intravitreal, VEGF Therapy, macula

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Article Date: 4/1/2014

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Dexamethasone Intravitreal Implant Following RVO: Rescue, Adjunct or Primary Therapy?

Dexamethasone Intravitreal Implant Following RVO: Rescue, Adjunct or Primary Therapy?

Ozurdex can be a safe, effective treatment option for macular edema in all three scenarios.

By Desiree Ifft, Contributing Editor

Since the Phase III GENEVA clinical trials demonstrated the safety and effectiveness of the dexamethasone intravitreal implant (Ozurdex, Allergan) for treatment of macular edema following retinal vein occlusion (RVO), how best to utilize the implant in clinical practice has been further studied. In addition, doctors have gained several years of experience using it, and VEGF therapies have been FDA-approved for the same indication. In light of what has been learned, where the implant fits into retina specialists’ approach to treatment of this group of patients has evolved.

Studies, Experience Lead to Expanded Use of Ozurdex

“We’re more comfortable using Ozurdex overall,” says Ron Gallemore, MD, PhD, Founder and Director of the Retina Macula Institute and Research Center in Los Angeles and Assistant Professor at the Jules Stein Eye Institute, UCLA School of Medicine. “The subset of patients that we consider good candidates for the implant is larger as well. We don’t hesitate to switch to it quickly when macular edema is resistant to intravitreal anti-VEGF therapy and a patient’s vision isn’t bouncing back after a few injections. In cases where the patient has a partial response to anti-VEGF therapy, but a hint of edema remains, we can often achieve a line or two more vision when we add Ozurdex. As many as 30% of our RVO patients are at least partially resistant to anti-VEGF treatment. Also, in our experience, using anti-VEGF injections and Ozurdex together can extend the interval between treatments compared with either of the two drugs alone.”

Dr. Gallemore and colleagues conducted a retrospective chart review involving RVO patients who received an Ozurdex implant to treat macular edema that had persisted after multiple bevacizumab (Avastin, Genentech) injections. On average, the patients receiving Ozurdex had a decrease in central foveal thickness of 146.8 ± 33.65 μm and improvement in visual acuity.1 The retrospective study was subsequently repeated as a prospective trial. In that study, in which eyes with RVO recalcitrant to anti-VEGF therapy were randomized to receive Ozurdex either every 16 weeks or prn, the implant significantly reduced retinal thickness and improved visual acuity.2 “A higher incidence of posterior subcapsular cataract was seen with repeat administration of Ozurdex,” Dr. Gallemore explains, “but, interestingly, multifocal electroretinogram showed statistically significant improvement in macular function after treatment with consecutive dexamethasone implants.”

The macular function improvement was seen in all of the patients who received Ozurdex, whether they received implants every 16 weeks or prn during the 48-week study. In the original GENEVA clinical trials, the implant was administered every 6 months, but the effect waned during that interval.3 However, the extension portions of GENEVA showed that further reduction of edema and recovery of vision can occur with repeat administration.4 “In the GENEVA extension trials, visual recovery was better for patients who were treated at the outset with Ozurdex, suggesting that earlier use of the implant may achieve better visual results,” Dr. Gallemore notes. “That said, it’s also important to know that patients who were initially randomized to the sham group also had a reduction in edema and recovery of vision when they were switched to treatment with Ozurdex, indicating that even if treatment with Ozurdex is delayed, it can still be beneficial. Today, most doctors using Ozurdex for patients with RVO-associated macular edema administer the implant every 2-3 months, especially in eyes that had not responded to, or had an inadequate response to, anti-VEGF agents.”

Dr. Gallemore may choose Ozurdex as primary therapy in specific situations, including RVO patients who refuse to have frequent intravitreal injections and patients with a recent history of heart attack or stroke. “Anti-VEGF treatment is relatively contraindicated in patients who have recently suffered MI or a stroke,” he says. He may also choose the implant as initial therapy for pregnant women for safety reasons and for maximizing visual results in patients who’ve had a vitrectomy because he expects the sustained-release dexamethasone to remain in the eye longer than other intravitreally injected steroids or anti-VEGF agents.5

Julia Haller, MD, Ophthalmologist-in-Chief of the Wills Eye Institute and Professor and Chair of the Department of Ophthalmology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, agrees. “We know that anti-VEGF drugs have a short half-life in vitrectomized eyes, so for those patients, I’m more likely to use the dexamethasone implant, which is our only current FDA-approved therapeutic option that provides extended drug delivery,” she says. “Given their effectiveness,6-9 most of us start with anti-VEGF injections for treating RVO-associated macular edema, but it’s important to keep in mind that steroids have anti-VEGF properties as well. Therefore, there is room for both treatments, either both upfront or sequentially. In some cases, before I combine treatments, I may try a different anti-VEGF agent if the initial choice is not effective. In other cases, such as in eyes that are already pseudophakic, I tend to get Ozurdex on board much sooner than I may have in the past. The same applies to eyes with a severe occlusion and very poor visual acuity, which I know from experience will likely have hard-to-control, recurring macular edema.” (See “Case Report: Dexamethasone Implant Plus Anti-VEGF Agent as Initial Treatment,” on the adjacent page.)

Intravitreal triamcinolone is a reasonable option when the decision is made to use a steroid, Dr. Haller points out, but she prefers the dexamethasone implant. “Triamcinolone can be effective for a few weeks or a month or two, but the dexamethasone implant is more potent, yet with a more favorable safety profile in terms of cataract progression, IOP elevation and potential toxicity.10-12 Also, not all formulations of triamcinolone are FDA-approved for ocular use, and problems with compounding pharmacies have raised concerns. Unless a patient has issues with insurance coverage and can’t afford it cost-wise, I would much rather use the implant than triamcinolone injections.”

Based on her own experience and the cumulative experience of other retina specialists, Dr. Haller says she’s more aggressive than in the past using Ozurdex for patients who are already using a topical IOP-lowering medication. “Once I started using Ozurdex in this group of patients, I realized how well it works and that the complications are very manageable. That put the implant on my radar screen more often as a solid option sooner rather than later. It’s very important to balance any potential implant-related complications with the need to eliminate the macular edema to preserve vision,” she says. She cites the recently published Shasta study as an indication that Ozurdex is being used safely and effectively in patients with controlled glaucoma.

A Real-world Evaluation of Ozurdex Use

Shasta is a 26-site, retrospective chart review study of patients with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) who received two or more dexamethasone implants.13 Patients who had previously received an Ozurdex implant as part of a clinical study were excluded. The 289 study subjects received a mean 3.2 implants (range of 2 to 9) during the study time period, either as monotherapy (for 29.1% of the patients) or in conjunction with other treatments. At baseline (i.e., at the time of their first implant), 31.5% of the patients had glaucoma or ocular hypertension, and 15.6% had a history of IOP elevation in response to steroid treatment documented in their charts.

According to Shasta data analysis, the percentage of patients who experienced a 2- to 3-line improvement in best-corrected visual acuity compared with baseline was similar after each implant. Overall, 62.9% of patients demonstrated at least a 2-line improvement in BCVA, and 48.1% of patients demonstrated at least a 3-line improvement at some point after treatment with Ozurdex.

With the reminder that Shasta is a retrospective study, lead author Antonio Capone, Jr., MD, considers its safety findings the most notable from the perspective of clinicians. “Very few patients had meaningful pressure rises,” he explains. “32.6% had an increase in IOP from baseline of at least 10 mmHg, and a similar proportion required pressure-lowering medications, but the vast majority were effectively managed with drops. A very small percentage, 1.7%, required incisional surgery. Also, the steroid response was very predictable, it peaked at 6 weeks and no stair-step increase in pressure was seen with subsequent implants. All of this runs counter to what I think many doctors would anticipate with a steroid treatment.”

Dr. Capone, who practices with Associated Retinal Consultants in Michigan and is a Clinical Professor of Biomedical Sciences at Oakland University’s William Beaumont School of Medicine, comments further on Shasta, pointing out that it involves somewhat of a selection bias. “These were patients who had been treated in clinical practices, so most had received anti-VEGF, laser and/or other steroid therapy before receiving Ozurdex implants. Only 39 Shasta patients were treatment-naïve when they began receiving Ozurdex. As such, this cohort is much more laden with treatment-refractory patients than most prospective clinical trials, which typically enroll treatment-naïve patients. Therefore, more of them have blunted vision outcomes.”

Along the same lines, Dr. Capone continues, “Other studies have shown us that patients with protracted RVO-related macular edema don’t do as well as those whose edema is resolved sooner,14,15 and in patients who have a significant response to anti-VEGF monotherapy, the response is most dramatic with the first injection. There may be additional positive impact with subsequent injections, but we’re learning that if macular edema isn’t at least 50% resolved after one injection, it is appropriate to consider adjunctive or alternative therapy with Ozurdex promptly. Again, the longer the edema persists, the less vision we’re able to preserve.”

Individualized Treatment is the Best Course of Action

An advantage of the Shasta study relative to prospective studies is that it reflects results obtained with Ozurdex in the real world, Dr. Capone says. More guidance on how best to treat RVO-associated macular edema will likely come from several studies currently under way (such as NCT01427751) that directly compare the safety and effectiveness of anti-VEGF agents with the dexamethasone implant.

In the meantime, according to Dr. Haller, “Taking care of patients with this condition to the best of our ability means determining which approach is best for each individual in terms of safety, efficacy, potential complications and burden of care.”

Case Report
Dexamethasone Implant Plus Anti-VEGF Agent as Initial Treatment

In eyes with severe retinal vein occlusion and very poor visual acuity on presentation, macular edema is often recurrent despite treatment. In some of these cases, a reasonable course of action may be combining therapies at the outset, as in this case.

The patient is a 45-year-old otherwise healthy male who presented with sudden loss of vision in his left eye. Visual acuity OS was counting fingers inferiorly at 6 feet. Clinical exam and color fundus photography (Figure 1) revealed a hemiretinal vein occlusion, which fluorescein angiography confirmed (Figure 2). Central retinal thickness was 624 µm as measured by Spectralis SD-OCT (Heidelberg Engineering) (Figure 3).

Figure 1. Color fundus image at presentation.

Figure 2. Fluorescein angiography (4:37:16) at presentation.

Figure 3. At the patient’s initial visit, central retinal thickness was 624 µm as measured by Spectralis SD-OCT.

Figure 4. Six months after initiation of therapy with a dexamethasone implant and an anti-VEGF injection, 1 month after a peripheral laser treatment, macular edema remained completely resolved.

Given the severity of the occlusion and macular edema and the patient’s lack of other health issues, the decision was made to immediately administer an anti-VEGF injection and a dexamethasone intravitreal implant. The patient indicated he understood the risks and benefits. For example, he was willing to accept the risk of steroid-induced cataract in favor of receiving the two treatments in an effort to restore as much of his vision as possible.

The patient returned for monthly follow-up visits, receiving four additional anti-VEGF injections. By the first follow-up visit, central retinal thickness had decreased to 153 µm. Five months after the initial visit, extreme ischemia, which is known to up-regulate VEGF, was still present, so the patient received peripheral laser treatment, which was his last treatment of any type to date. As of 1 month post laser (6 months after presentation), the macular edema remained completely resolved and visual acuity had improved to 20/50.

Julia Haller, MD

References

1. Sharareh B, Gallemore R, Taban M, Onishi S, Wallsh J. Recalcitrant macular edema after intravitreal bevacizumab is responsive to an intravitreal dexamethasone implant in retinal vein occlusion. Retina. 2013;33(6):1227-1231.

2. Gallemore RP, Wallsh J, Sharareh B, Liu S. Dexamethasone implant improves retinal function in retinal vein occlusion recalcitrant to anti-VEGF therapy. Scientific Poster PO244; presented during the Annual Meeting of the American Academy of Ophthalmology, Nov 17, 2013, New Orleans, USA.

3. Haller JA, Bandello F, Belfort R Jr, et al., for the 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.

4. Haller JA, Bandello F, Belfort R Jr, et al., for the Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12):2453-2460.

5. Chang-Lin JE, Burke JA, Peng Q, et al. Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest Ophthalmol Vis Sci. 2011;52(7):4605-4609.

6. 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(6):1102-1112.

7. 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(6):1124-1133.

8. Boyer D, Heier J, Brown DM, Clark WL, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-1032.

9. Holz FG , Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3):278-284.

10. Chu YK, Chung EJ, Kwon OW, Lee JH, Koh HJ. Objective evaluation of cataract progression associated with a high dose intravitreal triamcinolone injection. Eye. 2008;22(7):895-899.

11. Lang Y, Zemel E, Miller B, Perlman I. Retinal toxicity of intravitreal kenalog in albino rabbits. Retina. 2007;27(6):778-788.

12. Roth DB, Verma V, Realini T, et al. Long-term incidence and timing of intraocular hypertension after intravitreal triamcinolone acetonide injection. Ophthalmology. 2009;116:455-460.

13. Capone A Jr, Singer MA, Dodwell DG, et al. Efficacy and safety of two or more dexamethasone intravitreal implant injections for treatment of macular edema related to retinal vein occlusion (shasta study). Retina. 2014;34(2):342-351.

14. Yeh WS, Haller JA, Lanzetta P, et al. Effect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant. Ophthalmology 2012;119(6):1190-1198.

15. Daien V, Navarre S, Fesler P, et al. Visual acuity outcome and predictive factors after bevacizumab for central retinal vein occlusion. Eur J Ophthalmol 2012;22:1013-1018.



Retinal Physician, Volume: 11 , Issue: April 2014, page(s): 16-19

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