well as 24 book chapters. She serves as Chair of the Ophthalmic Technology Assessment Committee Retina Panel of the American Academy of Ophthalmology (AAO) and is a member of the AAO's Preferred Practice Patterns Retina Panel. Dr. Scott is a member of the Board of Directors of the American Society of Retina Specialists and serves on the editorial board of numerous ophthalmology journals, including Evidence-Based Eye Care, Graefe's Archive for Clinical and Experimental Ophthalmology, Journal of Academic Ophthalmology, Ophthalmic Surgery, Laser and Imaging, Ophthalmology Management, RETINA, Retina Times, Retina Today, Retinal Physician, and Review of Ophthalmology.

INTENDED AUDIENCE
This activity was developed for retinal specialists and other ophthalmologists involved in the care of patients with RVO.

STATEMENT OF NEED
Retinal vein occlusion (RVO) is a significant disease that affects an estimated 1.6% of the population above the age of 40. Treatment for RVO is at a crossroads. Grid laser therapy has been used as standard treatment for vision loss from macular edema or neovascularization due to BRVO, while treatment interventions for fixed visual loss associated with CRVO have not proven to be of benefit. Recent studies, however, have shown potential benefit from other treatment protocols.

Emerging research completed or published during 2008-09, and ongoing research to determine long-term outcomes from these treatments, suggest future debate and progress in the management of RVO-associated vision loss. Standards for care will evolve based on this new evidence, and clinician learners will benefit from a concise assimilation and discussion of this emerging research from retinal experts, and their current recommendations for RVO treatment standards.

LEARNING OBJECTIVES
After participating in this activity, participants should be able to do the following:

• Evaluate the latest clinical studies of intravitreal corticosteroids and anti-VEGF agents in the treatment of branch retinal vein occlusion and central retinal vein occlusion
• Assess safety issues in the treatment of retinal vein occlusion
• Plan appropriate care for patients with retinal vein occlusion

ACCREDITATION AND CERTIFICATION
The Annenberg Center for Health Sciences at Eisenhower is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Annenberg Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.^™ Physicians should only claim credit commensurate with the extent of their participation in the activity.

There is no charge for this activity. Statements of Credit will be mailed 4-6 weeks following activity participation, upon completion and return of the evaluation form to the Annenberg Center for Health Sciences (#4736), 39000 Bob Hope Drive, Rancho Mirage, CA 92270 or by fax to 760-773-4550.

DISCLOSURE
It is the policy of the Annenberg Center to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All faculty and planners participating in sponsored programs are expected to identify and reference off-label product use and disclose any relationship with those supporting the activity or any others with products or services available within the scope of the topic being discussed in the educational presentation.

In accordance with the Accreditation Council for Continuing Medical Education Standards, parallel documents from other accrediting bodies, and Annenberg Center policy, the following disclosures have been made:

David M. Brown, MD, FACS
Research Support
Alcon Laboratories; Alimera Sciences, Inc.; Allergan, Inc.; Eli Lilly and Company; Eyetech Pharmaceuticals; Genentech; Jerini Ophthalmic, Inc.; Molecular Partners; NeoVista, Inc.; Neurotech Pharmaceuticals; Novartis Pharmaceuticals; Othera Pharmaceuticals, Inc.; Pfizer, Inc.; Regeneron Pharmaceuticals; Sirion Therapeutics, Inc.
Consultant
Alcon Laboratories; Allergan, Inc.; Genentech; Molecular Partners; Novartis Pharmaceuticals; Oraya Therapeutics; Regeneron Pharmaceuticals; Steba Biotech Ltd.
Speakers Bureau
Genentech

Julia A. Haller, MD
Research Support
Regeneron Pharmaceuticals
Consultant
Allergan, Inc.; Genentech

Jeffrey S. Heier, MD
Research Support
Alcon Laboratories; Alimera Sciences, Inc.; Allergan, Inc.; Genentech; Genzyme; Molecular Partners; NeoVista, Inc.; Neurotech Pharmaceuticals; Novagali Pharma; Paloma Pharmaceuticals, Inc.; Regeneron Pharmaceuticals; Srini Pharmaceuticals; Schering-Plough
Consultant
Allergan, Inc.; Fovea Pharmaceuticals; Genentech; Genzyme; GlaxoSmithKline; Heidelberg Pharma; iScience; Kanghong Pharmaceutical; LPath Incorporated; Molecular Partners; NeoVista, Inc.; Neurotech Pharmaceuticals; Novagali Pharma; Oraya Therapeutics; Paloma Pharmaceuticals, Inc.; Regeneron Pharmaceuticals; Schering-Plough

Baruch D. Kuppermann, MD, PhD
Research Support
Alimera Sciences, Inc.; Allergan, Inc.; Regeneron Pharmaceuticals; ThromboGenics
Consultant
Allergan, Inc.; Glaukos Corporation; NeoVista, Inc.; Novagali Pharma; Ophthotech Corporation, Inc.

Ingrid U. Scott, MD, MPH
Consultant
Eyetech Pharmaceuticals; Genentech

The faculty for this activity have disclosed that there will be discussion about the use of products for non-FDA approved indications.

Richard Trubo (Medical Writer) has nothing to disclose.

All staff at the Annenberg Center for Health Sciences at Eisenhower have nothing to disclose.

The ideas and opinions presented in this educational activity are those of the faculty and do not necessarily reflect the views of the Annenberg Center and/or its agents. As in all educational activities, we encourage practitioners to use their own judgment in treating and addressing the needs of each individual patient, taking into account that patient's unique clinical situation. The Annenberg Center disclaims all liability and cannot be held responsible for any problems that may arise from participating in this activity or following treatment recommendations presented.

This activity is supported by an independent educational grant from Allergan, Inc., and Genentech.

This activity is an enduring material and consists of a print piece. Successful completion is achieved by reading the material, reflecting on its implications in your practice, and completing the assessment component.

The estimated time to complete the activity is 1 hour.

This activity was originally released in October 2010 and is eligible for credit through September 30, 2011.

This piece is based on a discussion among the faculty members and was written by a writer from the Annenberg Center. Faculty have final editorial control for the piece.

INTRODUCTION
Retinal vein occlusion (RVO) is the second most common retinal vascular disease. For years, the standards of care for 2 types of RVO – branch and central – have been based on the findings of 2 major trials: BVOS (Branch Vein Occlusion Study)1 and CVOS (Central Vein Occlusion Study).² Both of these studies were funded by the National Eye Institute, with major publications in 1984 (BVOS) and 1995 (CVOS).

Since that time, however, there have not been further large-scale clinical trials that have described new treatment options — until recently. New data from a number of key studies have recently been presented and published. As a result, a consensus is emerging, along with debate over a number of remaining issues, turning the present era into an exciting time for both ophthalmologists and patients relative to the management of RVO.

To help place this progress into context, a roundtable discussion with leading clinicians and researchers in the field was recently convened at the time of the 2010 annual meeting of ARVO (Association for Research in Vision and Ophthalmology), and this monograph features their insights and opinions. It also presents overviews of recent research and developments in the management of RVO that the panel considered particularly important.

Epidemiology of RVO
Worldwide, about 16.4 million people have RVO.3 In a recent analysis of population studies from the United States, Europe, Asia and Australia – using data on 68,751 individuals – the age- and sex-standardized prevalence of RVO was found to be 5.20 per 1000 (CI, 4.40-5.59) for any RVO.³ In RVO subtypes, the prevalence was:

•BRVO – 4.42 per 1000 for BRVO (CI, 3.65-5.19)

•CRVO – 0.80 per 1000 (CI, 0.61-0.99)

The same published report found differences in prevalence among ethnicity groups. In the white population, the prevalence of any RVO was found to be 3.7 per 1000 (CI, 2.8-4.6) in 5 studies. That compared with 3.9 per 1000 (CI, 1.8-6.0) in blacks, 5.7 per 1000 (CI, 4.5-6.8) in Asians, and 6.9 per 1000 (CI, 5.7-8.3) in Hispanics. In all ethnic populations, the prevalence of CRVO was lower than for BRVO.³

“Inasmuch as many of the risk factors for RVO are also risk factors for some other diseases as well – and include hypertension, diabetes and glaucoma – we can expect the rate of RVO to increase as these diseases escalate in prevalence in the population at large.”

Julia A. Haller, MD

Pathophysiology of RVO
Ophthalmic researchers continue to seek a more definitive understanding of the pathogenesis of RVO, which commonly leads to vision loss.

“A leading hypothesis surrounding the pathophysiology of retinal vein occlusion is that atherosclerotic changes in a retinal artery lead to compression of an adjacent retinal vein, causing turbulent venous blood flow and endothelial cell damage, which can lead to thrombus formation. Other potential causes for retinal vein occlusion include inflammation and hypercoagulable states.”

Ingrid U. Scott, MD, MPH

‘”In terms of pathophysiology, I am more and more convinced that everything is inflammatory – aging, heart disease, diabetes, macular degeneration, vein occlusions, and so on. If you look closely at the basic process of things that go wrong, it has a lot to do with inflammatory disease.”

Julia A. Haller, MD

When patients ask their ophthalmologists why they developed RVO (“How could this have possibly happened to me?”), they are often told about established risk factors such as hypertension, diabetes, hypercholesterolemia, glaucoma and age. Thus, it is important to advise patients to manage cardiovascular risks, including smoking and elevated cholesterol levels. In describing CRVO and BRVO to patients, and even to referring physicians, some clinicians also use an analogy comparing RVO to a stroke, which is more widely understood. In this context, the analogy may help primary care physicians think about vasculopathies, and better understand the need to optimize modifiable risk factors for vascular occlusive disease.

At the same, other ophthalmologists are hesitant to make the comparison between stroke and RVO. With primary care physicians, this analogy may bring to mind embolic disease and a need to anticoagulate. In talking with patients, ophthalmologists may choose instead to describe the condition as an “anatomic kink” in a vessel that predisposes them to RVO. In patients who have already been diagnosed with heart disease, they may already know that there are sites in the heart vessels where anatomic predispositions can lead to occlusions.

“The most important point to emphasize is that this is a systemic vascular disease that may have an eye manifestation. It is a sign of an overall systemic vascular disease that needs to be brought under control, and by doing so, can help prevent problems in the fellow eye.”

Jeffrey S. Heier, MD

RVO can also develop in a younger patient without any known risk factors. In such a case, a thorough workup is needed, looking for conditions like hyperviscosity syndromes. Yet even though a clotting workup can be extensive, it still may not yield the kind of information that would change therapeutic decision-making.

“In younger patients who are underinsured or have high deductibles, and who have limited funds in their wallet, I may suggest that they consider just taking a baby aspirin a day as a first step (which is the commonly prescribed therapy if a hyperviscosity syndrome is diagnosed). That being said, if the patients already have bruising from a vein occlusion, they may have even more bruising if they take a daily aspirin for very long.”

David M. Brown, MD

RECENT CLINICAL DATA
In this section of the monograph, important studies that are changing the face of RVO treatment will be described.

SCORE Study – CRVO Trial
The Standard Care vs COrticosteroid for REtinal Vein Occlusion (SCORE) Study includes 2 phase 3, prospective randomized controlled trials designed to evaluate the safety and efficacy of intravitreal triamcinolone acetonide for treating vision loss due to macular edema associated with retinal vein occlusion; one of the trials was conducted among patients with macular edema associated with CRVO,and the other among patients with macular edema associated with BRVO.

In the SCORE-CRVO trial, 271 participants with vision loss secondary to macular edema associated with CRVO were assigned in a 1:1:1 randomization to intravitreal injections of 1 mg or 4 mg triamcinolone or standard care therapy which, at the time the SCORE Study was designed, consisted of observation. Participants in the 1 mg and 4 mg triamcinolone groups were retreated at 4-month intervals unless at least 1 of the 3 following reasons to consider deferral of retreatment was met:

(1) The initial treatment was successful [optical coherence tomography (OCT)-measured macular thickness ≤ 225 μm, visual acuity ≥ Snellen equivalent of 20/25, or there was substantial improvement in macular edema from the prior treatment],

(2) The participant experienced a significant adverse effect from prior treatment, or

(3) Additional treatment was considered apparently futile. Treatment was considered apparently futile if a period of 8 or more months transpired during which there were 2 intravitreal triamcinolone treatments but there was no evidence of at least borderline improvement. Borderline improvement was present if, when compared with findings at the beginning of the period, there was an increase in visual acuity letter score of 5 or more or there was a decrease in calculated retinal thickening (actual thickness minus mean normal thickness) that was at least 50 μm and represented at least a 20% reduction in retinal thickening compared with the findings at the beginning of the period.

Investigators in the study were not prohibited from retreating study participants even if one of these 3 reasons for consideration of deferral was met.

The primary outcome of the study was the proportion of participants who experienced a gain in visual acuity letter score of 15 or more from baseline to month 12, as assessed by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) method.⁴

The mean age of participants was 68 years; 91% were Caucasian, 73% had hypertension, 23% had diabetes, and the mean ETDRS visual acuity letter score was 51.2 (Snellen equivalent, ~20/100).⁵

The mean duration of macular edema was 4.3 months (39% had a macular edema duration of <3 months, 42% 3 to 6 months, and 19% >7 months).⁵ The mean center point thickness, as measured by OCT, was 659 µm.⁵ The mean number of injections prior to 12 months was similar in the 2 triamcinolone groups (2.2 in the 1 mg arm and 2.0 in the 4 mg arm).⁵

Key findings of the SCORE-CRVO trial include:

• Both triamcinolone groups were superior to the observation cohort with respect to visual acuity at the primary outcome visit (12 months).
• The visual benefit of triamcinolone was demonstrated as early as 4 months.
• 7%, 27% and 26% of participants (in the observation, 1 mg and 4 mg groups, respectively) achieved the primary outcome (see Figure 1).
• The benefit appeared to persist to 24 months, although there was less power at 24 months due to small numbers.
• All 3 study groups showed OCT-measured center point thickness decreases from baseline through follow-up, with no difference among the groups in central retinal thickness at 12 months.
• Cataract formation occurred in greater numbers in the 4 mg arm. The same higher triamcinolone dose was also associated with a higher rate of cataract surgery and higher rate of intraocular pressure elevation.⁵

“There was no subgroup in which triamcinolone had an outcome that was inferior to observation. The findings of the SCORE-CRVO trial suggest that the visual benefit of triamcinolone may be due, at least in part, to an effect (such as an anti-inflammatory or neuroprotective effect) other than a reduction in retinal thickness, which occurred in all 3 groups. The study investigators concluded that intravitreal triamcinolone in a 1 mg dose should be considered for up to 12 months, and possibly up to 2 years, in patients with vision loss associated with macular edema secondary to CRVO who have characteristics similar to the participants in the SCORE-CRVO trial.”

Ingrid U. Scott, MD, MPH

SCORE Study – BRVO Trial
The SCORE-BRVO trial included 411 participants. Its methodology was similar to that of the SCORE-CRVO trial, comparing 1 mg and 4 mg doses of intravitreal triamcinolone with standard care therapy in patients with vision loss associated with macular edema secondary to BRVO. At the time the SCORE-BRVO trial was designed, standard care therapy for decreased vision due to macular edema associated with BRVO consisted of grid photocoagulation in eyes without dense macular hemorrhage, and deferral of photocoagulation until the hemorrhage clears in eyes with dense macular hemorrhage. Retreatment criteria were similar to those described above for the SCORE-CRVO trial. The primary outcome measure was the proportion of participants who experienced a gain in visual acuity letter score of 15 or more from baseline to month 12, as assessed by the E-ETDRS method.

Baseline characteristics were comparable to those of patients in the SCORE-CRVO trial, with a mean patient age of 67 years; 70% of patients with BRVO had hypertension, and the mean ETDRS visual acuity letter score was 57.0 (Snellen equivalent, ~20/80).⁶ The mean duration of macular edema was 4.4 months (37% had a macular edema duration of <3 months, 45% 3 to 6 months, and 18% >7 months).⁶ The mean center point thickness, as measured by OCT, was 525 µm.⁶

The mean number of injections prior to 12 months was similar in the 2 triamcinolone groups (2.2 in the 1 mg arm and 2.1 in the 4 mg arm), and the mean number of laser treatments prior to 12 months was 1.5.⁶

Key findings of the SCORE-BRVO trial include:

• There was no significant difference among the 3 patient cohorts with regard to visual acuity outcomes (gain, mean change, or loss) at the primary outcome visit (12 months).
• 26% of patients in the 1 mg injection group and 27% in the 4 mg group achieved the primary visual acuity outcome, compared with 29% in the observation group (see Figure 2).
• From months 12 through 36, the greatest improvement in mean visual acuity letter score occurred in the standard of care arm.⁶
• All 3 groups experienced a decline in retinal thickness from baseline to 12 months.
• The highest rates of adverse events (eg, elevated intraocular pressure and cataract) occurred in the 4 mg triamcinolone arm.

“In the SCORE-BRVO trial, after month 12 and extending through month 36, the mean improvement in visual acuity letter score and the reduction in retinal thickness were greatest in the standard of care (grid photocoagulation) group compared to the two triamcinolone groups. It appears that the outcomes associated with laser therapy get better and better over time.”

Ingrid U. Scott, MD, MPH

CRUISE Study
CRUISE (Central Retinal Vein OcclUsIon Study: Evaluation and Safety) was a phase III multicenter trial in which patients with macular edema following CRVO were randomized to receive monthly intraocular injections of the anti-VEGF therapy ranibizumab (0.3 mg or 0.5 mg) or sham injections. There were 392 patients enrolled in the trial, and patients with the worst vision (greater than 20/320 Snellen equivalent) and those with brisk afferent pupillary defect were among those excluded.

The primary efficacy outcome measure was the mean change from baseline best-corrected visual acuity (BCVA) letter score at the 6-month point.⁷

The CRUISE findings included:

• Patients in the ranibizumab treatment groups showed mean gains of 12.7 and 14.9 letters in the 0.3 mg and 0.5 mg cohorts, respectively, versus 0.8 letters in the sham group at month 6.
• The improvements that occurred in BCVA letter scores following the injection of ranibizumab developed rapidly, with gains averaging 9 letters just 7 days following the initial ranibizumab injection, which was significantly greater than what occurred in the sham group.
• At 6 months, there was a significantly larger number of ranibizumab-treated participants with BCVA of 20/40 or greater, compared with the sham group (<0.0001 for each ranibizumab group vs sham). Central foveal thickness decreased by a mean of 434 μm and 452 µm in the 0.3 mg and 0.5 mg treatment groups, versus only 168 µm in the sham arm.⁷

“Safety profiles in CRUISE were consistent with what we had seen in other studies (MARINA, ANCHOR, PIER), with no preponderance of systemic effects that we think could be related to anti-VEGF therapy. All ocular side effects were related to the intraocular injections.

“In terms of efficacy, it's important to make the point that once the patients reached the primary efficacy end point at 6 months in CRUISE, they were then continued onto an observation period where both the treatment and sham arms could receive PRN therapy if visual acuity was worse than 20/40, or if CFT was over 250 μm. When we went to PRN therapy, the ranibizumab-treated arms were maintained over 12 months, with about 4 injections over those subsequent 6 months.”

David M. Brown, MD

BRAVO Study
Still another study, BRAVO (BRAnch Retinal Vein Occlusion), was similar to CRUISE in evaluating the use of anti-VEGFs in the management of RVO, but patients had BRVO rather than CRVO. This 6-month, phase III study enrolled 397 participants with macular edema following BRVO. According to the inclusion criteria, participants had a visual acuity of 20/40 to 20/400, and their mean central foveal thickness was over 250 μm at screening. Patients were randomized 1:1:1 to receive monthly injections of ranibizumab (0.3 mg or 0.5 mg) or sham injections. The mean number of injections across all 3 patient cohorts was just short of 6, whether in the sham or drug groups.⁷

The BRAVO researchers reported:

• Both doses of ranibizumab led to an improvement in BCVA that was clinically and statistically significant compared with sham. The mean change from baseline BCVA letter scores was 16.6 and 18.3 in the 0.3 mg and 0.5 mg ranibizumab groups, respectively, compared with 7.3 in the sham group.⁸
• At 6 months, improvements of 15 or more letters in BCVA were noted in:
  55.2% of patients receiving 0.3 mg ranibizumab
  61.1% receiving 0.5 mg ranibizumab
  28.8% receiving sham injections
  (P <0.0001 for each ranibizumab group vs sham)
• At the same 6-month time point, CFT had declined by a mean of 337 µm and 345 μm in the drug cohorts, vs 158 µm in the sham participants.
• The safety profiles in BRAVO were comparable with previous phase III ranibizumab studies, with no new adverse events related to treatment.⁸

Dexamethasone (Ozurdex) Trial
Ozurdex is an intravitreal implant of dexamethasone, a potent corticosteroid with a relatively low ocular side effects profile. Approved by the FDA for RVO (ME) in June 2009, it is administered as a biodegradable implant. Although it was designed to be a 6-month drug delivery system, some research suggests the time frame may be less than that.

“When considering steroid therapy, there are 2 situations where I strongly consider Ozurdex (dexamethasone): In a patient who has had a previous vitrectomy (where the duration of effect of intravitreal injections is often decreased), and in a patient who may benefit from steroid therapy but has either demonstrated a previous intraocular pressure elevation from intavitreal steroids, or is at risk to do so.”

Jeffrey S. Heier, MD

A phase III study evaluated Ozurdex/dexamethasone in 1267 patients with vision loss due to macular edema associated with branch or central RVO (about twice as many individuals had BRVO as CRVO in the randomization). Patients were treated with a single dexamethasone implant (0.35 or 0.7 mg).⁹

The study conclusions included:

• More RVO patients gained 15 or more lines from baseline BCVA, compared to sham, with significant improvements occurring from days 30 through 90.
• The greatest response was noted at day 60, with about 29% in the treatment group showing ≥15 letter improvement, vs 11% in the sham cohort (see Figure 3).
• The results were qualitatively similar to what was found in the BRVO and CRVO subgroups, although improvements were more modest in the CRVO patients.⁹

“When looking at the IOP curve with the use of 0.7 mg implant, it peaks at day 60, and then returns to baseline levels by day 180. Also, no significant differences were seen among groups in the development of cataract or cataract surgery.”

Baruch D. Kuppermann, MD, PhD

MAKING TREATMENT DECISIONS
The patient's own history and circumstances are factors in the selection of therapies. For an 80-year-old patient who lives 2 hours away from the ophthalmologist's office and whose family frequently can't arrange to bring her in – and particularly if she is pseudophakic, known to be on steroids after cataract surgery, and never had a problem with pressure – an Ozurdex injection might be an appropriate starting point.

“Then, after a pressure check close to home, I will bring this particular patient back for retinal evaluation in 2 months. Of course, I would prefer it if she lived right down the block and she could come back in a month, but I'm comfortable getting her back in 60 days, looking at her OCT and seeing how she's doing. At that point, I may give her a supplementary anti-VEGF injection, and I don't feel that I've done her a disservice.

“At the same time, in the case of a BRVO I would also be very likely to give her a laser treatment to try to consolidate the gains that we've gotten to that point. So I would be looking more at combined treatment. I have a preference not to do laser right up front, but to defer it until after the patient has been pharmacologically treated, the retina is a little thinner, and hemorrhages have cleared.”

Julia A. Haller, MD

“ I typically use anti-VEGF treatment first because of the side effects profile, and the promising efficacy outcomes demonstrated in the phase 3 trials, and then depending on how the patient responds, I may add laser or steroids. Laser is often added in an attempt to increase durability of effect, and steroids to increase efficacy (in patients who demonstrate a suboptimal anti-VEGF effect). If I use steroids, I always bring back the patient in a month because I am concerned about pressure spikes, especially in some elderly patients who may have impaired outflow. By using steroids, there really isn't a decrease in the clinic burden and the family burden.”

Jeffrey S. Heier, MD

“I use quite a bit of combination therapy. If it looks like the patient needs multiple anti-VEGF injections – or in particular if there are areas of large laser capillary non-perfusion or leaking microaneurysms – I'll use the laser approximately a week after an anti-VEGF injection. This allows me to use less intense laser with a more focused beam. In terms of steroids, I generally only consider them in a vitrectomized patient or in uveitis.”

David M. Brown, MD

CASE STUDIES
This section of the monograph focuses on case studies and commentary that may further help guide the reader when managing his or her own patients with retinal vein occlusion.

BRVO Case
A 53-year-old female patient was referred to the retina specialist's office. She had a 6-week history of acute vision loss in the left eye due to branch retinal vein occlusion. The specialist evaluated her, including using fundus photography and OCT images. He confirmed the diagnosis and then considered how to treat the patient.

“If a patient presents with an acute branch retinal vein occlusion with decreased vision that is attributable to macular edema, it is reasonable to defer treatment if the patient is functioning at an acceptable level since the vision may improve spontaneously, for example as intraretinal hemorrhage clears. If the decreased vision persists, or if the patient is not functioning at an acceptable level, and the decreased vision is attributable to macular edema, treatment options that may be considered include observation, grid photocoagulation (if dense macular hemorrhage is not present), intravitreal steroid, and intravitreal anti-VEGF therapy.”

Ingrid U. Scott, MD, MPH

“It is important for the clinician to determine how much the BRVO is affecting this patient's life. A lot of patients with this condition are young. They need to work. They need to drive their cars. So factors like these must be taken into account.

“I tell patients that we have treatments that can make them better quickly; however, they may improve on their own with only observation. If a patient tells me, ‘Doc, I am doing just fine; I can live with this for a while' – I will watch her, no matter what her level of visual acuity or retinal thickness, because even poor visual acuity in macular edema can improve. So if it involves a non-dominant eye and she is functioning fine, I will give her some time. But if the patient tells me, ‘I cannot work with my vision like it is,' then I'm going to give her an anti-VEGF injection within a week or so.”

David M. Brown, MD

“In BRVO in particular, when the macula is full of blood, I won't necessarily treat the first time I see a patient. I may recommend deferring treatment because there is an occlusional component there that may resolve spontaneously as the blood goes away. But I do discuss all treatment options with the patient, whether it is laser versus anti-VEGF versus steroids.”

Baruch D. Kuppermann, MD, PhD

In both trials and clinical practice, there is a clinical impression that the use of anti-VEGF and/or steroid therapy tends to make intraretinal hemorrhages disappear more quickly than other approaches. Ongoing subgroup analyses of existing study data are expected to show how significant this effect on hemorrhages can be. There is no clear mechanism to explain how the pharmacological therapy may cause this positive effect on hemorrhaging, nor is it clear whether the resolution of macular hemorrhages contributes to improvements in visual acuity, but it is very likely that it does.

“I agree completely that if BRVO is affecting the patient's daily life, then I offer him treatment. When I have a patient with focal edema that I see on fluorescein angiography, I always try the laser. If it works, we are done.

“My experience is that patients with focal edema tend to be very different than those who present with diffuse edema. Usually, patients with diffuse edema also have lots of hemorrhage, and laser is

Jeffrey S. Heier, MD

Combination therapy may also play more of a role in the future.

“I continue to be interested in analyzing these data sets to help us understand how we can predict who is going to do better with one treatment versus another. Based on this information, we can prospectively design a more customized approach. Down the road, I believe we can characterize patients in much more sophisticated ways. So we can expect a lot of exciting developments in the future.”

Julia A. Haller, MD