The past 18 months has witnessed a flurry of study results regarding the treatment of macular edema related to retinal vein occlusions. Some of these new findings confirmed what many practitioners thought about approaching these cases, while others opened up new approaches altogether. Here, retinal specialists discuss how you can take these study results and put them to use in your practice.


Studying Steroids

The wave of new study results kicked off in 2009, when researchers published the results of the National Eye Institute-sponsored Standard of Care vs. Corticosteroid for Retinal Vein Occlusion study. For 411 patients with branch retinal vein occlusion, the investigators tested intravitreal triamcinolone vs. laser photocoagulation, the standard of care for BRVO. In 271 patients with central retinal vein occlusion, they compared the results of triamcinolone vs. observation, the standard of care in CRVO.

"What the researchers showed was that the old standby, laser, was just as good as triamcinolone if you waited long enough in BRVO," says Houston retinal specialist David Brown. "But, it did show that intravitreal steroids are better than observation in patients with CRVO. In those studies, though, very few patients gained vision with either modality, especially in CRVO." As is the case with steroids, intraocular pressure increases and cataract development were the main adverse events physicians had to contend with.

Around the same time that the SCORE results were being finalized, Allergan's Ozurdex dexamethasone implant was approved for the treatment of macular edema associated with BRVO and CRVO. In the implant's trial of 1,267 patients, 427 received a 0.7-mg implant, 414 received a 0.35-mg device and 426 received a sham treatment. After a single implant injection, the time to achieve a ≥15-letter improvement in best-corrected vision was significantly less in both implant groups compared with sham (p<0.001). The percentage of eyes with a ≥15-letter improvement in best-corrected vision was significantly higher in both implant groups compared with sham at days 30 to 90 (p<0.001). The researchers reported that improvements in best-corrected vision with the implant were seen in patients with BRVO and those with CRVO, though the patterns of response differed. The percentage of implant-treated eyes with an intraocular pressure of at least 25 mmHg peaked at 16 percent at day 60 (both doses) and was not different from sham by day 180.

"The Ozurdex studies showed quite a bit of improvement initially after the injection of the implant, and this tended to taper off with time," says Dr. Brown. "Most patients lose their gains by six months. It was approved based on that data, and it's possible that patients would do better if you re-injected an Ozurdex or added an anti-VEGF agent, but that's not known."

Wills Eye Institute retinal specialist Carl Regillo says there are situations where a steroid implant might be preferable to a steroid injection.

"I think the advantage of the Ozurdex, and this is a slight advantage over intravitreal triamcinolone suspension injected intravitreally, is the IOP elevation rate isn't quite as high with Ozurdex as it is with triamcinolone 4 mg, which is the standard dose," he says.

"You can still get efficacy with a lower dose of triamcinolone—which is sometimes done in practice—which is 2 mg or a half-dose, and the rates of IOP elevation are probably lower, probably due to a dose-response type of pressure issue. But Ozurdex may also provide for a better or longer duration of action in a vitrectomized eye, because a solution or suspension that you inject into a vitrectomized eye tends to clear more quickly. Because Ozurdex is slow-release pellet, it probably has a longer duration of action in the vitrectomized eye relative to triamcinolone suspension particles.

"For instance," continues Dr. Regillo, "If I had a pseudophake with a vein occlusion who is known to respond to steroids but had a vitrectomy, and a triamcinolone injection's effect is going to go away in two to three months, I'd consider Ozurdex to get a longer duration of action in that patient. Or if he had mild pressure problems but responded very well and enjoyed a very good vision benefit, I'd consider an Ozurdex in that setting."

San Antonio
retinal specialist Michael Singer offers tips for successfully working with the Ozurdex implant: "First, I give subconjunctival anesthesia because the Ozurdex uses a [relatively large] 22-ga. inserter," he says. "I then leave the room and see one or two other patients to give the anesthesia time to take effect. When I return, I have the patient lie down, and I place the speculum and sit or stand slightly below eye level. I retract the conjunctiva upwards with a Q-tip, go in at a 30 to 45 degree angle until I can't see the bevel anymore, rotate the needle 90 degrees and then go straight in until I run into the stopper. I then slowly depress the actuator, wait until I hear a click, and keep it in for five seconds. I wait because, as with any injection, there will be a recoil. In this instance, you're injecting into a structure composed of collagen and  elastin, so it's an elastic sub-stance with a certain amount of spring. If you pull it out quickly, the tissue can act like a siphon, and the pellet could go back up the injection hole. As I remove the injector, I place the conjunctiva over the area, creating a self-sealing wound. I then look to make sure the pellet is in the eye and that there's no hemorrhage."


Anti-VEGF Options

More recently, researchers reported results from the Genentech-sponsored BRAVO and CRUISE studies of the anti-vascular endothelial growth factor drug ranibizumab (Lucentis) in patients suffering from macular edema associated with CRVO (CRUISE) or BRVO (BRAVO).

CRUISE is a Phase III, double-masked study in which patients with macular edema (central subfield thickness of at least 250 µm) were randomized to receive six monthly intravitreal injections of 0.3-mg (n=132) or 0.5-mg (n=130) ranibizumab or sham injections (n=130) followed by observation with p.r.n. therapy to one year. In BRAVO, 132 patients received sham injections, 134 received 0.3-mg doses and 131 received 0.5-mg doses.

In CRUISE at one year, the change in central foveal thickness from baseline was -427.2 ±305.1 µm for sham vs. -452.8 ±269.3 µm for 0.3-mg patients and -462.1 ± 283.1 µm for 0.5-mg patients.

In terms of acuity in the CRUISE study, in the 0.3-mg group patients gained an average of 13.9 letters at a year. In the 0.5-mg group, they also gained an average of 13.9 letters.
The sham group gained 7.3 at a year. Forty-seven percent of the 0.3-mg group and 50.8 percent of the 0.5-mg group gained 15 or more letters, vs. 33 percent for sham.

In BRAVO at one year, the CFT change from baseline was -273.7 ±236.9 µm for sham vs.
-313.6 ±240.7 µm for 0.3-mg patients and -347.4  ±253.8 µm for 0.5-mg patients. At one year, the 0.3-mg patients gained an average of 16.4 letters and the 0.5-mg group gained 18.3 letters compared to baseline. Sham patients gained 12.1.

"There were very impressive im--provements in visual acuity in these two studies with Lucentis injected monthly for six months," notes Dr. Regillo. "Though you can't compare one study to another and we don't have a head-to-head comparison between steroids and anti-VEGF agents in this setting in a large-scale, prospective fashion, the visual results look more favorable in the Lucentis trials. This will continue to push this trend of performing a pharmacologic intervention first, possibly followed by laser treatment for branch vein occlusions."


Putting It All Together

Combining the latest results with doctors' firsthand experience with retinal vein occlusions will result in some changes in practice, say physicians.

"The standard of care now for CRVO, which used to be observation, is to watch the patient closely initially but to use Ozurdex or an anti-VEGF treatment within a few weeks if the macular edema persists or if he's bothered by his visual acuity loss," says Dr. Brown. "For the most part, that would give patients a pretty robust improvement in acuity concomitant with a decrease in edema. What remains to be seen is how much ongoing therapy they will need.

"For BRVO it will be a similar approach," adds Dr. Brown. "How-ever, since we know from about 25 years of clinical practice that grid and focal laser tend to decrease leakage and improve visual outcomes with BRVO, I think, compared to CRVO, a lot more physicians will be combining grid or focal laser with one of the other treatments. Most physicians will probably start with an Ozurdex implant or an anti-VEGF agent to flatten the retina, and do the laser afterward. If you perform laser on a retina in which the edema is gone, you can get by with much less power and have a much more focal laser burn than you can with a thickened retina. I think a lot of physicians will give one to six anti-VEGF injections and then, if necessary, go to laser."

Dr. Singer is studying a combination approach to macular edema secondary to retinal vein occlusions.

"After looking at the encouraging data from Ozurdex, followed by the Lucentis data, I thought, 'Oncology doesn't do one therapy for cancer, let's test combination therapy for vein occlusion,' " he says. "The idea was that, since macular edema in vein occlusion is multifactorial, a multi-pronged approach, using Avastin and Ozurdex, might be better than just one type of therapy. We've prospectively followed these combination patients on a monthly basis with the goals of getting better results than the original Ozurdex studies and finding out how long a combination therapy would last, to see if monthly dosing was necessary to maintain both increased vision and decreased retinal thickness on optical coherence tomography." Dr. Singer says he's currently analyzing the data, and the final results will be presented at the meeting of the American Society of Retinal Specialists in Vancouver.

Dr. Brown says there's another important aspect of vein occlusion therapy. "Almost every patient does really well with anti-VEGF therapy in terms of getting better from the time of presentation to right after the injection," he says. "However, there's a subset of CRVO patients who have infarcted some of their arterial supply relative to how bad the vein occlusion is. They used to be called ischemic CRVO patients, but since we know all vein occlusions are ischemic to some extent, I call these patients pre-proliferative CRVOs.
It's important to figure out which ones are really bad because once your drug wears off, these patients are very likely to get new blood vessel growth and neovascular glaucoma.
The best way to test for this is the relative afferent pupillary defect test, or the swinging flashlight test. If the patient has a big afferent defect, he's likely to be pre-proliferative, and you have to watch him more closely and warn him that if there's any neovascularization he may need panretinal photocoagulation. However, if you think he'll comply poorly with follow-up, you may have to consider PRP immediately. The reason the afferent defect test works to find these patients is because, if the process has killed off a lot of retina, the brain's not getting as much light from that eye as it is from the other."

Dr. Singer says, as his comments and those of his colleagues suggest, quick treatment with vein occlusions is effective treatment. "The concept still holds: The longer you sit on macular edema, the more photoreceptors you kill and the worse your vision is," he says. "I still believe in treating these patients early and often, and I think finding the right cocktail is a work in progress."


With regard to products discussed in the article, Dr. Brown is a consultant for Genentech, Alcon and Allergan. Dr. Regillo is a consultant for Genentech and AMO and Dr. Singer consults for Genentech and Allergan.