Standard of care for retinal vein occlusion may need to be reconsidered

For the better part of the last 2 decades, there has been little debate as to the preferred treatment of retinal vein occlusion.

Ever since the results of the Branch Vein Occlusion Study were published in 1984, gold standard therapy has called for grid laser photocoagulation to treat vision-reducing macular edema caused by branch retinal vein occlusion (BRVO). Almost a decade later, researchers in the Central Vein Occlusion Study established that careful monitoring instead of laser yielded equivalent, if not better, visual acuity for macular edema due to central retinal vein occlusion (CRVO).

Those two studies established the standard of care, which remained unchanged until the Retina Congress 2009, when three separate clinical trial programs reported data challenging the status quo. Suddenly, retinal specialists had at their disposal a plethora of data on new and effective treatments for the second-leading cause of vision loss due to retinal vascular disorders.

“We suddenly had level 1 evidence to help guide what we do for macular edema from venous occlusive disease. It’s both a blessing and a curse, but mainly a blessing,” Michael S. Ip, MD, said.

Level 1 evidence is now available to help guide retina specialists’ choice of treatment of macular edema from venous occlusive disease, according to Michael S. Ip, MD. Image: Ip MS

The SCORE Study supported the use of triamcinolone over observation for CRVO and confirmed the superior safety profile of laser in BRVO; Allergan presented data on its dexamethasone-containing Ozurdex implant for both BRVO and CRVO; and the BRAVO and CRUISE studies demonstrated the positive impact of Lucentis (ranibizumab, Genentech) on BRVO and CRVO, respectively.

One year later, both Ozurdex and ranibizumab are approved by the U.S. Food and Drug Administration for treatment of BRVO and CRVO, and there is strong rationale for 1-mg triamcinolone therapy in CRVO and supporting evidence for the use of laser photocoagulation in BRVO. Additionally, new evidence has emerged about the natural history of BRVO and CRVO. However, retinal specialists now find themselves with a problem: a deluge of data, but no head-to-head comparisons to know which treatment or combination of treatments is the most appropriate choice.

“In many cases, we are uncertain in how to treat our patients because of the multitude of treatment options available to our patients,” Dr. Ip said.

Natural history

In the Branch Vein Occlusion Study, about one-third of untreated patients had spontaneously improved vision, and photocoagulation doubled the odds of improved vision compared with observation. Based on that study, it has been assumed that a subset of BRVO patients would improve regardless of intervention. However, according to Tien Y. Wong, MD, MPH, PhD, whose research group recently published meta-analyses on the natural history of BRVO and CRVO, these assumptions may need to be re-evaluated. Namely, although vision generally improves among patients with BRVO, improvement beyond 20/40 is uncommon.

“We have so little real knowledge of the natural history of retinal vein occlusion since the major landmark trials,” he said. He also noted that a recent study pooling population-based data showed that about 16 million people worldwide may have retinal vein occlusion.

In the analysis of BRVO patients studied in previous clinical trials, nearly half returned to 20/40 vision or better within 6 months without treatment. But the natural history of BRVO was still associated with significant morbidity. Macular edema was found in 5% to 15% of cases, although it resolved without treatment in 18% to 41% of those cases; vitreous hemorrhage occurred in about 41% of cases; and about one-third of eyes with BRVO developed at least some retinal neovascularization.

“A substantial proportion continues to have poor vision. This is an important consideration for clinical care, and physicians should discuss with patients what would happen if they do not want any treatment,” Prof. Wong said.

While vision often improved after onset of BRVO, vision generally decreased after onset of CRVO, especially in eyes affected by the ischemic subtype. Although the exact reason for a worse visual prognosis for CRVO was outside the scope of the study, Prof. Wong noted that CRVO more frequently is ischemic in nature, which portends a more severe clinical course.

“In both BRVO and CRVO, the main causes of visual loss are macular edema and macular ischemia. In CRVO, when present, macular edema is generally diffuse, central and severe, whereas in BRVO, macular edema, even if present, may not involve the foveal center and is generally less severe,” Prof. Wong said.

In their analysis, Prof. Wong and colleagues found that about one-third of untreated eyes affected by CRVO initially diagnosed in the medical literature as non-ischemic CRVO later converted to ischemic CRVO. The ischemic subtype, in turn, was associated with substantial complication rates: 20% developed neovascularization and 60% developed glaucoma.

The greater associated morbidity of CRVO exists against a backdrop of a lack of efficacious treatment paradigms. In the Central Vein Occlusion Study, serial angiography showed reduced evidence of macular edema in eyes treated with laser, but a decrease in visual acuity from 20/160 to 20/200. In untreated eyes, visual acuity dropped from 20/125 to around 20/160.

Corticosteroids

The spate of new treatments and the rapidity of their introduction has created something of a clinical dilemma — a question not so much about whether anti-VEGFs and new formulations of corticosteroids should make their way to the clinic, but how they should be used once they get there.

Julia A. Haller

“It’s a good problem. I don’t think you can ever have too many options for treating a disease with as much morbidity as visual loss due to retinal venous occlusive disease,” Julia A. Haller, MD, an OSN Retina/Vitreous Board Member, said.

In the SCORE trials, in which 1-mg and 4-mg doses of intravitreal triamcinolone were compared with standard of care, steroid was beneficial for both BRVO and CRVO patients, although for BRVO, laser photocoagulation had a superior safety profile compared with either dose of triamcinolone.

In the BRVO cohort, 25.6% of patients in the 1-mg triamcinolone group, 27.2% in the 4-mg triamcinolone group and 28.9% in the laser photocoagulation group gained 15 or more letters of vision by the end of the study. However, 25% in the 1-mg group, 35% in the 4-mg group and 13% in the laser photocoagulation group developed new cataract. In addition, the rate of IOP rise and the need for IOP-lowering medications were higher in the corticosteroid groups.

On the other hand, in the CRVO cohort, 26.5% of patients in the 1-mg triamcinolone group, 26.6% in the 4-mg triamcinolone group and 6.8% in the observation group gained 15 or more letters of vision 12 months after initiation of treatment. Rates of cataract development and IOP elevation were again higher in the corticosteroid groups, with a dose-dependent association, but those issues were viewed as acceptable when vision gain was considered.

Based on the results of the two studies, the SCORE investigators suggested that while 1-mg triamcinolone is a viable option in CRVO, laser should continue to be the standard of care in BRVO.

It should be noted, though, that the 1-mg dose of triamcinolone was specifically formulated for use in the study and that no such dose of triamcinolone is readily available on the U.S. market, necessitating use of either Kenalog (triamcinolone acetonide, Bristol-Myers Squibb) or Triesence (triamcinolone acetonide, Alcon); both are available in 1-mg and 4-mg formulations.

“You would have to use either Kenalog or Triesence, and in general, if I use triamcinolone, I choose to use Triesence because it doesn’t contain the benzyl alcohol that is present in the Kenalog formulation,” Dr. Ip, who was the lead investigator on the SCORE-CRVO trial and a co-investigator on the SCORE-BRVO trial, said. “Potentially, these drugs have different safety profiles. Potentially, the formulation used in the SCORE study was safer than the side effect profile one would see with either Triesence or Kenalog.”

Corticosteroids, as a class, have been researched for retinal venous occlusion disorders because they are thought to have several effects on the multiple causes of blocked vasculature. Namely, they have anti-inflammatory effects and help regulate associated inflammatory immune responses, they may reduce vascular permeability so as to limit fibrin deposition, and they inhibit the synthesis of natural chemicals important in the formation of new blood vessels, specifically VEGF.

But progress in using corticosteroids has been trumped by safety concerns, and research over the past decade has been aimed at finding the right formulation of the right corticosteroid in the right dosage strength to improve vision after onset of RVO while limiting adverse outcomes.

One suggestion has been the use of dexamethasone, which has a considerably short half-life even though it is a stronger and more potent corticosteroid. But before the corticosteroid could reliably be used in the eye, a mechanism for keeping the drug at the desired site was needed.

The Ozurdex implant provides such a medium. The bioerodable implant, which is injected into the intravitreal space, was tested in clinical trials containing either 0.35 mg or 0.7 mg of dexamethasone. In that trial, 41% of BRVO and CRVO patients achieved a 15-letter gain at 6 months compared with 23% of patients who received a sham injection.

After 1 year of follow-up, 20% of patients required no reimplantation. Studies suggest that dexamethasone, when delivered via the Ozurdex implant, is available to the back of the eye for up to 6 months after injection.

“The pharmacological advantage of the steroid is that it has multiple mechanisms by which it is impacting on the disease process in the eye. It’s a multifactorial approach, if you will, rather than a silver bullet approach with the anti-VEGF,” Dr. Haller, who was an investigator in the Ozurdex implant trial, said. “And, of course, the decreased number of injections needed compared to anti-VEGF therapy has considerable potential clinical impact.”

Shortly after the release of data from a phase 3 clinical trial, the Ozurdex implant received approval from the FDA for treatment of macular edema secondary to RVO in late 2009.

Anti-VEGF

In June, the anti-VEGF agent ranibizumab was approved by the FDA for treatment of macular edema secondary to BRVO and CRVO. The rationale for using anti-VEGF in retinal venous occlusion disorders is strong, according to David M. Brown, MD, FACS, who was the lead investigator on the CRUISE study and an investigator on the BRAVO trial.

David M. Brown

“There has been basic science evidence that VEGF is upregulated in vein occlusions, as well as studies that show some of the highest VEGF levels in any human disease in vein occlusions. So, it makes sense that if you can block VEGF in vein occlusions, it might be effective in controlling the edema, which is the main reason people have decreased vision,” he said.

Patients in both the BRAVO and CRUISE trials had rapid resolution of macular edema and gains in visual acuity, often within the first week.

“Most of the edema was resolved by day 7, and the average patient had over seven or eight letters gained by 1 week,” Dr. Brown said.

In the CRUISE trial, mean gain in best corrected visual acuity at 6 months was 12.7 letters after treatment with 0.3 mg of ranibizumab and 14.9 letters after 0.5 mg of ranibizumab, but just 0.8 letters after sham injections. The percentage of patients gaining 15 or more letters was significantly higher among treated patients, as was reduction in central foveal thickness and the percentage of patients with final vision greater than 20/40.

In the BRAVO trial, BCVA increased by a mean of 16.6 letters in the 0.3-mg group and 18.3 letters in the 0.5-mg group, compared with 7.3 letters in the sham group. Again, the percentage of patients ending the study with vision better than 20/40, the reduction in macular thickness and percentage gaining 15 or more letters of vision were all significantly higher among treated patients.

“The thing that sets ranibizumab apart from any of the other treatments out there is that it’s a very rapid response in both anatomic and visual acuity data,” Dr. Brown said. “It’s particularly important in a working patient that has to have visual acuity to maintain a lifestyle that you can improve vision so rapidly with this agent compared to, say, laser for BRVO or natural history, where it can get better but it takes 3 to 4 months.”

Treatment considerations

Each of the recently proposed treatment options comes with questions yet to be answered. With regard to anti-VEGF therapy, those questions parallel experiences in treating age-related macular degeneration: How often does treatment need to be repeated, is as-needed therapy sufficient, and when can therapy be discontinued?

Treatments of AMD and RVO, however, do not have a direct correlation. For one, AMD affects the outer retinal layer, where damage can more readily affect photoreceptors.

“It’s a lot easier to go PRN with vein occlusion treatment without damaging your long-term visual acuity,” Dr. Brown said. “You see that in the second 6 months of BRAVO/CRUISE, where on a PRN regimen, visual acuities were basically maintained in the ranibizumab patients.”

Patients in the BRAVO and CRUISE trials initially treated with sham before crossing over to active treatment, however, did not achieve the same degree of visual gain as patients treated with ranibizumab from enrollment. This may suggest that early treatment is more beneficial. But because the crossover phase of the studies used only as-needed therapy, perhaps it shows that monthly dosing is more efficacious.

“In the second 6 months, everybody got active treatment, but it would have been nice to know if in that sham arm, how they would have done if you treated monthly,” Dr. Brown said. “Would you have gotten that same change? That would have been a great argument that you could wait, but we didn’t test it.”

On the other hand, the degree of visual gain among patients who crossed over to active treatment may also be skewed by the fact that an unknown number of patients will have spontaneous resolution, with reduction in macular edema and resulting vision gain.

Because the pathology is resolved in some patients without treatment, a trial period may be warranted before intervention. At the least, initiating less invasive therapy first and then following up with ever more aggressive therapy may be called for.

“I think that macular edema from a BRVO is not an emergency, and a trial of grid laser photocoagulation should be considered in most patients. If the grid laser photocoagulation is effective, you may spare the patient treatment with pharmacotherapy and the risks of intravitreal injections,” Dr. Ip said.

Not everyone, though, is in favor of delaying the initiation of treatment. According to Dr. Haller, there is accumulating evidence that prompt initiation of treatment may yield better visual results.

Safety is an ongoing concern, and so the potential to reduce exposure to treatment that might have a side effect may augment the risk-benefit calculus. For instance, a phakic patient at risk for glaucoma with an active CRVO might be a poor candidate for steroid but a good candidate for an anti-VEGF agent.

“If the anti-VEGF therapy doesn’t work, maybe triamcinolone can be used as a second line of therapy,” Dr. Ip said.

However, if the lens has previously been removed, Dr. Ip said, and there is no history of glaucoma, the SCORE study results indicate that triamcinolone is a viable first-line option.

Dr. Brown does not consider either glaucoma status or the status of the lens to be integral to the treatment decision, except that use of a corticosteroid may lead to IOP elevation. “The Ozurdex seems to have a lower rate of this, and it may be because of the short activity of dexamethasone, but it’s certainly not as low as the ranibizumab study,” he said.

The most prevalent risk associated with intravitreal ranibizumab appears to be endophthalmitis, which occurred in one patient in the BRAVO study but in no patients in the CRUISE study. Previous studies have estimated the risk of endophthalmitis after anti-VEGF injection to be about one in 3,000, a rate more comforting than the potential for cataract or IOP spike after corticosteroid use.

“If you even thought that the treatments were equally efficacious, I would tend to favor the one with the least side effects,” Dr. Brown said.

At the current time, there are no definitive answers as to how best to treat patients with occluded retinal veins, and several questions still remain. For instance, patients with retinal vein occlusion are at higher risk for stroke and vascular disease; how does the use of anti-VEGF agents affect that risk?

As with all clinical trial data, translating information from bench to bedside is difficult, especially because each trial has its own unique design and inclusion and exclusion criteria. The BRAVO, CRUISE and Ozurdex studies employed a 6-month treatment endpoint. Will treatment effects extend beyond this time point?

Lastly, all of these clinical trials enrolled patients with varying degrees of baseline visual acuity, and this may account, at least in part, for the differences in the natural history arms in these trials. Analysis of their results yields little information about what to do for patients with symptomatic vein occlusion but relatively good visual acuity.

Such questions would probably be best answered in a head-to-head clinical trial. However, such a trial would likely be expensive and unlikely to be funded by industry sources.

“Another problem is that the landscape is changing so fast that a head-to-head trial may lose its relevance given the rapidity with which new treatments for retinal vein occlusive diseases are being developed,” Dr. Ip said.

The sudden onset of new information for treating retinal vein occlusion, it seems, calls into question the current standard of care. But it also leaves open the question as to what the new standard should be. – by Bryan Bechtel

Is there any role for observation before initiating treatment for BRVO, perhaps to avoid the need for pharmacotherapy?

References:

• Apte RS. SCOREing in retinal venous occlusive disease. Arch Ophthalmol. 2009;127(9):1203-1204.
• Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104(1):34-41.
• Argon laser scatter photocoagulation for macular edema in branch vein occlusion. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98(3):271-282.
• Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.
• Bressler NM, Schachat AP. Management of macular edema from retinal vein occlusions: you can never have too many choices. Ophthalmology. 2010;117(6):1061-1063.
• Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.
• Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):425-1433.
• Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.
• Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114.
• McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117(6):1113-1123.
• Rogers S, McIntosh RL, Cheung N, et al; International Eye Disease Consortium. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-319.
• Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117(6):1094-1101.
• 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 care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128.

• David M. Brown, MD, FACS, can be reached at Retina Consultants of Houston, 6560 Fannin St., Suite 750, Houston, TX 77030; 713-524-3434; e-mail: dmbmd@houstonretina.com. Dr. Brown is a consultant and researcher for Allergan, Alcon and Genentech. He was an investigator in the BRAVO, CRUISE, SCORE and Ozurdex studies.
• Julia A. Haller, MD, can be reached at Wills Eye Institute, 840 Walnut St., Philadelphia, PA 19107; 215-928-3073; fax: 215-928-3853; e-mail: jhaller@willseye.org. Dr. Haller is a consultant for Genentech and Allergan.
• Michael S. Ip, MD, can be reached at University of Wisconsin, Fundus Photograph Reading Center, Park West One, 406 Science Drive, Suite 400, Madison, WI 53711-1068; 608-263-2853; fax: 608-262-1899; e-mail: msip@wisc.edu. Dr. Ip is a consultant for Genentech, receives research support from Allergan, and is a DSMC member for QLT and Sirion.
• Tien Y. Wong, MD, MPH, PhD, can be reached at Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Ave., Singapore 168751; 65-63224571; fax: 65-63231903; e-mail: ophwty@nus.edu.sg. Dr. Wong is on the advisory boards of and has served as a consultant for Novartis, Allergan and Pfizer.