Current Eye Research, 2014; 39(9): 938–943 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.885533
ORIGINAL ARTICLE
Comparison of Clinical Efficacy of Intravitreal Ranibizumab with and without Triamcinolone Acetonide in Macular Edema Secondary to Central Retinal Vein Occlusion Chuanfeng Fan1,2, Yu Wang2, Qiang Ji2, Bojun Zhao1 and Juan Xie2 1
Department of Ophthalmology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, PR China and 2Department of Ophthalmology, The Second People’s Hospital of Jinan, Jinan, PR China
ABSTRACT Purpose: To compare visual outcomes and spectral-domain optical coherence tomography results following treatment with intravitreal ranibizumab (IVR) or IVR combined with intravitreal triamcinolone acetonide (IVTA) for macular edema (ME) secondary to central retinal vein occlusion (CRVO). Methods: This prospective, case-controlled study examined 57 eyes (57 patients) with ME secondary to CRVO, which were treated with IVR (0.5 mg, n = 30 eyes) or IVR (0.5 mg) and IVTA (1 mg, n = 27 eyes) as the initial therapy. Further intravitreal treatment was administered as necessary. Results: All 57 patients completed at least 6 months of follow-up. At baseline, mean ( ± standard error) bestcorrected visual acuity (BCVA) was 45.8 ± 23.2 letters in the IVR group and 47.3 ± 19.3 letters in the IVR + IVTA group (p = 0.790). Significant improvement in BCVA over baseline was observed in both groups at all six study visits (IVR group: p = 0.0003, 0.0001, 0.0018, 0.0145, 0.0107, 0.005; IVR + IVTA group: p = 0.0001, 0.0001, 0.0004, 0.0068, 0.0007, 0.0002), with no significant BCVA differences between groups. Significant reduction in mean central subfield thickness, compared with baseline, was also observed in both groups at all six study visits (IVR group, p = 0.0001; IVR + IVTA group, p = 0.0001), with no significant difference between groups in the magnitude of macular thickness reduction. The mean number of injections was significantly higher (p = 0.0001) in the IVR group (4.23 ± 0.56) than in the IVR + IVTA group (3.42 ± 0.41). Conclusions: Treating ME secondary to CRVO with IVR or IVR + IVTA had similar effects on central macular thickness and BCVA in patients with ME secondary to CRVO over a 6-month follow-up period. The mean number of intravitreal injections was higher in the IVR group than in the IVR + IVTA group. Keywords: Best-corrected visual acuity, central retinal vein occlusion, macular edema, ranibizumab, triamcinolone acetonide
INTRODUCTION
consequence of CRVO that causes irreversible visual loss is macular edema (ME), which is very difficult to treat. In recent years, intravitreal injections of triamcinolone acetonide or anti-VEGF agents have been effective, to a certain extent. Unfortunately, triamcinolone acetonide has serious side effects and ranibizumab is very expensive, so both therapies have certain restrictions. In an effort to determine the optimal therapy, this study was designed to compare
Central retinal vein occlusion (CRVO) is very commonly seen in clinical practice, and it often causes severe visual impairment. The CRVO prevalence rate gradually increases with age. Epidemiological data have shown that people over the age of 30 years have a CRVO prevalence rate of 0.3–0.5%, translating into about 250 million cases worldwide.1 The main
Received 2 October 2013; revised 6 January 2014; accepted 12 January 2014; published online 17 March 2014 Correspondence: Bojun Zhao, MD, Department of Ophthalmology, Shandong Provincial Hospital, Shandong University, No. 324 Jingwu Weiqi Road, Jinan, Shandong, 250021, PR China. Tel: +86 15318808857. Fax: +86 053181270613. E-mail: [email protected]
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Using Intravitreal Ranibizumab for Macular Edema clinical outcomes of intravitreal ranibizumab (IVR, LucentisÕ ) monotherapy, and IVR combined with intravitreal triamcinolone acetonide in eyes with ME secondary to CRVO.
MATERIALS AND METHODS The study was approved by The Second People’s Hospital of Jinan institutional review board. The study conduct adhered to the tenets of the Declaration of Helsinki. All patients provided written informed consent after they were informed about study procedures and the risks/benefits of the intraocular injection therapies examined. This prospective, controlled study examined patients presenting to the Second People’s Hospital of Jinan City with ME secondary to CRVO between August 2012 and February 2013. A total of 57 eyes from 57 patients (28 men and 29 women) were included in analyses. Patients ranged in age from 40 to 73 years. Patients were randomly divided into two treatment groups: those who received IVR (0.5 mg; LucentisÕ , Genentech, South San Francisco, CA) monotherapy (n = 30 eyes) and those that received combination treatment with IVR (0.5 mg) and IVTA (1 mg; Kunming Jida Pharmaceutical Co., Ltd., Kunming, China, n = 27 eyes).
Patients Patients had to meet all the following inclusion criteria to be included in analyses: (1) symptom duration 53 months, (2) best-corrected visual acuity (BCVA) worse than 20/40 (early treatment of diabetic retinopathy study [ETDRS] equivalent = 70 letters), (3) central macular thickness (CMT) on optical coherence tomography (OCT) 275 mm, and (4) fundus fluorescein angiogram (FFA) showing wide-spread diffuse leakage involving the macular and the fovea. If patients had any of the following exclusion criteria, their records were excluded from analyses: (1) intraocular pressure (IOP) 421 mmHg, (2) iris neovascularization, (3) previous history of intraocular surgery, and (4) previous grid photocoagulation or anti-VEGF treatments for other eye diseases (e.g. hypertension, diabetic retinopathy, uveitis, and macular disease).
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room with a sharp 29-Gauge needle. The needle was inserted into the eye through the pars plana, 3.5–4 mm from the limbus. Either ranibizumab (0.5 mg in 0.05 mL) or a mixture of ranibizumab (0.5 mg in 0.05 mL) and triamcinolone acetonide (1 mg in 0.025 mL, Kunming Jida Pharmaceutical Co., Ltd., Kunming, China) was injected.
Panretinal Photocoagulation When fundus fluorescein angiography revealed ischemic central retinal vein occlusion with retinal or disc neovascularization, 3–4 sessions of panretinal photocoagulation (PRP) sessions were conducted within 1 month to prevent neovascular glaucoma.
Patient Follow-up All patients returned for follow-up 1 d, 1 week, and 1 month after their first intravitreal injection. Patients were followed up monthly thereafter. The BCVA and IOP (Goldman tonometer, PacScan 300AP, Sonomed, NY) were measured, slit lamp, and indirect ophthalmoscopy were performed, and spectraldomain optical coherence tomography (OCT) images were collected to measure central macular retinal thickness (CMT). Color fundus photographs were also taken and complications were observed and noted. Eyes were retreated when any of the following conditions occurred: (1) visual acuity loss 10 ETDRS letters and macular effusion was observed on OCT images, (2) central retinal thickness, measured on OCT, increased by 4100 mm compared with the previous measurement, (3) new effusion was present on OCT.
Statistical Analyses Data are presented as mean ± standard error. All statistical calculations were performed using standard software (SPSS version 15.0, SPSS, Inc., Chicago, IL). Visual acuity and CMT changes before and after treatment were compared using t-tests. The Chisquare test was used to compare incidence rates between groups. A p value 50.05 was considered statistically significant.
The Intravitreal Injection Procedure RESULTS All patients were informed of the purpose, potential benefits, and possible complications of intravitreal drug therapy. When ready, subjects signed an informed consent form before each intraocular injection. All injections were performed in the operating !
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Baseline clinical characteristics of the IVR and the IVR + IVTA groups are summarized and compared in Table 1. No significant differences between the groups were found.
940 C. Fan et al. The BCVA, IOP, and CMT were monitored over time to determine and compare the efficacy of the two treatments. No significant differences between groups existed at any time point measured for BCVA or CMT (Table 2). At 1, 2, and 6 months, IOP was significantly higher in the IVR + IVTA combination therapy group than in the IVR monotherapy group. The BCVA had significantly improved over baseline values at all follow-up visits in both the IVR and the IVR + IVTA groups. At the last follow-up visit (6 months), 19 eyes (63.3%) in the IVR group, and 20 eyes (74.1%) in the IVR + IVTA group had a visual gain of more than 15 ETDRS letters, a difference that was not statistically significant ( 2 = 0.759, p = 0.384). The CMT at baseline was 469.6 ± 26.8 mm in the IVR group and 476.9 ± 29.2 mm in the IVR + IVTA group (p = 0.329). A significant reduction in CMT from baseline was observed in both study groups at all study visits (Table 2). The minimum CMT occurred 3 months into treatment in both groups. Additionally, there were no significant differences in CMT between treatment groups at any follow-up visit (Table 2). Intraocular pressure at baseline was normal in both groups at 13.3 ± 3.3 mmHg in the IVR group and 14.8 ± 3.7 mmHg in the IVR + IVTA group (p = 0.111). No significant differences from baseline were seen in IOP for either group at any time point examined.
TABLE 1 Baseline clinical characteristics. IVR
IVR + IVTA
n (eyes) 30 27 Age (years) 61.8 ± 7.8 62.3 ± 8.9 Sex (male/female) 14/16 14/13 Duration of ME (months) 1.3 ± 0.6 1.5 ± 0.8 Systolic blood pressure 153.4 ± 38.9 159.8 ± 32.7 (mmHg) Diastolic blood pressure 85.6 ± 18.3 89.1 ± 17.5 (mmHg) Macular ischemia/no ischemia 18/12 14/13 PRP (yes/no) 19/11 16/11
P 0.822 0.696 0.287 0.507 0.465 0.536 0.752
IVR, intravitreal ranibizumab; IVTA, intravitreal triamcinolone acetonide; ME, macular edema; PRP, panretinal photocoagulation.
Additionally, there was no difference in IOP between treatment groups at 3, 4, or 5 months, but it was significantly higher in the IVR + IVTA groups at 1, 2, and 6 months. Although there were no significant changes in mean IOP from baseline, three eyes had an IOP421 mmHg in the IVR + IVTA group. All episodes of elevated IOP were controlled with antiglaucomatous medication. The average number of injections administered in the IVR group was 4.23 ± 0.56 injections. This was significantly higher than the 3.42 ± 0.41 injections given to the IVR + IVTA group (p = 0.0001). No significant cataract formation was observed, and no serious complications of the injection procedure (e.g. endophthalmitis, retinal detachment) occurred.
DISCUSSION Macular edema is the most common cause of severe visual loss in eyes with CRVO. According to a National Eye Institute (Bethesda, MD) survey,3 macular edema will seriously diminish a patient’s quality of life. The Central Vein Occlusion Study showed that traditional treatment methods (e.g. laser photocoagulation) can reduce macular edema and prevent retinal and iris neovascularization, but they do not significantly restore visual function.4 Newer therapies, such as internal limiting membrane stripping/peeling during vitrectomy and the macular puncture technique,5 have been reported to be useful, but have not been widely used because of serious complications. Intravitreal injection of triamcinolone acetonide has been proven effective in treating ME secondary to CRVO,6 but postoperative complications, including cataract development and increased IOP, have limited the application of this approach in the clinical setting. Approximately 25% of patients develop elevated IOP from intraocular steroid use.7 A 2009 multi-center, randomized, controlled trial8 examined the safety and efficacy of 1 mg and 4 mg IVTA in 271 eyes with macular edema. The results indicated a comparable efficacy of the two doses, but that the 1 mg dose had a better safety profile than the 4 mg dose.
TABLE 2 Best-corrected visual acuity, central macular thickness, and intraocular pressure during the 6 month monitoring period. Time (months) 0 1 2 3 4 5 6
ETDRS best-corrected visual acuity (letters)
Central macular thickness (mm)
IOP (mmHg)
IVR
IVR + IVTA
p
IVR
IVR + IVTA
p
IVR
IVR + IVTA
p
45.8 ± 23.2 66.8 ± 18.4 70.3 ± 17.9 65.2 ± 22.8 61.6 ± 25.3 60.3 ± 19.2 62.9 ± 22.2
47.3 ± 19.3 71.9 ± 20.7 74.4 ± 21.5 69.1 ± 23.1 65.8 ± 28.1 67.8 ± 22.4 72.3 ± 26.2
0.790 0.329 0.436 0.524 0.555 0.179 0.148
469.6 ± 46.8 385.3 ± 21.7 282.4 ± 16.4 306.4 ± 26.9 325.7 ± 16.8 298.4 ± 25.8 305.3 ± 22.3
476.9 ± 29.2 372.2 ± 37.3 293.7 ± 34.2 285.7 ± 18.7 317.3 ± 22.1 307.3 ± 21.1 298.8 ± 27.3
0.329 0.106 0.112 0.090 0.109 0.162 0.327
13.3 ± 3.3 12.6 ± 4.8 13.5 ± 3.8 13.6 ± 2.6 14.0 ± 2.8 13.6 ± 2.3 13.4 ± 3.2
14.8 ± 3.7 16.2 ± 4.2 15.8 ± 3.5 13.9 ± 2.8 15.7 ± 3.8 15.1 ± 4.2 15.9 ± 3.4
0.111 0.004 0.021 0.676 0.058 0.096 0.006
Data are presented as mean ± standard error. ETDRS, early treatment of diabetic retinopathy study; IVR, intravitreal ranibizumab; IVTA, intravitreal triamcinolone acetonide; IOP, intraocular pressure. Current Eye Research
Using Intravitreal Ranibizumab for Macular Edema
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FIGURE 1 A typical case of macular edema secondary to central retinal vein occlusion in a 54-year-old man. Fundus photographs before (a) and 1 week (b), 1 month (c), 2 months (d), and 6 months (e) after therapy (three intravitreal injections of 0.5 mg ranibizumab and 1.0 mg triamcinolone acetonide) are shown.
In recent years, IVR3,9 has been used to treat ME secondary to CRVO with exciting results. As a recombinant humanized antigen-binding fragment (rhuFab), ranibizumab has a low molecular weight and can easily penetrate the retina. This drug and Eylea are the only anti-VEGF agents that are FDAapproved for intraocular use in the treatment of eye disease. Ranibizumab’s overall safety and efficacy !
2014 Informa Healthcare USA, Inc.
have been well established in the treatment of agerelated macular degeneration.10 It has been shown to limit vascular leakage, prevent neovascularization, and reduce macular edema.11 Intravitreal anti-VEGF therapies do not treat the disease. They only treat symptoms of the disease, and the vast majority of patients require repeated intravitreal injections. Ranibizumab is very expensive and
942 C. Fan et al.
FIGURE 2 Optic coherence tomography images of macular edema secondary to central retinal vein occlusion in a 54-year-old man before (a) and 1 week (b), 1 month (c), 2 months (d), 3 months (e), and 6 months (f) after therapy are shown. Early treatment of diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) was 10 letters before treatment. Following treatment, the patient’s vision drastically improved, and 6 months after the first injection, ETDRS BCVA was 50 letters.
many Chinese patients cannot afford the high cost of this treatment. This has greatly limited its application in China, and thus it is important to determine the efficacy of alternative treatment options. This study was designed to compare the efficacy IVR and IVR + IVTA in the treatment of ME secondary to CRVO to determine if there is a more cost-effective therapy. Best-corrected visual acuity significantly improved with either IVR or IVR + IVTA therapy. Additionally, BCVA was not statistically different between the treatment groups at any time point examined. Central macular thickness, as measured with OCT, was significantly reduced from baseline in both treatment groups at all follow-up visits. The minimum CMT was observed in both groups at 3 months and there was no significant difference in CMT between groups at any time point examined. Therefore, these data show a comparable efficacy of IVR and IVR + IVTA. Intraocular pressure was also examined in this study because of the known influence of intraocular steroids on IOP. No significant differences between pre- and post-treatment IOP were observed in either
group at any follow-up visits. Additionally, average IOP was not statistically different between treatment groups at 3, 4, or 5 months into treatment. Intraocular pressure was slightly, but significantly, higher in the IVR + IVTA group than in the IVR group at 1, 2, and 6 months. This difference likely resulted from three subjects in the IVR + IVTA group that had an IOP421 mmHg. All elevated IOP episodes were successfully controlled with antiglaucomatous medication. Significant cataract formation was not noted and no endophthalmitis or retinal detachments occurred in either study group. Therefore, IVR and IVR + IVTA had similar safety profiles. The mean number of injections in the IVR + IVTA group (3.42 ± 0.41) was significantly lower than that in the IVR group (4.23 ± 0.56 injections, p = 0.0001). Therefore, it is possible that combining IVR and IVTA may reduce the required number of injections in the treatment of ME secondary to CRVO. Fewer injections mean lower costs, and this information is particularly important for patients who struggle to pay for the high cost of repeated IVR injections. Treating macular edema secondary to diabetic retinopathy with intraocular triamcinolone acetonide Current Eye Research
Using Intravitreal Ranibizumab for Macular Edema and bevacizumab does not increase the therapy’s long-term efficacy,12 but we found that the number of injections needed was less in the IVR + IVTA group than in the IVR group. It is likely that IVR and IVTA have synergistic effects. Triamcinolone acetonide has broad anti-inflammatory activity and ranibizumab – a humanized, affinity-matured anti-VEGF antibody fragment – binds and neutralizes all VEGF-A isoforms. Thus, this combination specifically prevents the recurrence of macular edema. In conclusion, IVR and IVR + IVTA were both associated with improvements in mean BCVA and CMT in patients with ME secondary to CRVO during a 6-month observation period. No significant difference in efficacy was noted between the two treatment groups. Eyes in the IVR group received a significantly higher number of injections than those in the IVR + IVTA group. To the best of our knowledge (based on a Medline literature search), this is the first report to directly compare IVR and IVR + IVTA in the treatment of ME secondary with CRVO. Our study showed the IVR + IVTA is safe and effective and may reduce the overall cost of therapy. Our study was limited by its small sample size and relatively short follow-up period. Further studies with a longer follow-up period and a larger number of patients are warranted to further assess the safety and efficacy of IVR + IVTA therapy.
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DECLARATION OF INTEREST This work was partly funded by ‘‘Shandong Nature Science Foundation (ref:2R2010HM098), China’’. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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retinal vein occlusion in a general Japanese population: the Hisayama study. Invest Ophthalmol Vis Sci 2011;52: 5905–5909. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology 1995; 102:1425–1433. Spaide RF, Chang LK, Klancnik JM, Yannuzzi LA, Sorenson J, Slakter JS, et al. Prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol 2009;147:298–306. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. Ophthalmology 1995;102:1425–1433. Mandelcorn MS, Nrusimhadevara RK. Internal limiting membrane peeling for decompression of macular edema in retinal vein occlusion: a report of 14 cases. Retina 2004;24: 348–355. Cekic¸ O, Chang S, Tseng JJ, Barile GR, Del Priore LV, Weissman H, et al. Intravitreal triamcinolone injection for treatment of macular edema secondary to branch retinal vein occlusion. Retina 2005;25:851–855. Holekamp NM, Thomas MA, Pearson A. The safety profile of long-term, high-dose intraocular corticosteroid delivery. Am J Ophthalmol 2005;139:421–428. Ip MS, Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA, Fisher M, et al. 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 Ophthalmol 2009;127:1101–1114. Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, 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: 1061–1063. Pieramici DJ, Avery RL. Ranibizumab: treatment in patients with neovascular age-related macular degeneration. Expert Opin Biol Ther 2006;6:1237–1245. Mete A, Saygili O, Mete A, Gungor K, Bayram M, Bekir N. Does ranibizumab (LucentisÕ ) change retrobulbar blood flow in patients with neovascular age-related macular degeneration? Ophthalmic Res 2012;47:141–145. Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 2009;116:1142–1150.
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ORIGINAL ARTICLE
Comparison of Clinical Efficacy of Intravitreal Ranibizumab with and without Triamcinolone Acetonide in Macular Edema Secondary to Central Retinal Vein Occlusion Chuanfeng Fan1,2, Yu Wang2, Qiang Ji2, Bojun Zhao1 and Juan Xie2 1
Department of Ophthalmology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, PR China and 2Department of Ophthalmology, The Second People’s Hospital of Jinan, Jinan, PR China
ABSTRACT Purpose: To compare visual outcomes and spectral-domain optical coherence tomography results following treatment with intravitreal ranibizumab (IVR) or IVR combined with intravitreal triamcinolone acetonide (IVTA) for macular edema (ME) secondary to central retinal vein occlusion (CRVO). Methods: This prospective, case-controlled study examined 57 eyes (57 patients) with ME secondary to CRVO, which were treated with IVR (0.5 mg, n = 30 eyes) or IVR (0.5 mg) and IVTA (1 mg, n = 27 eyes) as the initial therapy. Further intravitreal treatment was administered as necessary. Results: All 57 patients completed at least 6 months of follow-up. At baseline, mean ( ± standard error) bestcorrected visual acuity (BCVA) was 45.8 ± 23.2 letters in the IVR group and 47.3 ± 19.3 letters in the IVR + IVTA group (p = 0.790). Significant improvement in BCVA over baseline was observed in both groups at all six study visits (IVR group: p = 0.0003, 0.0001, 0.0018, 0.0145, 0.0107, 0.005; IVR + IVTA group: p = 0.0001, 0.0001, 0.0004, 0.0068, 0.0007, 0.0002), with no significant BCVA differences between groups. Significant reduction in mean central subfield thickness, compared with baseline, was also observed in both groups at all six study visits (IVR group, p = 0.0001; IVR + IVTA group, p = 0.0001), with no significant difference between groups in the magnitude of macular thickness reduction. The mean number of injections was significantly higher (p = 0.0001) in the IVR group (4.23 ± 0.56) than in the IVR + IVTA group (3.42 ± 0.41). Conclusions: Treating ME secondary to CRVO with IVR or IVR + IVTA had similar effects on central macular thickness and BCVA in patients with ME secondary to CRVO over a 6-month follow-up period. The mean number of intravitreal injections was higher in the IVR group than in the IVR + IVTA group. Keywords: Best-corrected visual acuity, central retinal vein occlusion, macular edema, ranibizumab, triamcinolone acetonide
INTRODUCTION
consequence of CRVO that causes irreversible visual loss is macular edema (ME), which is very difficult to treat. In recent years, intravitreal injections of triamcinolone acetonide or anti-VEGF agents have been effective, to a certain extent. Unfortunately, triamcinolone acetonide has serious side effects and ranibizumab is very expensive, so both therapies have certain restrictions. In an effort to determine the optimal therapy, this study was designed to compare
Central retinal vein occlusion (CRVO) is very commonly seen in clinical practice, and it often causes severe visual impairment. The CRVO prevalence rate gradually increases with age. Epidemiological data have shown that people over the age of 30 years have a CRVO prevalence rate of 0.3–0.5%, translating into about 250 million cases worldwide.1 The main
Received 2 October 2013; revised 6 January 2014; accepted 12 January 2014; published online 17 March 2014 Correspondence: Bojun Zhao, MD, Department of Ophthalmology, Shandong Provincial Hospital, Shandong University, No. 324 Jingwu Weiqi Road, Jinan, Shandong, 250021, PR China. Tel: +86 15318808857. Fax: +86 053181270613. E-mail: [email protected]
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Using Intravitreal Ranibizumab for Macular Edema clinical outcomes of intravitreal ranibizumab (IVR, LucentisÕ ) monotherapy, and IVR combined with intravitreal triamcinolone acetonide in eyes with ME secondary to CRVO.
MATERIALS AND METHODS The study was approved by The Second People’s Hospital of Jinan institutional review board. The study conduct adhered to the tenets of the Declaration of Helsinki. All patients provided written informed consent after they were informed about study procedures and the risks/benefits of the intraocular injection therapies examined. This prospective, controlled study examined patients presenting to the Second People’s Hospital of Jinan City with ME secondary to CRVO between August 2012 and February 2013. A total of 57 eyes from 57 patients (28 men and 29 women) were included in analyses. Patients ranged in age from 40 to 73 years. Patients were randomly divided into two treatment groups: those who received IVR (0.5 mg; LucentisÕ , Genentech, South San Francisco, CA) monotherapy (n = 30 eyes) and those that received combination treatment with IVR (0.5 mg) and IVTA (1 mg; Kunming Jida Pharmaceutical Co., Ltd., Kunming, China, n = 27 eyes).
Patients Patients had to meet all the following inclusion criteria to be included in analyses: (1) symptom duration 53 months, (2) best-corrected visual acuity (BCVA) worse than 20/40 (early treatment of diabetic retinopathy study [ETDRS] equivalent = 70 letters), (3) central macular thickness (CMT) on optical coherence tomography (OCT) 275 mm, and (4) fundus fluorescein angiogram (FFA) showing wide-spread diffuse leakage involving the macular and the fovea. If patients had any of the following exclusion criteria, their records were excluded from analyses: (1) intraocular pressure (IOP) 421 mmHg, (2) iris neovascularization, (3) previous history of intraocular surgery, and (4) previous grid photocoagulation or anti-VEGF treatments for other eye diseases (e.g. hypertension, diabetic retinopathy, uveitis, and macular disease).
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room with a sharp 29-Gauge needle. The needle was inserted into the eye through the pars plana, 3.5–4 mm from the limbus. Either ranibizumab (0.5 mg in 0.05 mL) or a mixture of ranibizumab (0.5 mg in 0.05 mL) and triamcinolone acetonide (1 mg in 0.025 mL, Kunming Jida Pharmaceutical Co., Ltd., Kunming, China) was injected.
Panretinal Photocoagulation When fundus fluorescein angiography revealed ischemic central retinal vein occlusion with retinal or disc neovascularization, 3–4 sessions of panretinal photocoagulation (PRP) sessions were conducted within 1 month to prevent neovascular glaucoma.
Patient Follow-up All patients returned for follow-up 1 d, 1 week, and 1 month after their first intravitreal injection. Patients were followed up monthly thereafter. The BCVA and IOP (Goldman tonometer, PacScan 300AP, Sonomed, NY) were measured, slit lamp, and indirect ophthalmoscopy were performed, and spectraldomain optical coherence tomography (OCT) images were collected to measure central macular retinal thickness (CMT). Color fundus photographs were also taken and complications were observed and noted. Eyes were retreated when any of the following conditions occurred: (1) visual acuity loss 10 ETDRS letters and macular effusion was observed on OCT images, (2) central retinal thickness, measured on OCT, increased by 4100 mm compared with the previous measurement, (3) new effusion was present on OCT.
Statistical Analyses Data are presented as mean ± standard error. All statistical calculations were performed using standard software (SPSS version 15.0, SPSS, Inc., Chicago, IL). Visual acuity and CMT changes before and after treatment were compared using t-tests. The Chisquare test was used to compare incidence rates between groups. A p value 50.05 was considered statistically significant.
The Intravitreal Injection Procedure RESULTS All patients were informed of the purpose, potential benefits, and possible complications of intravitreal drug therapy. When ready, subjects signed an informed consent form before each intraocular injection. All injections were performed in the operating !
2014 Informa Healthcare USA, Inc.
Baseline clinical characteristics of the IVR and the IVR + IVTA groups are summarized and compared in Table 1. No significant differences between the groups were found.
940 C. Fan et al. The BCVA, IOP, and CMT were monitored over time to determine and compare the efficacy of the two treatments. No significant differences between groups existed at any time point measured for BCVA or CMT (Table 2). At 1, 2, and 6 months, IOP was significantly higher in the IVR + IVTA combination therapy group than in the IVR monotherapy group. The BCVA had significantly improved over baseline values at all follow-up visits in both the IVR and the IVR + IVTA groups. At the last follow-up visit (6 months), 19 eyes (63.3%) in the IVR group, and 20 eyes (74.1%) in the IVR + IVTA group had a visual gain of more than 15 ETDRS letters, a difference that was not statistically significant ( 2 = 0.759, p = 0.384). The CMT at baseline was 469.6 ± 26.8 mm in the IVR group and 476.9 ± 29.2 mm in the IVR + IVTA group (p = 0.329). A significant reduction in CMT from baseline was observed in both study groups at all study visits (Table 2). The minimum CMT occurred 3 months into treatment in both groups. Additionally, there were no significant differences in CMT between treatment groups at any follow-up visit (Table 2). Intraocular pressure at baseline was normal in both groups at 13.3 ± 3.3 mmHg in the IVR group and 14.8 ± 3.7 mmHg in the IVR + IVTA group (p = 0.111). No significant differences from baseline were seen in IOP for either group at any time point examined.
TABLE 1 Baseline clinical characteristics. IVR
IVR + IVTA
n (eyes) 30 27 Age (years) 61.8 ± 7.8 62.3 ± 8.9 Sex (male/female) 14/16 14/13 Duration of ME (months) 1.3 ± 0.6 1.5 ± 0.8 Systolic blood pressure 153.4 ± 38.9 159.8 ± 32.7 (mmHg) Diastolic blood pressure 85.6 ± 18.3 89.1 ± 17.5 (mmHg) Macular ischemia/no ischemia 18/12 14/13 PRP (yes/no) 19/11 16/11
P 0.822 0.696 0.287 0.507 0.465 0.536 0.752
IVR, intravitreal ranibizumab; IVTA, intravitreal triamcinolone acetonide; ME, macular edema; PRP, panretinal photocoagulation.
Additionally, there was no difference in IOP between treatment groups at 3, 4, or 5 months, but it was significantly higher in the IVR + IVTA groups at 1, 2, and 6 months. Although there were no significant changes in mean IOP from baseline, three eyes had an IOP421 mmHg in the IVR + IVTA group. All episodes of elevated IOP were controlled with antiglaucomatous medication. The average number of injections administered in the IVR group was 4.23 ± 0.56 injections. This was significantly higher than the 3.42 ± 0.41 injections given to the IVR + IVTA group (p = 0.0001). No significant cataract formation was observed, and no serious complications of the injection procedure (e.g. endophthalmitis, retinal detachment) occurred.
DISCUSSION Macular edema is the most common cause of severe visual loss in eyes with CRVO. According to a National Eye Institute (Bethesda, MD) survey,3 macular edema will seriously diminish a patient’s quality of life. The Central Vein Occlusion Study showed that traditional treatment methods (e.g. laser photocoagulation) can reduce macular edema and prevent retinal and iris neovascularization, but they do not significantly restore visual function.4 Newer therapies, such as internal limiting membrane stripping/peeling during vitrectomy and the macular puncture technique,5 have been reported to be useful, but have not been widely used because of serious complications. Intravitreal injection of triamcinolone acetonide has been proven effective in treating ME secondary to CRVO,6 but postoperative complications, including cataract development and increased IOP, have limited the application of this approach in the clinical setting. Approximately 25% of patients develop elevated IOP from intraocular steroid use.7 A 2009 multi-center, randomized, controlled trial8 examined the safety and efficacy of 1 mg and 4 mg IVTA in 271 eyes with macular edema. The results indicated a comparable efficacy of the two doses, but that the 1 mg dose had a better safety profile than the 4 mg dose.
TABLE 2 Best-corrected visual acuity, central macular thickness, and intraocular pressure during the 6 month monitoring period. Time (months) 0 1 2 3 4 5 6
ETDRS best-corrected visual acuity (letters)
Central macular thickness (mm)
IOP (mmHg)
IVR
IVR + IVTA
p
IVR
IVR + IVTA
p
IVR
IVR + IVTA
p
45.8 ± 23.2 66.8 ± 18.4 70.3 ± 17.9 65.2 ± 22.8 61.6 ± 25.3 60.3 ± 19.2 62.9 ± 22.2
47.3 ± 19.3 71.9 ± 20.7 74.4 ± 21.5 69.1 ± 23.1 65.8 ± 28.1 67.8 ± 22.4 72.3 ± 26.2
0.790 0.329 0.436 0.524 0.555 0.179 0.148
469.6 ± 46.8 385.3 ± 21.7 282.4 ± 16.4 306.4 ± 26.9 325.7 ± 16.8 298.4 ± 25.8 305.3 ± 22.3
476.9 ± 29.2 372.2 ± 37.3 293.7 ± 34.2 285.7 ± 18.7 317.3 ± 22.1 307.3 ± 21.1 298.8 ± 27.3
0.329 0.106 0.112 0.090 0.109 0.162 0.327
13.3 ± 3.3 12.6 ± 4.8 13.5 ± 3.8 13.6 ± 2.6 14.0 ± 2.8 13.6 ± 2.3 13.4 ± 3.2
14.8 ± 3.7 16.2 ± 4.2 15.8 ± 3.5 13.9 ± 2.8 15.7 ± 3.8 15.1 ± 4.2 15.9 ± 3.4
0.111 0.004 0.021 0.676 0.058 0.096 0.006
Data are presented as mean ± standard error. ETDRS, early treatment of diabetic retinopathy study; IVR, intravitreal ranibizumab; IVTA, intravitreal triamcinolone acetonide; IOP, intraocular pressure. Current Eye Research
Using Intravitreal Ranibizumab for Macular Edema
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FIGURE 1 A typical case of macular edema secondary to central retinal vein occlusion in a 54-year-old man. Fundus photographs before (a) and 1 week (b), 1 month (c), 2 months (d), and 6 months (e) after therapy (three intravitreal injections of 0.5 mg ranibizumab and 1.0 mg triamcinolone acetonide) are shown.
In recent years, IVR3,9 has been used to treat ME secondary to CRVO with exciting results. As a recombinant humanized antigen-binding fragment (rhuFab), ranibizumab has a low molecular weight and can easily penetrate the retina. This drug and Eylea are the only anti-VEGF agents that are FDAapproved for intraocular use in the treatment of eye disease. Ranibizumab’s overall safety and efficacy !
2014 Informa Healthcare USA, Inc.
have been well established in the treatment of agerelated macular degeneration.10 It has been shown to limit vascular leakage, prevent neovascularization, and reduce macular edema.11 Intravitreal anti-VEGF therapies do not treat the disease. They only treat symptoms of the disease, and the vast majority of patients require repeated intravitreal injections. Ranibizumab is very expensive and
942 C. Fan et al.
FIGURE 2 Optic coherence tomography images of macular edema secondary to central retinal vein occlusion in a 54-year-old man before (a) and 1 week (b), 1 month (c), 2 months (d), 3 months (e), and 6 months (f) after therapy are shown. Early treatment of diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) was 10 letters before treatment. Following treatment, the patient’s vision drastically improved, and 6 months after the first injection, ETDRS BCVA was 50 letters.
many Chinese patients cannot afford the high cost of this treatment. This has greatly limited its application in China, and thus it is important to determine the efficacy of alternative treatment options. This study was designed to compare the efficacy IVR and IVR + IVTA in the treatment of ME secondary to CRVO to determine if there is a more cost-effective therapy. Best-corrected visual acuity significantly improved with either IVR or IVR + IVTA therapy. Additionally, BCVA was not statistically different between the treatment groups at any time point examined. Central macular thickness, as measured with OCT, was significantly reduced from baseline in both treatment groups at all follow-up visits. The minimum CMT was observed in both groups at 3 months and there was no significant difference in CMT between groups at any time point examined. Therefore, these data show a comparable efficacy of IVR and IVR + IVTA. Intraocular pressure was also examined in this study because of the known influence of intraocular steroids on IOP. No significant differences between pre- and post-treatment IOP were observed in either
group at any follow-up visits. Additionally, average IOP was not statistically different between treatment groups at 3, 4, or 5 months into treatment. Intraocular pressure was slightly, but significantly, higher in the IVR + IVTA group than in the IVR group at 1, 2, and 6 months. This difference likely resulted from three subjects in the IVR + IVTA group that had an IOP421 mmHg. All elevated IOP episodes were successfully controlled with antiglaucomatous medication. Significant cataract formation was not noted and no endophthalmitis or retinal detachments occurred in either study group. Therefore, IVR and IVR + IVTA had similar safety profiles. The mean number of injections in the IVR + IVTA group (3.42 ± 0.41) was significantly lower than that in the IVR group (4.23 ± 0.56 injections, p = 0.0001). Therefore, it is possible that combining IVR and IVTA may reduce the required number of injections in the treatment of ME secondary to CRVO. Fewer injections mean lower costs, and this information is particularly important for patients who struggle to pay for the high cost of repeated IVR injections. Treating macular edema secondary to diabetic retinopathy with intraocular triamcinolone acetonide Current Eye Research
Using Intravitreal Ranibizumab for Macular Edema and bevacizumab does not increase the therapy’s long-term efficacy,12 but we found that the number of injections needed was less in the IVR + IVTA group than in the IVR group. It is likely that IVR and IVTA have synergistic effects. Triamcinolone acetonide has broad anti-inflammatory activity and ranibizumab – a humanized, affinity-matured anti-VEGF antibody fragment – binds and neutralizes all VEGF-A isoforms. Thus, this combination specifically prevents the recurrence of macular edema. In conclusion, IVR and IVR + IVTA were both associated with improvements in mean BCVA and CMT in patients with ME secondary to CRVO during a 6-month observation period. No significant difference in efficacy was noted between the two treatment groups. Eyes in the IVR group received a significantly higher number of injections than those in the IVR + IVTA group. To the best of our knowledge (based on a Medline literature search), this is the first report to directly compare IVR and IVR + IVTA in the treatment of ME secondary with CRVO. Our study showed the IVR + IVTA is safe and effective and may reduce the overall cost of therapy. Our study was limited by its small sample size and relatively short follow-up period. Further studies with a longer follow-up period and a larger number of patients are warranted to further assess the safety and efficacy of IVR + IVTA therapy.
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DECLARATION OF INTEREST This work was partly funded by ‘‘Shandong Nature Science Foundation (ref:2R2010HM098), China’’. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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