JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 31, Number 8, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0119
Efficacy and Safety of Dexamethasone Intravitreal Implant for Treatment of Refractory Macular Edema Secondary to Retinal Vein Occlusion in Taiwan Shwu-Jiuan Sheu,1,2 Tsung-Tien Wu,1,2 and Yu-Harn Horng1
Purpose: To evaluate the long-term efficacy and safety of slow-release dexamethasone intravitreal implant (DEX implant) in patients with refractory macular edema (ME) secondary to retinal vein occlusion (RVO) in Taiwan. Methods: We conducted a retrospective chart review of patients with a diagnosis of ME secondary to RVO who received the DEX implant at Kaohsiung Veterans General Hospital from October 2010 to February 2014. Results: A total of 28 patients with an average age of 60.7 – 11.1 years were examined. Of these patients, 17 were diagnosed with branch RVO (BRVO) and 11 were diagnosed with central RVO (CRVO). The mean maximal change in vision from the baseline after the final injection was an improvement of 1.7 – 2.8 lines (equivalent to 8.5 ETDRS letters; p < 0.0001). The response to the first injection was similar across both BRVO and CRVO groups, but patients with BRVO showed a more favorable response than those with CRVO after the second injection. The response in patients who had refractory ME after at least 3 previous interventions was similar to the whole group. Three patients (10.7%) had elevated intraocular pressure (IOP) that was well controlled by IOP-lowering medications. None of these patients required laser or glaucoma surgery. Five patients (17.9%) exhibited cataract progression during the observation period. Conclusion: The DEX implant is an effective and safe treatment for ME, secondary to RVO, including refractory ME. Introduction
etinal vein occlusion (RVO) is the second most common retinal vascular disease in adults. The prevalence increases with age. RVO can be divided into 2 main types; the prevalence of branch RVO (BRVO) is *5-fold higher compared with central RVO (CRVO).1,2 CRVO can be further classified into ischemic or nonischemic CRVO. In both types of RVO, macular edema (ME) is a major cause of visual impairment. Treatment of ME secondary to RVO mainly targets various points in the pathogenesis pathway. Treatment modalities have improved substantially in recent years. Before the era of intravitreal pharmacotherapy, treatment guidelines were formulated according to the results of the Central Vein Occlusion Study and Branch Vein Occlusion Study, which recommended observation for CRVO and grid laser photocoagulation for BRVO without spontaneous resolution 3 months after disease onset, respectively.3,4 1 2
Pharmacotherapy has recently substantially advanced the management of ME, and several effective treatments are currently available. Numerous trials have supported using antivascular endothelial growth factor (anti-VEGF) therapy in treating ME secondary to RVO; the outcomes of antiVEGF therapy are unprecedented, and this therapy has an excellent side effect profile. However, according to antiVEGF studies conducted thus far, responses to treatment may vary and frequent injections are required.5–12 Corticosteroids have also been used as a treatment strategy for ME secondary to RVO, based on evidence revealing that inflammation plays a crucial role in RVO.13 The Standard Care versus Corticosteroid for the Retinal Vein Occlusion study represents the most cited study on this topic and showed that the results of intravitreal administration of triamcinolone (TA) were similar to those of a grid laser in treating ME secondary to BRVO and that intravitreal administration of TA considerably benefited patients with ME secondary to CRVO.14,15 However, TA-related elevated
Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. School of Medicine, National Yang-Ming University, Taipei, Taiwan.
SHEU, WU, AND HORNG
Baseline Demographics and Patient Characteristics All patients (n = 28)
BRVO patients (n = 17)
CRVO patients (n = 11)
61.3 (11.3) 35.3–81.5
59.6 (11.2) 41.0–74.1
7 (41.2) 10 (58.8)
5 (45.5) 6 (54.5)
2 (11.8) 14 (82.4) 2 (11.8)
2 (18.2) 8 (72.7) 0 (0.0)
17 (100) NA
NA 11 (100)
1 (5.9) 15 (88.2) 1 (5.9)
3 (27.3) 8 (72.7) NA
2 (11.8) 15 (88.2)
1 (9.1) 10 (90.9)
Age, year Mean (SD) 60.7 (11.1) Range 35.3–81.5 Sex, n (%) Female 12 (42.9) Male 16 (57.1) Underlying systemic diseases Diabetes 4 (14.3) Hypertension 22 (78.6) Cardiovascular disease 2 (7.1) Diagnosis in study eye, n (%) BRVO 17 (60.7) CRVO 11 (39.3) Lens status in study eye, n (%) None 4 (14.3) Cataract 23 (82.1) Pseudophakia 1 (3.6) Comorbid glaucoma or ocular hypertension, n (%) Yes 3 (10.7) No 25 (89.3) Duration of RVO at time of first DEX implant injection (months) Mean (SD) 13.8 (13.2) Range 1.0–56.0 Mean (SD) BCVA in the study eye (lines) 9.2 (4.4) Snellen 20/125 Mean (SD) central retinal thickness, mm 438.4 (120.8)
15.4 (15.7) 1.0–56.0 10.1 (3.9) 20/100 445.8 (130.5)
11.4 (8.2) 1.0–26.0 7.8 (4.8) 20/160 426.9 (109.1)
BRVO, branch RVO; CRVO, central RVO; DEX, dexamethasone; NA, not applicable; RVO, retinal vein occlusion; SD, standard deviation.
intraocular pressure (IOP) and cataract progression are critical concerns, especially in patients receiving 4 mg of TA. Slow-release dexamethasone implants (DEX implant) (Ozurdex; Allergan, Inc., Irvine, CA) were reported to be effective in reducing ME and have been approved for treating diabetic ME and ME secondary to uveitis or RVO.16 Few studies have been conducted to evaluate the long-term effect of slow-release DEX implants on ME secondary to RVO in an Asian population. According to previous reports, the prevalence of RVO in Asia is different from global and United States, neither were the risk factors for RVO.17–20 Regional data are important for real-life practice guidance. The purpose of this study is to assess the long-term efficacy and safety of DEX implant in Taiwan, especially in patients with refractory ME who have failed to respond to other treatments.21–25
Methods We conducted a retrospective chart review of patients with a diagnosis of ME secondary to RVO who received slow-release 0.7-mg DEX implants at the Kaohsiung Veterans General Hospital from October 2010 to February 2014. The Institutional Review Board and Ethics Committee of Kaohsiung Veterans General Hospital approved this study, which adhered to the tenets of the Declaration of Helsinki. Data on demographic characteristics, medical history, date of disease onset, comorbidities, initial and final visual acuity (VA), slit-lamp biomicroscopy, IOP, fundus photography, central retinal thickness (CRT) according to
optical coherence tomography (OCT), and the types of treatment were analyzed. Statistical analysis was performed using SPSS Version 12.0 (SPSS, Inc., Chicago, IL). Descriptive statistics are expressed as the mean and standard deviation. Snellen VA measurements were converted to approximate ETDRS letter scores for statistical manipulations according to methods described previously.26 Baseline data were defined as the final value measured on or before the day of the first DEX implant intravitreal injection. Key safety indicators were cataract and IOP. All data analyses were based on observed values, and no missing values were imputed. Changes in vision and CRT from the baseline were evaluated using paired t-tests. The peak effect was defined as the change of maximal vision or the minimal OCT value of CRT. Refractory ME was defined as ME that persisted or recurred after 3 or more previous interventions (macular laser photocoagulation or intravitreal pharmacotherapy).
Results A total of 28 patients, namely 12 women and 16 men with an average age of 60.7 – 11.1 years, were examined. Mean follow-up time was 18.57 – 13.76 months. Of these patients, 17 were diagnosed with BRVO and 11 were diagnosed with CRVO. Hypertension was the most common systemic. Most (82.1%) patients had cataract at the baseline examination. Most RVO cases were chronic with a mean duration of 13.8 months between disease onset and the first DEX implant injection (Table 1 and Fig. 1). Seventeen (60.7%) patients
OZURDEX FOR REFRACTORY MACULAR EDEMA IN RVO
FIG. 1. Age distribution of the patients. Most cases were chronic, with a duration of 13.8 months between disease onset and the first DEX implant injection. This duration was 24 months or more in 6 cases. BRVO, branch retinal vein occlusion; CRVO, central RVO; DEX, dexamethasone. had received treatments before using the DEX implant; specifically, 12 patients had undergone anti-VEGF treatment, 2 patients had received subtenon administration of triamcinolone, and 12 patients had undergone laser treatment (Table 2). Fourteen patients received a second DEX implant, 6 received a third implant, and 3 received a fourth implant (only patients with CRVO). The mean number of injections was 2.2 for CRVO patients and 1.6 for BRVO patients. Most repeated injections were performed 4 months after the previous injection; the mean injection interval in the BRVO group was 8.8 months and that in the CRVO group was 6.8 months (Table 3). The mean peak change in vision from the baseline after the final injection was an improvement of 1.7 – 2.8 lines (equivalent to 8.5 ETDRS letters; p < 0.0001). The response to the first injection was similar in the BRVO and CRVO groups, but patients with BRVO exhibited a more favorable response than those with CRVO after the second injection. The response in patients who had refractory ME after at least 3 previous interventions (including laser and in-
travitreal anti-VEGF treatments) was as favorable as that in the entire sample (Fig. 2A, F). Since the baseline vision varied a lot in our patient group, which might confound the effect of vision gain, we adjust the baseline vision and other reported factors to perform logistic regression analysis. The results showed that patients with low baseline vision or patients diagnosed with BRVO had a significantly higher chance to have better visual gain after injection. The response in patients with refractory ME did not show any significance from the others (Table 4). The mean baseline CRT among all patients was 442 – 137 mm. The mean CRT improved significantly from baseline after the first DEX implant injection ( p < 0.0001). Mean changes in the CRT from baseline ranged from -431 to -4 mm after the first 4 DEX implant injections (Fig. 3). The percentages of patients with BRVO and CRVO who showed a CRT&250 mm after DEX injection were 28.6% (6/21) and 45.0% (9/20), respectively. After the first DEX implant injection, 14.3% received additional intravitreal anti-VEGF therapy. Laser photocoagulation
Table 2. Intraocular Treatments and Procedures for Complications of Retinal Vein Occlusion in the Study Eye Before and After the First DEX Implant Injection
Any treatment or procedure for RVO (other than DEX implant), n (%) Intravitreal injection, n (%) Anti-VEGF treatment Intravitreal bevacizumab Intravitreal ranibizumab Bevacizumab + ranibizumab DEX implant Laser/surgical intervention, n (%) Vitrectomy surgery, n (%) Steroid treatment, n (%) No treatment or procedure for RVO (other than DEX implant), n (%)
Before the first DEX implant injection (n = 28)
After the first DEX implant injection (n = 28)
12 5 4 3 0 12 0 2 11
4 0 2 2 28 18 1 0 8
(42.9) (17.9) (14.3) (10.7) (0.0) (42.9) (0.0) (7.1) (39.3)
Patients could receive more than one type of treatment or procedure before and after DEX implant treatment.
(14.3) (0.0) (7.1) (7.1) (100.0) (64.3) (3.6) (0.0) (28.6)
SHEU, WU, AND HORNG
Time Between DEX Implant Injections
Mean interval between DEX implant injections for each patient Mean interval, n (%) 1 Month (&45 days) 2 Months (46–75 days) 3 Months (76–105 days) 4 Months (106–135 days) 5 Months (136–165 days) 6 Months (166–195 days) > 6 Months (>195 days) Mean (SD) across all patients, days Months Median, days Months Range, days
All patients 0 0 1 2 2 2 8 240.9
(0.0) (0.0) (6.7) (13.3) (13.3) (13.3) (53.4) (143.6) 8.0 206.3 6.9 98–665
BRVO patients 0 0 1 1 1 1 5 264.8
(0.0) (0.0) (11.1) (11.1) (11.1) (11.1) (55.6) (176.4) 8.8 224.0 7.5 98–665
CRVO patients 0 0 0 1 1 1 3 205.1
(0.0) (0.0) (0.0) (16.7) (16.7) (16.7) (50.0) (73.2) 6.8 193.0 6.4 119–322
Based on the mean number of days between injections for each patient.
was administered to 18 patients (64.3%) as an adjuvant therapy to reduce the need for pharmacotherapy because all required treatments were not reimbursed by the Taiwan National Health Insurance program. Laser photocoagulation was employed when ME subsided to target the nonperfused areas, which were identified using fluorescein angiography (FAG). One patient received a pars plana vitrectomy for the epiretinal membrane (Table 2).
FIG. 2. Percentage of patients exhibiting visual improvement from the baseline after each intravitreal injection of a DEX implant. The entire sample exhibited at least 2-line (A) or 3-line (B) improvement. At least 2-line improvement in patients with BRVO (C) and CRVO (D). At least 2-line improvement in patients with chronic ME (interval S 3 months, E) and refractory ME (at least 3 previous interventions, F). ME, macular edema.
Regarding safety, 3 patients (10.7%) had elevated IOP that required IOP-lowering medications; 1 patient used 2 medications and 2 patients received 3 medications. No patients required laser or glaucoma surgery. Five patients (17.9%) exhibited cataract progression during the observation period, and 4 of these patients received phacoemulsification and intraocular lens implantation by the end of the study period.
OZURDEX FOR REFRACTORY MACULAR EDEMA IN RVO
Analysis of Possible Factors to Improved Vision After DEX Injection
Improved after first DEX implant OR (95% CI)
Age Baseline vision Diagnosis (ref: CRVO) Duration of RVO at time of first DEX implant injection (months) Refractory macular edema (ref: