Developing Effective Steroid/Anti-VEGF Combination Therapy Regimens

Recent additions to our therapeutic options have yielded new opportunities.

Michael A. Singer, MD

As a result of multicenter, phase 3 clinical trials, many new options have become available over the last two years to treat retinal vein occlusion. These trials—BRAVO/CRUISE,^1,2 Ozurdex GENEVA,³ SCORE⁴ and GALILEO/COPERNICUS—evaluated four different drugs and showed efficacy in certain disease states. Comparing these trials is problematic since their results were produced by differing study designs.

Nevertheless, as a result of these trials, there are now different treatments available to patients with macular edema due to RVO: (1) the anti-VEGF drugs, ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech); (2) steroids, including the Ozurdex dexamethasone insert (Allergan) and triamcinolone acetonide; and soon (3) VEGF Trap-Eye (Regeneron).

The problem that now arises is how we as clinicians treat patients in “real-world” situations. What do we do when Mrs. Jones arrives in our office with an RVO and vision reduced to 20/100 by macular edema? I have asked this question of many clinicians around the world and the vast majority of them say, “I would give an anti-VEGF injection.” The next question is: Which one?

The best data in terms of visual acuity improvement can be found in the BRAVO and CRUISE studies, in which the mean letter gains were 18.3 letters in the BRAVO study and 14.9 letters in the CRUISE study. Sixty-one percent of patients in the BRAVO and 47.7% of patients in the CRUISE study gained three lines or more at six months. However, in order to get that response, one must remember that patients were given six monthly injections of ranibizumab.^1,2

The problem is, therefore, twofold: (1) will the patient be willing to return every month for six months for an injection in the eye, and (2) will the physician use ranibizumab? The issue of administering six shots is very important because patients who received three injections only gained 80% of the six-month response, ie, 15.3 letters in BRAVO and 12.2 letters in CRUISE. Similarly, with three injections, only 50.4% of patients in BRAVO and 36.9% of patients in CRUISE were three-line gainers.^1,2 Patients with RVOs are generally younger than those with AMD, and many are still working, so monthly visits may affect their employment. In addition, some may balk at the idea of six injections.

Another issue is that many clinicians believe ranibizumab and bevacizumab are equivalent. The CATT study will answer this question for age-related macular degeneration, but AMD is not RVO or diabetic macular edema. The amount of VEGF is significantly higher in RVO and DME than AMD; for these patients, bevacizumab may not be as effective in decreasing edema and increasing vision as ranibizumab.

Ozurdex, a sustained-release device consisting of dexamethasone 0.7 mg, also showed improvement in visual acuity versus sham in the GENEVA study. In that study, patients gained a maximum mean of 10 letters during the first six months, and 29.3% were three-line gainers. The curves in the Ozurdex study showed that the peak effect was at 60 days; the effect decreased at 90 days and further decreased at six months.³ Ozurdex, being a sustained-release device, addresses the issue of monthly injections, but the visual acuity improvements may not be as good as monthly ranibizumab.

COMBINATION THERAPY DATA

As a result of this dilemma, our practice decided to do a study looking at combination therapy of an anti-VEGF drug and dexamethasone 0.7 mg implant (Ozurdex) to see if there could be synergy in terms of increasing the visual acuity results of Ozurdex while still minimizing the burden of monthly injections.⁶ Thirty-two patients were enrolled in this prospective study and followed monthly to determine whether there was indeed synergy between these two medications in terms of visual acuity and to determine how long their combined effects would last. Initially, the study was conducted using bevacizumab and a dexamethasone 0.7-mg implant because these were the only drugs that were reimbursed by our local Medicare carrier at the time.

The initial phase of the study involved 32 patients with a diagnosis of either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Sixteen had CRVO and 16 had BRVO. There were 14 patients who had received bevacizumab therapy prior to entrance into the study, and 18 patients received their first bevacizumab injection as part of this study. The study protocol dictated that all patients were to be treated with bevacizumab at baseline, and then they would receive an Ozurdex implant two weeks later.

Patients were then evaluated at baseline (visit 1), week 2 (visit 2), weeks 4 to 6 (visit 3), and every four weeks thereafter, until the next bevacizumab injection occurred. Patients were eligible for retreatment with bevacizumab if their retinal thickness increased by 50 μm from the lowest recorded level on spectral-domain OCT (Cirrus) or if their visual acuity decreased by six letters.

In terms of vision, 78% (25 of 32) of patients gained vision with combination therapy at any point in the study. Sixteen percent (five of 32) of patients had no change in vision, and 6% (two of 32) of patients experienced a decrease in vision. The maximum mean visual improvement was 17 letters, and 47% (15 of 32) of patients had an improvement in vision at any point in the study of 15 or more letters.

Mean central field thickness measured on OCT decreased from 459 μm to 265 μm over six months. Patients' swelling decreased the most during the initial two weeks of treatment (mean 123 μm) after bevacizumab injection and an additional 50 μm two weeks after Ozurdex injection.

We also analyzed the data in terms of the percentage of patients who became “dry” centrally after injection. In our series, we defined this as an OCT measurement <300 μm. Three patients, or 9%, presented initially this way. This number increased to 31% after initial bevacizumab injection, and it further increased to 72% two weeks after Ozurdex injection. It remained between 60% and 80% for the remainder of the six months.

The mean time to reinjection of those patients who were retreated was 108 days from Ozurdex to reinjection, which was 122 days from the original bevacizumab injection. The standard deviation was 24.9 days, and 34% of patients went six months or more without a repeat injection.⁶ The one-year results are to be presented at a major retina meeting in the third quarter of this year.

RETINAL VEIN OCCLUSIONS CASE STUDIES

The following cases illustrate the use of combination therapy in retinal vein occlusion. Patients were initially treated with bevacizumab and switched to ranibizumab after it was approved in July 2010.

• Case 1. A 68-year-old woman with a CRVO OD had presenting vision of 20/60 and OCT central field thickness (CFT) of 670 μm. She received bevacizumab injection and vision improved to 20/40, and the OCT thickness decreased to 449um. The vision improved to 20/30 after Ozurdex injection and the OCT remained dry at 252 μm. Four months from the original injection, the vision decreased to 20/70, and the OCT swelled to 433 μm. The patient was switched to ranibizumab injection; the OCT CFT (central field thickness) improved to 254 μm and the vision improved to 20/40. Two weeks later, she received an Ozurdex injection which caused the OCT to remain dry and the vision to stabilize at 20/30 for another three months (four months total).

Case 1. Figures A-C: Fundus photo, FA and OCT of a 68-year-old woman with a CRVO OD and 20/60 vision, central field thickness is 670 μm. Figure D: She received bevacizumab injection and vision improved to 20/40, and the OCT thickness decreased to 449 μm. Figure E: The vision improved to 20/30 after Ozurdex injection and the OCT remained dry at 252 μm. Figure F: Four months from the original injection, the vision decreased to 20/70, and the OCT swelled to 433 μm. Figure G: The patient was switched to ranibizumab injection and OCT improved to 254 μm and the vision improved to 20/40. Figures H-I: Two weeks later, she received an Ozurdex injection, which caused the OCT to remain dry and the vision to stabilize at 20/30 for another three months (four months total).

• Case 2. An 87-year-old woman presented in July 2010 with a BRVO OS. The initial vision was 20/200 and the OCT CFT was 812 μm. The patient received ranibizumab injection; her vision improved to 20/70 and her CFT decreased to 302 μm. She then received Ozurdex injection two weeks later.

Her vision then improved to 20/40; the OCT remained dry. Four months from the original ranibizumab injection her vision decreased to 20/200, and the OCT swelled to 613 μm. Repeat combination therapy with ranibizumab/Ozurdex improved the vision to 20/40 and the OCT remained dry for three more months.

Case 2. Figures A-C: An 87-year-old woman presented in July 2010 with a BRVO OS. The initial visual acuity was 20/200 and the OCT central field thickness was 812 μm. Figure D: Ranibizumab injection given and her vision improved to 20/70, OCT thickness decreased to 302 μm. Figures E-F: Ozurdex was injected. Vision improved to 20/40; the OCT remained dry. Figure G: Four months from the original ranibizumab injection, vision decreased to 20/200 and OCT swelled to 613 μm. Figures H-I: Repeat combination therapy with Lucentis/Ozurdex injection improved vision to 20/40, and the OCT remained dry for another three months.

OTHER DISEASE CASE STUDIES

Other potential uses for combination therapy include treatment in diseases such as AMD and diabetic retinopathy. We have found that this therapy is well suited for cases that are recalcitrant to monthly therapy. This therapy enables the retina to become and stay dry for a number of months by extending the interval between injections. The cases below illustrate how we have used this technique in our clinical practice. (Note: the following cases demonstrate off-label use of Ozurdex; in these cases the patients paid cash for their own medicine.)

• Case 3. A 42-year-old man with proliferative diabetic retinopathy OD and vitreous hemorrhage is status post vitrectomy. He has recalcitrant macular edema and recurrent vitreous hemorrhages requiring 17 bevacizumab injections over the last 16 months. His macular CFT was 767 μm and his visual acuity was 20/70. He received bevacizumab and his OCT CFT decreased to 540 μm and his vision improved to 20/40-2. He then had a dexamethasone 0.7-mg implant (Ozurdex) injection. At his next visit the CFT decreased to 251 μm and his vision remained stable at 20/40. He stayed dry for two more months and his vision improved to 20/30. At five months, the patient started to re-accumulate fluid; his OCT thickness increased to 383 μm and his vision decreased to 20/60.

Case 3. A 42-year-old man with proliferative diabetic retinopathy OD and vitreous hemorrhage is status post vitrectomy, with recalcitrant macular edema and recurrent vitreous hemorrhages requiring bevacizumab injections as often as every three weeks to control his conditions. He has required 17 injections over the last 16 months. Figure A: His macular edema was 767 μm and his visual acuity was 20/70. Figure B: He received bevacizumab and his OCT decreased to 540 μm and his vision increased to 20/40-2. He then had an Ozurdex injection. Figure C: At his next visit, his OCT decreased to 251 μm and his vision remained stable at 20/40. Figures D-E: He stayed dry for two more months and his vision improved to 20/30. Figure F: Five months later, the patient started to reaccumulate fluid. OCT thickness increased to 383 μm and his vision decreased to 20/60.

• Case 4. A 76-year-old man developed wet AMD in his left eye in 2006 and had over 40 injections of ranibizumab or bevacizumab on a monthly basis. His vision, which initially had been as good as 20/40 at baseline, dropped to 20/150 depending on central edema, which ranged from 267 to 601 μm. The patient then underwent combination therapy with ranibizumab followed by Ozurdex and improved his vision to 20/40. His OCT remained dry for three months and then reaccumulated fluid.

Case 4. A 76-year-old male patient who suffered from AMD and received over 40 monthly injections of ranibizumab or bevacizumab. Shown are OCTs at month 1 (Figure A), month 12 (Figure B), month 36 (Figure C) and month 40 (Figure D). Two weeks following the 40th ranibizumab injection (Figure E), Ozurdex was injected. Figures F-H show the OCTs from months 41 through 43. The OCT was dry after month 43; however, fluid then re-accumulated (Figure I).

CONCLUSION

Combination therapy for macular edema associated with venous occlusive disease is an option with the possible advantage of using different mechanisms of action. While possibly not as good as monthly ranibizumab monotherapy in RVO, it does provide an option for patients who need more flexibility in their dosing schedules.

The option of combination therapy (although off-label) can be considered for patients whose macular edema is unresponsive to monthly ranibizumab therapy or to create an “injection holiday.” It also can be used in post-vitrectomy patients who do not have vitreous to act as a reservoir for the drugs. Combination therapy obviously has drawbacks in terms of intraocular pressure and should be used judiciously in patients with glaucoma, but it does enlarge our arsenal in the battle against macular edema. RP

REFERENCES

1. 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;117:1124-1133.
2. 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;117:1102-1112.
3. Haller JA, Bandello F, Belfort R, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117:1134-1146.
4. 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 Ophthalmology. 2009;127:1101-1114.
5. Boyer DM. Anti-VEGF therapy for CRVO: Copernicus Study. Paper presented at: Angiogenesis 2011; Miami, FL; February 12, 2011.
6. Singer M. Effect of combination therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion. Paper presented at: Annual meeting of the American Society of Retina Specialists; Vancouver, Canada; August 29, 2010.