Treatment of Retinal Vein Occlusion
The second of two parts
HUSSEIN ALMUHTASEB, MD, MSc, FEBO • ANDREW LOTERY, MD, FRCOphth
In the last issue of Retinal Physician, we discussed the evidence for treatment of retinal vein occlusion with anti-VEGF drugs (bevacizumab [Avastin, Genentech, South San Francisco, CA] and ranibizumab [Lucentis, Genentech]). For an overview of the treatment paradigms for different types of RVO, see Figures 1 and 2 (pages 30 and 31).
Figure 1. History of BRVO trials.
Figure 2. History of CRVO trials.
In the second part of our review, we continue our update on the data for the use of anti-VEGF agents with specific emphasis on the use of aflibercept (Eylea, Regeneron, Tarrytown, NY). In addition, we discuss which anti-VEGF agent to start therapy with, when to switch between agents, and whether combination therapy of anti-VEGF agents with steroids is justified.
AFLIBERCEPT IN BRVO
Aflibercept is a recombinant fusion protein consisting of VEGF-binding receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. In 2015, a multicenter, randomized trial called VIBRANT evaluated intravitreal aflibercept for branch RVO-associated macular edema (ME) (Table 1).1,2 Unlike BRAVO, which compared ranibizumab treatment with sham, this study directly compared aflibercept treatment with grid-pattern laser photocoagulation. A total of 183 eyes with BRVO or hemiretinal vein occlusion and best-corrected visual acuity between 20/40 and 20/320 were randomized to either 2-mg-monthly intravitreal aflibercept injections with sham grid-pattern laser at baseline or grid-pattern laser. Interestingly, laser was instituted at baseline, instead of after three months of observation as in the Branch Vein Occlusion Study or the BRAVO rescue protocol. Both groups were eligible to receive laser as rescue therapy at certain time points; however, the laser group was not eligible for anti-VEGF rescue treatment. At week 24, 52.7% of eyes gained 15 or more letters in the aflibercept group vs 26.7% in the laser group. Mean ETDRS letter improvement score was 17.0 in the aflibercept group vs 6.9 in the laser group at 24 weeks.2 (Text in quotations excerpted from Oellers et al. Role of aflibercept for macular edema following branch retinal vein occlusion: comparison of clinical trials. Clin Ophthalmol. 2016;10:411–418.)
|STUDY||DRUG||CONTROL||NUMBER OF EYES||DURATION||MEAN # OF INJECTIONS||CHANGE IN BCVA (MEAN NUMBER OF LETTERS)||% OF EYES GAINING ≥15 LETTERS|
|SCORE-BRVO||Triamcinolone, 1 mg and 4 mg||Grid-pattern laser||411||12 months||1 mg||4 mg||Grid-pattern laser applications||1 mg||4 mg||Grid||1 mg||4 mg||Grid|
|GENEVA-BRVO||Dexamethasone implant, 0.35 mg and 0.7 mg||Sham, 0.7-mg implant at 6 months||830||12 months||0.7 mg||0.35 mg||Sham||0.7 mg/0.7 mg||Sham/0.7 mg||0.7 mg||0.35 mg||Sham|
|1.86||1.85||0.83||~+6||~+6||23% (6 months)||21% (6 months)||20% (6 months)|
|BRAVO||Ranibizumab, 0.3 mg and 0.5 mg||Sham (PRN 0.5 mg ranibizumab for all after 6 months, rescue grid ≥3 months)||397||12 months||0.3 mg||0.5 mg||Sham||0.3 mg||0.5 mg||Sham||0.3 mg||0.5 mg||Sham|
|HORIZON-BRAVO||Ranibizumab, 0.3 mg and 0.5 mg||Sham, followed by 0.5 mg PRN, grid-pattern laser||205||24 months||0.3 mg||0.5 mg||Sham||0.3 mg||0.5 mg||Sham||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg|
|RETAIN-BRVO||Ranibizumab, 0.5 mg||-||34||49 months||2.6 (year 2), 2.1 (year 3), and 2.0 (year 4)||20.1||62%; 71.3% ≥20/40|
|SHORE-BRVO||Ranibizumab, 0.5 mg PRN vs monthly (months 7-15)||-||115||15 months||Monthly||PRN||Monthly||PRN||Monthly (both CRVO and BRVO)||PRN (both CRVO and BRVO)|
|VIBRANT||Aflibercept, 2 mg||Grid-pattern laser/aflibercept (post week 24)||183||12 months||Aflibercept||Grid-pattern laser||Aflibercept||Grid-pattern laser/aflibecept||Aflibercept||Grid-pattern laser/aflibercept|
|8.7||No injections before week 24||17.1||12.2||57%||41%|
|Brighter||Ranibizumab, 0.5 mg stabilization criteria-driven PRN with/without laser||Laser||455||24 months (results at month 6)||Ranibizumab||Ranibizumab + laser||Laser||Ranibizumab||Ranibizumab + laser||Laser||Ranibizumab||Ranibizumab + laser||Laser|
|Laser in Brighter||N/A||0.8||1.2|
|MARVEL||Bevacizumab||Ranibizumab, 0.5 mg||75||6 months||3||3.2||15.6||18.1||57.80%||59.40%|
|THESE VALUES ARE NOT DIRECTLY COMPARABLE BECAUSE STUDY POPULATIONS VARIED DUE TO DIFFERENT ENTRY CRITERIA AND INDIVIDUAL STUDY DURATION; BCVA = BEST-CORRECTED VISUAL ACUITY|
The study found a significantly greater proportion of eyes with perfused retina at six months in the aflibercept group compared with the laser group, whereas both groups had comparable baseline perfusion status. In terms of serious adverse events, three eyes in the laser group developed retinal neovascularization, but none did in the aflibercept group.2
No systemic vascular adverse events were reported in the aflibercept group. The study concluded that intravitreal aflibercept is an effective treatment for BRVO-associated ME. Contrary to BRAVO, which continued to treat patients on a PRN basis after six months, VIBRANT treated patients every eight weeks going forward until month 12.
In the aflibercept group, eyes received aflibercept every four weeks through week 24 and every eight weeks through week 48 with rescue grid laser if needed at week 36. In the grid laser group, all of the eyes received grid laser at baseline and, if prespecified rescue criteria were met, one additional laser treatment from week 12 to 20 and aflibercept every eight weeks after three monthly doses from week 24 onward (the laser/aflibercept group).3
After six monthly injections, aflibercept every eight weeks maintained control of ME and visual benefits through week 52. In the laser group, rescue aflibercept given from week 24 onward resulted in substantial visual improvements at week 52.3
AFLIBERCEPT IN CRVO
Two parallel, randomized, multicenter, double-masked, phase 3 trials, COPERNICUS and GALILEO, evaluated the efficacy and safety of 2 mg of aflibercept for the treatment of ME secondary to CRVO,4-7 and the results prompted the drug’s approval by the FDA for treatment of CRVO in 2012.
The CRUISE, HORIZON, COPERNICUS, and GALILEO studies demonstrated that long-term anti-VEGF treatment is necessary to control ME in many eyes with CRVO, likely because continued ischemia leads to persistently elevated VEGF production (Table 2, next page).8
|STUDY||DRUG||CONTROL||NUMBER OF EYES||DURATION||MEAN # INJECTIONS||CHANGE IN BCVA (MEAN NUMBER OF LETTERS)*||% OF EYES GAINING ≥15 LETTERS*|
|SCORE-CRVO||Triamcinolone, 1 mg and 4 mg||Observation||271||12 months||1 mg||4 mg||Observation||1 mg||4 mg||Observation||1 mg||4 mg||Observation|
|GENEVA-CRVO||Dexamethasone implant, 0.35 mg and 0.7 mg||Sham, 0.7 mg implant at 6 months||437||12 months||0.7 mg||0.35 mg||Sham||0.7 mg/0.7 mg||Sham/0.7 mg||0.7 mg||0.35 mg||Sham|
|1.86||1.85||0.83||2||-1||18% (6 months)||17% (6 months)||12% (6 months)|
|CRUISE||Ranibizumab, 0.3 mg and 0.5 mg||Sham, PRN 0.5 mg ranibizumab after week 24||392||12 months||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg||0.3/0.5 mg||0.5/0.5 mg||Sham/0.5 mg|
|HORIZON-CRUISE||Ranibizumab, 0.5 mg (months 12-24)||Sham||304||24 months||3.8||3.5||2.9||12||8.2||7.6||38.60%||45.10%||38.30%|
|RETAIN-CRVO||Ranibizumab, 0.5 mg||-||32||49.7 months||4.5 (year 2), 3.6 (year 3), and 3.3 (year 4)||12.6||≥20/40; 64.3% (no edema), 27.8% (persistent edema)|
|SHORE-CRVO||Ranibizumab, 0.5 mg PRN vs monthly (months 7-15)||-||87||15 months||Monthly||PRN||Monthly||PRN||Monthly (both CRVO/BRVO)||PRN (both CRVO/BRVO)|
|COPERNICUS||Aflibercept, 2 mg||Sham, PRN aflibercept after week 24||189||12 months||2 mg||Sham||2 mg||Sham||2 mg||Sham|
|Crystal||Ranibizumab, 0.5 mg stabilization criteria-driven||Single arm||357||24 months (results at month 12)||0.5 mg 8.1||Single arm||12.3||Single arm||49.20%||Single arm|
|VALUES ARE NOT DIRECTLY COMPARABLE BECAUSE STUDY POPULATIONS VARIED DUE TO DIFFERENT ENTRY CRITERIA AND INDIVIDUAL STUDY DURATION; BCVA = BEST-CORRECTED VISUAL ACUITY|
In the COPERNICUS and GALILEO trials, there was a significantly greater reduction in central retinal thickness (CRT) at six months in the aflibercept group than in the sham group. However, this difference was maintained over time only in the GALILEO trial, in which patients continued their assigned treatments for up to 12 months.
In the COPERNICUS trial, patients in the sham group also received aflibercept during the extension period, which caused a similar decrease in CRT as in the original intervention group. Aflibercept did not appear to increase the incidence of ocular or nonocular adverse events compared with sham in either trial.
The COPERNICUS year 2 results demonstrated that the visual and anatomic improvements decreased after changing from fixed to PRN dosing, and they declined further when the monthly monitoring frequency was decreased to quarterly.
These outcomes suggest that a PRN dosing regimen with at least quarterly evaluations and the treatment of edema only after it has recurred may not be sufficient, at least for some patients, to maintain the improvements gained after a fixed monthly dosing treatment regimen. PRN dosing may lead to fewer injections than a fixed monthly regimen, but it should come with the requirement of monthly visits.8
Given that, outside a clinical study setting, a close monitoring schedule might be impractical, a treat-and-extend regimen or a fixed-dosing regimen of aflibercept every two months, after an initial period of monthly doses, could be a viable treatment option to reduce the monitoring burden.9
FURTHER TREATMENT CONCERNS
Having summarized the available evidence of the use of the different anti-VEGF agents for the treatment of RVO, we attempt here to shed some light on some debatable issues, such as which anti-VEGF agent to start with, when to switch between agents, and whether there is space for combination therapy of anti-VEGF with steroids.
Which Drug and at What Frequency?
Several codes must be deciphered to refine patient care further in the real world.
Several questions remain to be answered:
1. With which anti-VEGF should we start?
2. What treatment frequency to implement (monthly, PRN, treat and extend)?
3. Is combined treatment useful (anti-VEGF and steroids/laser)?
4. When should we switch between anti-VEGFs or to switch to steroids?
To our knowledge, there have not yet been any direct head-to-head studies of ranibizumab and aflibercept undertaken in BRVO at this time. In BRAVO, 61% of subjects gained ≥15 letters (0.5-mg group), compared with 57% in VIBRANT (week 52). Mean letter gains were 18 in BRAVO vs 17 in VIBRANT.3,13 A recent meta-analysis concluded equivalent efficacy of both drugs based on the available studies.9
However, nonequivalent endpoints (BRAVO’s primary endpoint was mean change in BCVA, whereas VIBRANT’s was the proportion of eyes improving by 15 or more letters), as well as different inclusion and exclusion criteria, make this comparison challenging.2
Because bevacizumab use is not FDA-approved, its usage in BRVO patients remains off-label. The MARVEL study failed to demonstrate noninferiority to ranibizumab. In our opinion, there is currently insufficient evidence to conclude whether one of these anti-VEGF agents is more effective in BRVO.
Other factors are therefore likely to drive current drug selection, such as which drug is reimbursed. The LEAVO study will provide randomized clinical trial evidence on the effectiveness of these three medications in CRVO patients.
In a study that examined the patterns of ranibizumab and aflibercept treatment of CRVO in routine clinical practice in the United States,14 Lotery and Regnier concluded that, in routine clinical practice, patients should receive a comparable number of injections in the first year of treatment with ranibizumab or aflibercept. This paradigm may have implications for commissioning and service development of CRVO care pathways.
PROACTIVE VS REACTIVE
Both the HORIZON and SHORE studies showed that a monthly PRN regimen could have equivalent visual and anatomical outcomes in patients previously treated with monthly injections. However, both a monthly fixed regimen and a monthly PRN regimen were associated with significant healthcare burden.2
Treat and extend is a treatment pattern in which the clinician can still be proactive in his/her regimen. This treatment protocol has been gaining popularity due to its simplicity and postulated effectiveness, compared to other reactive treatment options.
However, to date there have been only limited clinical trials fully evaluating its presumed benefits. In one noncontrolled study,15 treat-and-extend was suggested to be a reasonable regimen with the advantage of reducing the clinical burden in terms of office visits.
A ROLE FOR COMBINATION THERAPY IN RECALCITRANT ME
To our knowledge, no studies have examined the efficacy of anti-VEGF medication alone vs anti-VEGF medication plus grid-pattern-laser photocoagulation. However, a randomized, controlled trial demonstrated the superiority of intravitreal ranibizumab compared with grid-pattern laser for eyes with BRVO.16
In both the BRAVO and VIBRANT studies, rescue laser was allowed in their respective anti-VEGF groups (Table 1). Rescue laser was performed in 19% (0.3 mg) and 20% (0.5 mg) in the ranibizumab groups of the BRAVO study. In VIBRANT, laser was not needed in any of the recruited eyes during the first six months. However, in the aflibercept group, 10.6% of eyes received rescue laser at week 36, and in the laser/aflibercept group, 80.7% received rescue intravitreal injections from week 24 to week 48.3
However, a recent study did not show a reduced anti-VEGF treatment burden secondary to scatter laser photocoagulation to nonperfused areas identified by a wide-angle fluorescein angiography in eyes treated with intravitreal ranibizumab given on a monthly PRN basis.17
Two prospective trials evaluating steroids — SCORE and GENEVA — demonstrated similar visual outcomes in the treatment groups, compared with their respective control groups. Interestingly, the GENEVA study demonstrated faster visual recovery in long-term-release dexamethasone-implanted (Ozurdex, Allergan, Irvine, CA) eyes, compared with sham (Table 1).
No clinical trials have studied the effects of combination therapy of intravitreal triamcinolone acetonide (IVTA) or dexamethasone and anti-VEGF medications. More evidence is needed to evaluate the efficacy of combined treatment. However, combination therapy may be reasonable for patients with recalcitrant edema despite frequent anti-VEGF therapy.
Bressler and Schachat proposed that comparing common clinical endpoints, such as percentages of eyes losing or gaining 3 lines of vision at the clinically relevant endpoint, would be useful for comparisons among trials.18 For example, while 56% of aflibercept-treated CRVO eyes gained ≥15 letters at six months in the COPERNICUS trial (vs 12% sham), 48% of ranibizumab eyes at six months in the CRUISE trial (vs 17% sham), 29% following dexamethasone implantation at 30 days in the GENEVA trial (vs 11% sham), and 27% of IVTA-treated patients at one year in the SCORE trial (vs 7% sham) gained ≥15 letters. However, it is critical to recognize that examining the data in this manner does not account for true intertrial comparisons because these trials lacked uniformity in multiple aspects.8
A meta-analysis comparing aflibercept, bevacizumab, dexamethasone, ranibizumab, and triamcinolone for the treatment of ME secondary to CRVO found no differences among ranibizumab, aflibercept, bevacizumab, and triamcinolone for improving vision, but it did find that dexamethasone was not as effective as ranibizumab or aflibercept.19
Switching to steroids. Anti-VEGF agents are the preferred first-line drugs due to their efficacy and side effect profiles. Steroids can be used as a second-line drug in resistant cases or as an adjunct from the start.20
A retrospective study by Sharareh et al21 examined 18 patients categorized as complete or partial responders to bevacizumab who were given dexamethasone implants. The study showed that both subgroups responded with improvements in both central macular thickness (CMT) (average 147 μm) and VA (mean improvement of 0.25 logMAR).
The OMAR study evaluated the effects of the dexamethasone implant and triamcinolone in cases of refractory cystoid ME despite repeated bevacizumab therapy due to RVO.22 It showed that adding steroids improved CMT significantly (P<.0001), although final BCVA did not change significantly after steroid introduction (P=.06). There was no difference between triamcinolone and dexamethasone regarding anatomic or functional outcomes.
As an adjunct, a case series by Singer et al23 showed that a dexamethasone implant with bevacizumab showed a synergistic effect in CRVO and BRVO patients, increasing VA and prolonging the time between injections, compared with either of these medications alone. In addition, ~55% of patients had a maximum VA gain of 3 letters with a mean increase of 3.4 lines, and 18% of patients did not require reinjection.
Another study by Maturi et al24 compared patients who received bevacizumab alone and patients who received combination therapy with dexamethasone implants; and at six months, there was a greater reduction in mean CMT in the combined group compared with the monotherapy group, despite no significant differences in VA.
These data show that dexamethasone implants and, to a lesser extent, triamcinolone can be suitable options in resistant cases, either as monotherapy or an adjunct to bevacizumab or ranibizumab.20
Switching between anti-VEGFs. A single case series examined the benefit of switching to ranibizumab in cases resistant to bevacizumab and showed that there was an improvement in both VA and anatomy in these patients.25
A larger study published by Papakostas et al included 42 patients with CRVO nonresponsive to bevacizumab/ranibizumab who were switched to aflibercept.26 The median number of injections prior to the switch was seven, and the group included 70% who were partially responsive and 9.5% who were nonresponsive to bevacizumab and/or ranibizumab.
Post-switch VA improved at one month but was no longer statistically significant at the end of follow-up. However, anatomically, there was a significant and sustained improvement from median CRT of 536 to 279 μm at the end of follow-up (P=.0013). Interestingly, the median interval between injections increased from 5.6 weeks to 7.6 weeks (P<.0001).
The retina community is fortunate to have a broad range of treatment options in its arsenal for patients with loss of vision secondary to ME due to RVO. Beyond treating the eye, it is also important to treat the whole patient. Therefore, identifying and treating any systemic medical problems (hypertension, hyperlipidemia, or other multiple hypercoagulable states) to reduce further complications is important.
Anti-VEGF drugs have revolutionized the management of this blinding condition. At the moment, both ranibizumab and aflibercept used early are effective treatment options. It is imperative that patients be initiated on treatment as soon as the diagnosis is established.
Most participants in the CRUISE trial (71.2%) had a duration of ME of less than three months, and approximately 55% of participants in the aflibercept trials (COPERNICUS and GALILEO) had less than a two-month duration.
Subgroup analysis of all of the anti-VEGF trials to date indicates that the visual outcome is best in participants with a shorter duration of ME. It is therefore essential that patients be referred and treated promptly.
In the COPERNICUS and GALILEO trials, perfusion improved with aflibercept yet worsened with sham. In the aflibercept group, 68% of patients were perfused at baseline (fewer than 10 disc areas of nonperfusion) vs 79% at week 24.4,5
In the six-month results of BRIGHTER study (ranibizumab for BRVO), the exploratory analysis showed similar BCVA gains between patients with macular ischemia (Central Reading Center [CRC]-assessed) and patients without macular ischemia,11 suggesting that better VA gains may be obtained at six months with early treatment initiation, irrespective of the baseline BCVA scores.
In the CRYSTAL study (12-month results), ranibizumab treatment resulted in significant BCVA gains in a broad population of patients with ME secondary to CRVO, including those with macular ischemia at baseline.12
Although the noninferiority of bevacizumab to other anti-VEGF agents is still to be established, its safety and efficacy have been studied both in short retrospective case series and in head-to-head clinical trials. A recent editorial in the British Medical Journal highlighted the challenges of governments supporting off-label use of bevacizumab.27
The combination of anti-VEGF drugs with steroids or laser may be a reasonable option for eyes with recalcitrant edema despite frequent anti-VEGF injections, but further study is needed on how to best manage these patients.
In summary, the outlook for patients with RVO has vastly improved due to the implementation of anti-VEGF therapies. Prompt commencement of therapy yields the best outcomes. RP
Hussein Almuhtaseb, MD, MSc, FEBO, and Andrew Lotery, MD, FRCOphth, serve on the faculty of the University Hospital Southampton of the National Health Service of the United Kingdom. Neither author reports any financial interests in products mentioned in this article. Dr. Lotery can be reached via e-mail at firstname.lastname@example.org.
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2. Oellers P, Grewal DS, Fekrat A. Role of aflibercept for macular edema following branch retinal vein occlusion: comparison of clinical trials. Clin Ophthalmol. 2016;10:411-418.
3. Clark WL, Boyer DS, Heier JS, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: 52-week results of the VIBRANT study. Ophthalmology. 2016;123:330-336.
4. 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.
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22. Ozkok A, Saleh OA, Sigford DK, Heroman JW, Schaal S. The OMAR study: Comparison of Ozurdex and triamcinolone acetonide for refractory cystoid macular edema in retinal vein occlusion. Retina. 2015;35:1393-1400.
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25. Hanhart J, Chowers I. Evaluation of the response to ranibizumab therapy following bevacizumab treatment failure in eyes with diabetic macular edema. Case Rep Ophthalmol. 2015;6:44-50.
26. Papakostas TD, Lim L, van Zyl T, et al. Intravitreal aflibercept for macular oedema secondary to central retinal vein occlusion in patients with prior treatment with bevacizumab or ranibizumab. Eye (Lond). 2016;30:79-84.
27. Lotery A, MacEwen C. What is stopping the NHS from using bevacizumab for macular degeneration and other retinal disorders? BMJ. 2014;349:6887.