Great Debates in RVO Therapy
An anti-VEGF and steroid gain FDA sanction, but many clinical questions remain.
FRANK CELIA, CONTRIBUTING EDITOR
Even before the recent FDA approval of rani bizumab's new indication for edema secondary to retinal vein occlusion, three other developments had already altered and vastly improved the standard of care for this common clinical scenario. First came the June 2009 FDA green light for a dexamethasone intravitreal implant (Allergan's Ozurdex). Then, later that year, two landmark studies unveiled six-month data showing ranibizumab to be both safe and effective. Finally, and perhaps most significantly, 12-month data from those studies released this spring found vision gained at six months continued largely undiminished after six months of subsequent prn dosage.1
The buoyant mood was further heightened by the discovery that those in the placebo arms of the ranibizumab studies who were switched to a therapeutic dose at six months also gained significant vision, but never quite caught up to those treated from the outset. Thus, prompt, aggressive anti-VEGF therapy appears beneficial for all patients with bilateral symptoms and signs — welcome news in a disease where, until recently, doing nothing for three months and praying for edema to resolve on its own often constituted a viable treatment strategy. A similar crossover effect appeared in the Ozurdex data, as well.
But, as always when new standards emerge, questions multiply as fast as answers. How steroids, anti-VEGF agents and laser therapy will be managed to yield optimal visual outcomes remains to be determined. Additionally, real-world factors, such as cost, insurance coverage and patient compliance, will likely play a role in determining which treatment patterns prevail. Below, experts provide their insights on several ongoing debates.
STEROIDS vs ANTI-VEGF AGENTS
From a strictly evidence-based, data-analysis perspective, anti-VEGF therapy appears to have the edge over steroids. It yields slightly better visual outcomes and its safety profile stands head and shoulders above steroids. In the aforementioned landmark studies, BRAVO and CRUISE, after six months of ranibizumab therapy, between 55% and 61% of patients with branch retinal vein occlusion (BRVO) gained at least three lines of BCVA, and about 47% of patients with central retinal vein occlusion (CRVO) gained at least three lines of BCVA.2,3
Ozurdex data found 41% of patients gained at least three lines of vision.4 However, adverse effects occurred more frequently. Twenty-five percent of patients experienced elevated IOP, 20% developed a conjunctival hemorrhage and 4% required cataract surgery.5 By contrast, among nearly 800 patients studied in the BRAVO and CRUISE trials, researchers found only one case of retinal detachment, one case of endophthalmitis and one case of vitreous hemorrhage.2,3
These results have gone a long way toward convincing many retina specialists that anti-VEGF therapy ranks as the preferred first-line therapy for RVO.
Yet, from a pragmatic standpoint, steroids retain considerable appeal, mainly due to their much easier dosing schedule. Patients with RVO tend to be younger, with more family and work obligations than age-related macular degeneration patients. The monthly hassle of intravitreal anti-VEGF injections may prove onerous to some. Also, retina specialists with a large cohort of AMD patients receiving anti-VEGF injections on a monthly or q6w schedule might lack the capacity to introduce another regimen that requires frequent injections.
Meanwhile, studies have found that 20% of Ozurdex recipients required only a single injection for an entire year.4 The implant is designed to be delivered once every six months, but that is still a great advantage over the nine or 10 injections a year necessary in ranibizumab therapy.
Much depends on the patient's needs, says Julia A. Haller, MD, Ophthalmologist-in-Chief of the Wills Eye Institute in Philadelphia and one of the investigators for both the dexamethasone implant and previous ranibizumab studies. "I would factor in a number of considerations. Can the patient can come back monthly? How does that work out with his or her life and family? Was there previous cataract surgery? A history of pressure elevation with steroids? In the case of vitrectomized eyes, the implant is emerging as the treatment of choice, since standard injectables will clear very quickly from the eye," Dr. Haller says. "But all things being equal, I would probably start off with the Ozurdex injection, knowing that, for 20% of patients in the studies, visual acuity recovered and the macula thinned to normal out to a full year with only one injection. Since every eye is different, we need to customize therapy as we follow patients along." Pressure spikes and cataract formation are concerns, she says, but so is quality of life. "I do think about [side effects] of course, but since they were almost always mild and easily managed in the thousands of patients treated to date with the dexamethasone implant, they are not generally deal-breakers," she says.
With the economic outlook still grim and millions facing long-term unemployment, financial issues continue to have an impact on patient management decisions. However, in the steroid vs anti-VEGF debate, both classes of drugs offer much cheaper off-label alternatives, alleviating these concerns to some extent. Bevacizumab and triamcinolone cost a fraction of their FDA-approved cousins, while offering similar visual outcomes and safety profiles.
However, it should be noted that triamcinolone's standing was hurt somewhat by its failure to outperform grid photocoagulation in edema associated with branch retinal vein occlusion in the SCORE Study.6 Also, the method of delivery used in the Ozurdex biodegradable implant, which is injected into the vitreous without need for surgical implantation and removal, is considered superior to triamcinolone's. "I was never a big fan of Kenalog, having seen numerous complications during my training," says Szilard Kiss, MD, director of clinical research at Weill Cornell Medical College in New York. "But I did use it. However, after the SCORE data came out and Ozurdex became available, I really see an even more limited role for intraocular triamcinolone."
Though triamcinolone and Ozurdex lack the level of parity that exists between Lucentis and Avastin, most practitioners agree that triamcinolone remains a viable option for patients with financial troubles.
Finally, laser photocoagulation still holds a place in the armamentarium, experts say, probably later in the process, perhaps as a means of decreasing the need for monthly anti-VEGF dosage. However, because lasers have not been studied as intensely as drugs, this evidence remains anecdotal. Practitioners should also be aware that Medicare's 91-day global rule applies to in-office laser procedures, so reimbursement for drug therapy three months after laser surgery could be problematic.
Clinicians are keenly interested in prospects for combination therapy. Michael Singer, MD, of San Antonio, has achieved favorable outcomes with a combination of Avastin and Ozurdex and now considers this his de facto first-line choice. In his clinic, only patients with advanced glaucoma or known steroid reactions receive Avastin monotherapy.
"I don't usually use steroids alone on anybody with vein occlusion," says Dr. Singer. "Even though I like Ozurdex and think it's a great drug, its duration of peak action is relatively limited. You only get about two months of topnotch duration."
The two drugs appear synergistic; 45% to 50% of his combination therapy patients achieve three lines or better of vision improvement, while enjoying drastically curtailed dosing schedules. He started off giving patients an anti-VEGF injection, then seeing them again at two weeks, when they received the Ozurdex implant. After following these patients monthly, he was very pleased with the results. "They're very predictable and tight. I can almost predict it to the day," he says. Potential steroid side effects still require monitoring, but the reduced dosing schedule is a worthwhile benefit.
Dr. Singer is analyzing outcomes data in a study of 40 or so combination therapy patients, which he plans to unveil at this year's ASRS meeting in late August.
AVASTIN vs LUCENTIS
How FDA approval of Lucentis for RVO will affect this ongoing contretemps remains to be seen. A Patterns and Trends survey done last year by the American Society of Retinal Specialists found that 50% of respondents favored bevacizumab over ranibizumab. But knowledgeable retina insiders call the survey conservative. Outside clinical trials, Avastin is more likely to be the choice of rank-and-file retina specialists, with the drug's far lower cost being the driving factor. While some insurers cover Lucentis, others have been reluctant to do so. Consequently, many practitioners circumvent reimbursement uncertainties by prescribing the cheaper drug.
During years of clinical trials and study, the theoretical risks associated with Avastin have not translated into statistically significant complications, and practitioners consider the drug almost as efficacious as its counterpart Lucentis. Nevertheless, worries linger that some systemic vascular or ocular side effect might yet emerge. With no immediate plans for a head-to-head comparison in RVO, practitioners eagerly await the results of the ongoing Comparison of AMD Treatments Trials: Lucentis-Avastin (CATT), due early next year.
But due to RVO's greater VEGF involvement, some call the comparison of RVO and AMD tantamount to apples and oranges. "Look at the amount of VEGF that's liberated from the retina in a retinal vein occlusion," notes Dr. Singer. "The area alone is significantly larger than in macular degeneration. I think that is where the rubber meets the road. Lucentis is a much stronger molecule, it binds a lot more free VEGF quickly, and it lasts maybe a little longer." Anecdotal evidence suggests that, for this reason, Lucentis may possess an advantage over Avastin in RVO not seen in other retinal diseases, according to Dr. Singer.
WHEN TO TREAT
A recent post on the Web site of the American Academy of Ophthalmology noted that, in a review of 12 studies, the vision of untreated BRVO patients fared poorly, with statistically significant improvement beyond 20/40 uncommon, even when macular edema resolved without treatment. "I read that and my reaction is: You can have macular edema resolving, you may not have swelling anymore, but you are still losing photoreceptors," says Dr. Singer. "Just because the retina is thin doesn't mean you will see."
He cites these data as further reason to eschew the wait-and-see approach that marked previous RVO standards of care. Because a third of BRVO cases resolve on their own, a three-month waiting period was considered prudent before deciding whether to treat, especially if the patient maintained 20/40 vision. Indeed, in central retinal vein occlusion — which makes up 20% of all RVO cases — no agreed-upon treatment existed; physicians could do little more than watch and wait.
Now, Dr. Singer seldom postpones therapy more than a month. Any worsening parameter, even 20/25 vision, establishes cause for initiation. "Treating the patients within the first three or four months really makes a big difference," Dr. Singer says. The lack of improvement seen in the "crossed-over" placebo arms in the BRAVO and CRUISE 12-month data may be due to the delay in prompt therapy, he believes.
Nevertheless, caution has its place. Endophthalmitis, retinal tears and vitreous hemorrhage are rare but do occur in anti-VEGF therapy, as do pressure spikes and cataract formation in steroid treatment. When disease affects only one eye, especially the nondominant one, and lifestyle remains undiminished, some doctors still choose to monitor patients.
Other Noteworthy Studies on RVONow that retinal specialists have two approved therapies for RVO, patient management questions will proliferate exponentially more than in the days when standard of care entailed little beyond watching patients and hoping for the best. Hence, the retina world will be closely monitoring studies now under way for guidance. Here are a few worthy of attention:
• RAVE: The landmark BRAVO and CRUISE studies excluded ischemic patients. Ischemic CRVO patients present special challenges because 70% develop rubeosis and 50% develop neovascular glaucoma. The RAVE study (Rubeosis Anti-VEGF Trial for Pre-Proliferative CRVO) aims to evaluate ranibizumab as an alternative to destroying peripheral visual fields with laser treatment. Preliminary findings show that, although many patients gained visual acuity, one-third lost the gains after anti-VEGF treatment ceased. RAVE also found 50% of these patients developed neovascularization during three years of follow up. The study is expected to conclude in 2013.
• Quality of Life: How patients tolerate the monthly hassle of anti-VEGF injections ranks high among quality-of-life concerns, especially since RVO patients tend to be younger and still in their working years. A study known as The Impact of Lucentis on Psychological Morbidity in Patients with Retinal Vein Occlusion, underway at Retina Associates of Cleveland, seeks to ap - praise the emotional well-being of subjects on such a regimen.
• FAVOR: Any steroid that can improve upon this class' existing safety profile will gain a leg up in the RVO market. FAVOR (Fluocinolone Acetonide Intravitreal Inserts for Vein Occlusion) will assess the safety and efficacy of fluocinolone, a novel steroid insert, in patients with macular edema secondary to RVO. Data collection is to conclude this fall.
• RELATE: After edema has been controlled with anti-VEGF therapy or steroids, laser photocoagulation may still be beneficial, particularly for long-term visual health. But evidence for this remains anecdotal. RELATE (Ranibizumab Dose Comparison and the Role of Laser in Retinal Vein Occlusions) hopes to shed light on this issue, in addition to comparing 0.5- and 2.0-mg doses of Lucentis.
• VEGF Trap-Eye: Might another anti-VEGF agent prove even more effective, safer or longer lasting than Lucentis and Avastin? The sustained effects of VEGF Trap-Eye, shown in various AMD trials, have researchers considering this possibility for RVO as well. Data collection in the Vascular Endothelial Growth Factor Trap-Eye: Investigation and Safety in Central Retinal Vein Occlusion study are expected to conclude by January of next year.
• CATT: Though experts say an RVO head-to-head comparison seems unlikely, all eyes will be on the results of the CATT (Comparison of AMD Treatments Trials: Lucentis-Avastin) study early next year — the thinking being that what applies to AMD might also have merit in RVO therapy. However, it bears mention that some researchers caution against equivocating AMD with RVO, arguing that the significantly higher VEGF release during RVO ultimately could give Lucentis an advantage.
In earlier models of venous occlusive disease, researchers believed that osmotic forces caused edema in cases of nonischemic RVO. Current research suggests that edema now appears to be mostly VEGF-mediated, which means all RVOs involve ischemia to some degree. Thus, rather than ischemic vs nonischemic RVO, a more accurate division might be perfused vs nonperfused.
Research also indicates that nonperfusion can occur farther out in the peripheral retina than previously thought. In fact, nonperfusion commonly occurs far outside the view of conventional angiography.
Identifying and carefully monitoring nonperfusion patients is vital; even when edema resolves, these patients remain at high risk for serious complications, most notably neovascularization. "You might be treating the patient and controlling the edema, and everything seems to be going great. So you let them go away for the summer, and they show up three months later with neovascular glaucoma," cautions Houston's David M. Brown, MD, an investigator on the ranibizumab studies. The presence of relative afferent pupillary defect, Dr. Brown suggests, is the easiest way to diagnose nonperfusion disease.
PROTOCOLS IN TRANSITION
The clinical picture described here probably won't endure long. Sustained-release anti-VEGF agents could change the outlook entirely, and the profession's nascent understanding of combination therapy will figure prominently in future studies but is as yet left to clinical judgment. What appears certain is that patients afflicted with the second leading cause of retinal vascular blindness can now rely on medical treatment instead of the crossed fingers and lucky stars with which so many in previous generations had to make do. RP
1. Ho AC, Gray S, Rundel A, et al. Ranibizumab in patients with macular edema following retinal vein occlusion: 12-month outcomes of BRAVO and CRUISE. Poster presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 6, 2010; Fort Lauderdale, FL.
2. Campochiaro PA, Heier JS, Feiner L, et al.; BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1102-1112.
3. Brown DM, Campochiaro PA, Singh RP, et al.; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six month primary end point results of a phase III study. Ophthalmology. 2010;117:1124-1133.
4. Haller JA. 6-month randomized controlled clinical trial of an intravitreal dexamethasone implant in macular edema associated with retinal vein occlusion. Paper presented at: Retina Congress 2009;October 4, 2009; New York, NY.
5. Ozurdex prescribing information; Allergan, Inc. Available at: ww.allergan.com/assets/pdf/ozurdex_pi.pdf. Accessed June 30, 2010.
6. Scott IU, Ip MS, VanVeldhuisen PC, et al.; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard of care to treat vision loss associated with macular edema secondary to branch vein occlusion: the Standard Care v. Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127:1115-1128.