CONTROVERSIES IN CARE
Anti-VEGF Dosing Strategies For Macular Edema due to RVO
EDITED BY MICHAEL COLUCCIELLO, MD
The number of pharmacological alternatives for treating macular edema in retinal venous occlusive disease more efficaciously than laser photocoagulation continues to increase. We now have the ability to significantly improve VA in 50% to 60% of RVO patients with macular edema, perhaps even at a higher rate earlier in the disease course.
The intravitreal pharmacological options retinal physicians use most are the anti-VEGF drugs. These agents are quite successful in resolving macular edema due to RVO, but the vast majority of patients must receive repeated dosing to maintain remission.
As a result, the common, often daily, concern a retinal physician encounters is to formulate a strategy for a given RVO patient: When to administer the next dose to prevent the patient’s exposure to potential irreversible cellular damage from recurrent macular edema, while maximizing treatment efficiency and reducing treatment burden and inconvenience for the patient and his or her family?
The Role of Clinical Trials
Evidence-based medicine is important in obtaining outcomes for our patients that replicate the good results in the studies that led to the FDA approval of a given therapy.
The studies and subsequent approval do not mandate the dosing schedule, however; a physician in clinical practice may make adjustments to fashion treatment for any specific individual situation.
Two anti-VEGF agents, ranibizumab (Lucentis, Genentech, South San Francisco, CA) and aflibercept (Eylea, Regeneron, Tarrytown, NY), have undergone large, randomized, controlled clinical trials to determine efficacy in macular edema due to RVO. Two clinical trials evaluated the efficacy of ranibizumab in RVO: BRAVO for branch RVO and CRUISE for central RVO; two clinical trials have evaluated the efficacy of aflibercept for the treatment of macular edema in central RVO: COPERNICUS and GALILEO.
These studies have demonstrated the effectiveness of the anti-VEGF agents when given monthly for six consecutive months. At six months, the percentage of patients gaining 15 or more letters was 55% in BRAVO,1 46% in CRUISE,2 56% in COPERNICUS,3 and 60% in GALILEO4 (vs 12% to 28% of sham groups in each study).
Eighty percent of the vision gains at the one-year mark of the BRAVO and CRUISE occurred by the third or fourth injection.5 This fact could be used as a basis upon which to formulate a treatment plan for a given patient.
How do we replicate these results in real life? How do we reduce the treatment burden for patients needing therapy, potentially for years, while maintaining effectiveness?
We are fortunate this month to have Michael Stewart, MD, and Robert Johnson, MD, provide answers to these questions.
BRVO and CRVO Are Different
ROBERT JOHNSON, MD
As retina specialists, we are fortunate to have excellent treatment options available for our patients with RVO. Results of randomized phase 3 trials of ranibizumab (CRUISE) and aflibercept (COPERNICUS and GALILEO) have shown excellent efficacy for the treatment of CRVO.1-4 Moreover, the FDA has approved ranibizumab for the treatment of BRVO.5
However, while these trials have provided invaluable information, they also leave practitioners with unanswered questions. Should we treat all patients exactly as in these trials? What about patients that don’t meet the eligibility criteria the trials set forth — for example, those patients that might initially have better vision (>20/40) than enrolled in the trials?
A careful review of the clinical data, together with practical experience, can serve as a guide for establishing a treatment strategy for these patients. In doing so, we need to bear in mind that the natural history of CRVO differs from BRVO, with the latter usually having a far more favorable prognosis.
While the inclusion criteria and primary study endpoints differed in the CRVO treatment trials, they did enroll patients with VA between 20/40 and 20/320 and central foveal thickness >250 μm. These patients received six sequential monthly intravitreal injections of either ranibizumab or aflibercept. Similar vision and OCT inclusion criteria applied for the BRVO ranibizumab treatment trial.5
We can glean some helpful facts from these trials:
• Patients with a shorter period of symptomatic vision loss showed the highest percentage of vision gain of 15 or more letters.
• Patients in the control group who did not receive treatment during the first six months never achieved the same VA gains after switching to active treatment.
• Most patients required additional treatment following six monthly injections.
• The COPERNICUS trial showed somewhat increased central foveal thickness at 12 months (after six months of PRN treatment) than at six months.
• In the CRUISE and COPERNICUS trials, on average, VA gains dropped slightly during the PRN arm but returned to the gains achieved prior to switching to PRN dosing.
Recently, my colleagues and I presented the preliminary results of the SHORE study at the Macula Society Meeting.6 This uniquely configured study addressed the question of efficacy of ranibizumab treatment monthly, compared with as-needed dosing, after a minimum of seven monthly injections in RVO patients.
A key component in this study was that we randomized the patients from month seven to month 15 to either monthly injections or as-needed treatment after achieving a stable disease state, based on visual acuity and OCT criteria.
This study showed that similar treatment results were possible with close follow-up and as-needed treatment as possible with ongoing monthly injections. These data are reassuring to those practitioners like me, who want to reduce safely the treatment burden on our patients as much possible.
Prior to switching to a PRN dosing regimen, however, we should attempt to achieve stable VA and resolution of macular edema. While the latter is not always possible, my own experience indicates that withdrawing treatment too early typically results in rebound of macular edema and reduced vision. In very resistant cases, I do consider other classes of drugs, particularly in pseudophakic eyes without glaucoma.
RVO But Good Visual Acuity
Another situation that practitioners face is how best to treat those RVO patients with very good vision, such as better than 20/40. Because these patients were not included in these trials, we don’t have scientific evidence as to the merits of recommending treatment.
In my own practice, for those patients with a small BRVO and minimal impact on the central fovea, I believe that a short period of observation is very reasonable. If the vision decreases, or the macular edema increases, both the patient and I feel better about committing to what might be a lengthy treatment course.
In contrast, because the natural history of CRVO is not as favorable, I tend to treat earlier in these patients.
1. Campochiaro PA, Brown DM, Awh CC et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: Twelve-month outcomes of a phase III study. Ophthalmology. 2011;118:2041-2049.
2. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor trap-eye for macular edema secondary to central retinal vein occlusion. Six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119:1024- 1032.
3. Holz, F. G., Roider, J., Ogura, Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97:278-284.
4. Brown DM, Heier, JS, Clark W, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS Study. Am J Ophthalmol. 2013;155:429-437.
5. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118:1594-1602.
6. Johnson RN, Yau L, Sternberg G. Effect of alternate ranibizumab dosing regimens on visual and anatomic outcomes in patients with retinal vein occlusion: The SHORE study. Paper presented at: Macula Society annual meeting; Dana Point, CA; March 1, 2013.
Evidence-based Treatment for RVO
MICHAEL W. STEWART, MD
The BRAVO1 and CRUISE2 trials established that grid pattern laser photocoagulation for macular edema due to BRVO is of modest benefit, but that the treatment has no place in the management of CRVO.
Since the publication of these trials, extensive research has shown that upregulation of VEGF is an important driver of blood-retinal barrier breakdown in patients with RVO.3
Rosenfeld et al first showed that VEGF blockade could benefit eyes with CRVO.4 Subsequent trials have produced level II evidence that bevacizumab improves macular edema and VA in patients with RVO5 and level I evidence supporting the use of ranibizumab6 and aflibercept.7,8
Unfortunately, CATT-like trials directly comparing the three drugs have not been performed. Although bevacizumab (Avastin, Genentech) benefits many RVO patients, many surgeons believe that the higher-affinity drugs more effectively dry the macula and restore vision.
Figure. Fundus photo shows cystoid macular edema secondary to branch RVO.
My Treatment Approach
My initial approach to RVO includes performing fluorescein angiography to assess retinal perfusion. Ischemic CRVO does not preclude anti-VEGF therapy: The COPERNICUS trial showed that even eyes with relative afferent pupillary defects and >10 disc areas of nonperfusion may benefit from anti-VEGF therapy7 — but the degree of retinal perfusion enables me to formulate a better prognosis and encourages me to carefully watch for iris neovascularization, particularly if anti-VEGF therapy is discontinued.
For years, I primarily used bevacizumab, but I recently switched many of my RVO patients to aflibercept. I generally use a treat-and-extend strategy for RVOs — although, admittedly, this drug has not been proven in prospective RVO trials — and I extend slowly, by no more than by one week every visit to err on the side of “overtreatment.”
I believe this is of particular importance because the phase 3 trials (COPERNICUS, GALILEO, CRUISE/HORIZON)9-11 all showed increasing macular thickness and decreasing VA when patients underwent examinations less frequently (every two to three months) and received treatment PRN. The injection frequency in eyes with DME may drop after the first year, but discontinuing anti-VEGF therapy in eyes with RVOs is particularly difficult, and treatment often continues for years.
When Anti-VEGF Fails
Rapid resolution of macular edema is important for optimal visual recovery in eyes with RVO, so if eyes respond inadequately to the first three injections, I will readily switch to a higher–binding affinity drug (aflibercept > ranibizumab > bevacizumab).
Alternatively, increasingly the frequency of injections to every two weeks with bevacizumab or with bevacizumab alternating with ranibizumab or aflibercept is an effective strategy for RVOs, AMD, and DME.12
Finally, if anti-VEGF injections fail, switching to an intraocular corticosteroid — triamcinolone injections or dexamethasone inserts (Ozurdex, Allergan, Irvine, CA) — may be an effective second-line therapy.
Poorly responding eyes often have peripheral retinal nonperfusion and may be considered for scatter laser photocoagulation. Some eyes with BRVO, particularly those that tend to develop areas of extrafoveal edema, may benefit from partial grid laser photocoagulation to reduce the treatment burden.RP
1. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271-282.
2. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102:1425-1433.
3. Aiello LP, Avery RI, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.
4. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36:336-339.
5. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol. 2009;93:452-456.
6. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118:2041-2049.
7. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155:429-437.
8. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97:278- 284.
9. Clark WL. Two-year results of the COPERNICUS study evaluation intravitreal aflibercept injection (IAI) for macular edema secondary to central retinal vein occlusion (CRVO). Invest Ophthalmol Vis Sci. 2013;54:ARVO E-Abstract 4514.
10. Ogura Y, Korobelnik J-F, Roider J, et al. Eighteen-month results f the GALILEO study evaluating intravitreal aflibercept injection (IAI) for macular edema secondary to central retinal vein occlusion (CRVO). Invest Ophthalmol Vis Sci. 2013;54:ARVO E-Abstract 4516.
11. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119:802-809.
12. Stewart MW, Rosenfeld PJ, Pehha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab and aflibercept (vascular endothelial growth factor Trap-eye). Retina. 2012;32:434-457.
Michael Colucciello, MD, is a partner at South Jersey Eye Physicians and a clinical associate at the University of Pennsylvania/Scheie Eye Institute, Philadelphia. He is a member of the Retina Society and the American Society of Retina Specialists. He has no financial disclosures to report. Dr. Colucciello can be reached via e-mail at firstname.lastname@example.org.
Michael W. Stewart, MD, is associate professor and chair man of ophthalmology at the Mayo Clinic Florida in Jacksonville. He has no financial disclosures to report.
Robert Johnson, MD, practices with West Coast Retina and is assistant clinical professor of ophthalmology at the University of California, San Francisco. He has no financial disclosures to report.