RETINA SPECIALISTS ARE USING INTRAVITREAL INJECTIONS of triamcinolone acetonide (Kenalog) for many retinal indications, with varying results. One area in which the injections have shown promise is in the treatment of macular edema secondary to retinal vein occlusions, the second most common retinal vascular disease behind diabetic retinopathy. The currently available outcome data, however, consist of small, non-randomized studies with short follow-up periods.
In this article, I'll discuss the outcomes reported in these studies, and how physicians' experience in the field with macular edema associated with retinal vein occlusions is influencing the design of the only randomized, multicenter study of IVTA for retinal vein occlusions, the Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study.
All images courtesy Michael Ip, M D
|A patient who presented with central retinal vein occlusion OS in July 2003. He had 1-2+ posterior capsular opacification, as well, and 20/400 vision in the affected eye.|
My colleagues and I reported the results of a retrospective study including 13 eyes of 13 patients with macular edema associated with central retinal vein occlusion who had been treated with an intravitreal injection of Kenalog (4 mg/0.1cc). The average pre-injection acuity was 20/500 in the affected eye. Patients had been experiencing symptoms for a median duration of eight months.
At six months, the mean visual acuity was 20/180 in the study eye. Although there was significant improvement in acuity in the eyes with non-ischemic CRVO (five eyes), the eight patients with ischemic disease showed no significant visual improvement. No patient experienced decreased acuity. The patients' mean foveal thickness on optical coherence tomography decreased from 590 µm at baseline to 212 µm at one month, and to 193 µm at three months.
Between three and six months, macular edema recurred in four patients, and three were re-injected with triamcinolone. Two of the three showed an improvement in acuity. At the six-month follow-up, mean foveal thickness for all 13 patients was 281 µm. One patient had an intraocular pressure increase that was controlled with two aqueous suppressants; there were no other adverse events.1
|An optical coherence tomography image of the eye, showing the macular edema. The physician injected Kenalog intravitreally.|
|Nine days after the Kenalog injection, the swelling had decreased markedly, and the patient's vision improved from 20/400 to 20/40.|
|Three months after the Kenalog injection, the macular edema remained decreased, and the vision improved from 20/40 nine days post-injection to 20/30.|
All of the eyes in the study showed improvement in macular edema with a corresponding improvement in volumetric OCT measurements. The VOCT measurements improved from a mean of 4.2 mm 3; to 2.6 mm 3 (P<.001). The mean best-corrected acuity improved from 58 letters (range: 37 to 72) at baseline to 78 letters (range: 50 to 100) at the last follow-up (average follow-up: five months). The improvement in acuity was statistically significant (P=.01). Six eyes achieved a final acuity > 20/50. Three eyes (30 percent) without a previous history of glaucoma were treated with topical aqueous suppressant therapy for increased IOP. One eye with a history of open-angle glaucoma underwent a trabeculectomy.2
In the setting of branch retinal vein occlusion, small-scale studies have also shown promising preliminary results.
In one prospective, comparative, interventional report from Germany, researchers studied 28 eyes of 28 patients. A study group of 10 patients received an intravitreal injection of 20 to 25 mg of triamcinolone, and the other 18 patients served as controls.
At an average follow-up of nine months, mean visual acuity increased significantly from 0.27 ±0.11 preop (around 20/70) to 0.45 ±0.27 postop (around 20/45). Nine eyes (90 percent) gained visual acuity, with six showing an increase of at least two lines. In the ischemic subgroup, acuity didn't change significantly. In the non-ischemic group, however, acuity increased from a baseline value of 0.29 ±0.09 (around 20/70) to 0.53 ±0.24 (between 20/32 and 20/40).
|The macula nine days post-IVTA injection. Vision is 20/40.|
The availability of new technology, especially OCT, has made it possible to document retinal thickness, intraretinal cystic changes and vitreomacular traction in patients with macular edema secondary to retinal vein occlusions. Often, following intravitreal triamcinolone injection, we find a dramatic anatomic improvement in macular edema that's associated with an improvement in acuity. However, there are also cases in which there isn't significant improvement in acuity despite significant anatomic improvement.
In reports of outcomes following intravitreal triamcinolone injection for the treatment of macular edema, up to a third of patients may develop an IOP increase.4 Although this IOP increase is transient and can be controlled with topical glaucoma medication in most cases, some patients have needed surgical intervention. There is also the possibility of cataract formation and progression post-injection at rates that aren't clearly defined from small-scale studies. We're also not sure how the risk of complications may change after repeated injections to treat recurrent edema.
We also need to clarify the risk of endophthalmitis associated with intravitreal injections. Researchers estimate the risk of non-infectious endophthalmitis after IVTA injection to be as high as 2 percent, and the risk of infectious endophthalmitis to be between 0.16 and 0.6 percent.5,6 Endophthalmitis has been rarely reported after intravitreal injection of gas or agents other than antivirals or triamcinolone. Intravitreal injection of antivirals may be associated with different rates of endophthlamitis because they are often injected into immunocompromised patients with cytomegalovirus retinitis, who don't have a strong ability to launch an immune response.
Although anecdotal and retrospective studies give us some indication of Kenalog's effects on macular edema related to retinal vein occlusions, we must remember that the efficacy and safety of IVTA haven't yet been defined by prospective, randomized, controlled clinical trials. The small number of patients treated in the published case reports and case series, the short duration of follow-up, the lack of concurrent controls, and the lack of randomization into treatment groups prevent meaningful statistical analysis of visual acuity outcomes and potential complications. To get at the real outcome numbers, we've initiated a large-scale study, the SCORE Study.
Knowing the SCORE
The SCORE Study is a multicenter, randomized clinical trial designed to investigate the safety and efficacy of IVTA injection(s) for the treatment of macular edema associated with central and branch retinal vein occlusion. The chair of the study is Michael Ip, MD, from the University of Wisconsin-Madison, and I serve as co-chair. The coordinating center is the Emmes Corporation in Rockville, Md.
Here's a look at the study:
• Study design. In the study, 630 patients will be randomized to receive IVTA 4 mg, 1 mg or standard of care in a 1:1:1 ratio for macular edema associated with CRVO, and 630 patients will be similarly randomized in a BRVO group. Based on the study experience to date, there is a 2:1 screening to randomization ratio, so there's a good chance that a patient who's screened will be entered into the study. We will follow the patients for three years.
For eyes with CRVO, standard of care consists of observation. For eyes with BRVO without a dense macular hemorrhage, standard of care consists of immediate grid laser photocoagulation. For eyes with BRVO with a dense macular hemorrhage, standard of care consists of observation followed by grid laser treatment if and when clearing of the hemorrhage permits the laser application.
The trial is also significant in that it employs a new formulation of triamcinolone acetonide specifically designed for intravitreal injection by Allergan.
Currently, the commercial formulation of triamcinolone, Kenalog, isn't approved for intraocular use and contains preservatives. The intraocular formulation we're using in the trial is preservative-free, endotoxin-free, comes in a prepackaged sterile syringe designed for intraocular use and is being used under an FDA Investigational New Drug Application (IND). The results of the study may be used by the U.S. Food and Drug Administration for granting approval to the agent in the future.
Enrollment in the study, which began in the fall of 2004, started slower than expected, but the rate of enrollment has increased over the past several months. One reason for the somewhat slow initial enrollment is the continued use of Kenalog off-label. While the results of anecdotal and small-scale reports are promising, continuing to treat patients with Kenalog outside of this randomized controlled clinical trial prevents us from gathering truly meaningful data on intravitreal triamcinolone's efficacy and long-term side-effects. We hope the ophthalmic community will instead refer eligible patients to a study center.
• Eligibility changes. The SCORE Study investigators in the field are learning more about treating macular edema secondary to retinal vein occlusions, and this knowledge enabled us to expand the study's eligibility criteria without compromising the study's scientific integrity or our patients' safety. The following is what they're learning and how, in some cases, we're changing the study to reflect this knowledge.
Experience with Kenalog has shown that there are retinal vein occlusion patients with macular edema who have acuities worse than 20/200 who may benefit, at least in the short term, from steroid injection. Several SCORE Study investigators have seen patients with worse than 20/200 vision show improvement with intravitreal Kenalog.
With these facts in mind, we expanded the vision study eligibility criteria from a range of between 20/40 and 20/200 (73 and 34 letters) to between 20/40 and 20/320 (73 and 24 letters). The caveat with this expanded acuity range is that a patient's occlusion must, in the investigator's opinion, be perfused, since perfused occlusions are the ones believed to have the potential to improve with treatment.
Our second alteration was to the duration of occlusion allowed in the study. Initially, we limited the study to occlusions of at least three to 18 months in duration, because we didn't want to enroll patients in an interventional trial who might improve spontaneously. At the same time, we didn't want to enroll patients with long- standing occlusions who would be extremely unlikely to improve after any intervention. We've since broadened this range to include patients with occlusions of two to 18 months duration.
With this new range, investigators who would like to treat a patient with a two-month old occlusion don't have to sit on their hands for another month as they would have with the old duration criterion.
It's important to note, though, that the study protocol has a built-in mechanism to prevent enrollment of patients who are improving spontaneously: a screening visit followed by a randomization visit spaced seven to 21 days apart. If the patient's clinical exam changes significantly during that time, or the patient's vision improves significantly, he or she won't be eligible for study inclusion.
SCORE Study investigators have also noted that they frequently see patients with branch retinal vein occlusion who have received some grid laser treatment for macular edema secondary to vein occlusion who have persistent leakage and still have room for more laser treatment. According to the original study protocol, any history of prior laser treatment was an exclusion criterion. Now, if a patient has persistent leakage on fluorescein angiography contiguous with the fovea, and either no evidence of prior laser treatment or evidence of clearly inadequate prior laser treatment, he or she can be included in the study.
Certain cases of macular edema secondary to retinal vein occlusion appear to respond well to intravitreal steroid injection, but the long-term safety and efficacy of this treatment modality are still unknown. With the support of the ophthalmology community, we hope that the SCORE Study will be able to provide these answers and optimize the management of patients with macular edema associated with retinal vein occlusion.
Dr. Scott is professor of ophthalmology and health evaluation sciences at Penn State College of Medicine.
Additional information about eligibility criteria and the SCORE Study, including a list of the clinical investigation sites, can be found online at http://spitfire.emmes.com/study/score/ or by calling (301) 251-1161.
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2. Park CH, Jaffe GJ, Fekrat S. Intravitreal triamcinolone in eyes with cystoid macular edema associated with central retinal vein occlusion. Am J Ophthalmol 2003;136:419-425.
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6. Moshfeghi DM, Kaiser PK, Bakri SJ, et al. Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide injection. Ophthalmic Surg Lasers Imaging 2005;36:1:24-9.