INTRAVITREAL RANIBIZUMAB FOR RETINAL VEIN OCCLUSION THROUGH 1 YEAR IN CLINICAL PRACTICE TROELS BRYNSKOV, MD,*† HENRIK KEMP, MD,* TORBEN L. SØRENSEN, MD, DMSC*† Purpose: To evaluate the efficacy and safety of intravitreal ranibizumab for branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) in daily clinical practice. Methods: A prospective study enrolling all patients diagnosed with BRVO or CRVO who received intravitreal ranibizumab therapy at our department. Results: Fifty-seven patients had BRVO and 49 had CRVO. By 12 months, the patients with BRVO improved a mean of 11.6 (P , 0.0001) ETDRS (Early Treatment Diabetic Retinopathy Study) letters, whereas the patients with CRVO improved a mean of 1.8 letters (P = 0.50). The proportion of patients gaining $15 ETDRS letters was 26.3% for BRVO and 16.7% for CRVO. The proportion of patients losing $15 ETDRS letters was 0% for BRVO and 8.3% for CRVO. The reduction in foveal center point thickness at 12 months was 248 mm for BRVO (P , 0.0001) and 222 mm for CRVO (P , 0.0001). Functional outcome did not mirror anatomical outcome, and younger patients had better outcome. Conclusion: Our 12-month results of BRVO treated with intravitreal ranibizumab in daily clinical practice are similar to the results of the BRAVO trial that led to the approval of the therapy. However, our results for CRVO failed to reproduce the results of the CRUISE trial. RETINA 34:1637–1643, 2014
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CRUISE7—two large randomized multicenter studies— recently found ranibizumab (Lucentis; Novartis, Basel, Switzerland) beneficial for BRVO and CRVO, and the Danish Health and Medicines Authority approved intravitreal injections with ranibizumab for RVO in January 2011. Daily clinical practice is often different from the setting of randomized clinical trials. We, therefore, prospectively collected treatment data of all patients receiving intravitreal ranibizumab for CRVO and BRVO at our department to evaluate and compare the efficacy and safety with the randomized controlled trials that led to the introduction of the therapy.
etinal vein occlusion (RVO) is a vascular disease that is caused by an obstruction in either a branch retinal vein (BRVO) or in the central retinal vein (CRVO). This leads to a retinal edema that can seriously reduce visual acuity when the fovea is involved. Branch retinal vein occlusion can improve spontaneously but can also deteriorate further whereas CRVO rarely improves spontaneously and often deteriorates without treatment.1,2 Treatment of macular edema in RVO has long posed a challenge to clinicians. Until recently, the guiding principle for the management of unresolving BRVO was central grid laser, whereas no treatment was available for CRVO.3 Intraocular vascular endothelial growth factor (VEGF) is highly elevated in RVO,4,5 and novel therapeutic approaches have emerged for the management of macular edema in RVO such as intravitreal corticosteroid injections and intravitreal anti-VEGF injections. BRAVO6 and
Material and Methods Patients We consecutively included all patients with RVO who received intravitreal ranibizumab from January 2011 to April 2013. Patient data were continuously updated in a database. We excluded patients with diabetic macular edema, severe macular traction, previous injection with dexamethasone implant, or cataract surgery during the treatment period. The first visit
From the *Department of Ophthalmology, Copenhagen University Hospital Roskilde, Roskilde, Denmark; and †Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Troels Brynskov, MD, Department of Ophthalmology, Copenhagen University Hospital Roskilde, Køgevej 7-13, Roskilde DK-4000, Denmark; e-mail: [email protected]
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after the initiation of ranibizumab therapy was defined as the 5-month follow-up. The visit in the range 9 to 15 months closest to 12 months was defined as the 12-month follow-up. If a patient was discontinued from further treatment before 9 months, the last observation was carried forward for the 12-month analysis. Patients diagnosed with hemicentral vein occlusion were considered as BRVO in line with the criteria for the BRAVO study.7 All patients who had received a minimum of one intravitreal injection with ranibizumab for RVO were included in the safety analysis. Clinical Examination and Outcome Measures At the first visit, a full medical history was taken. Slit-lamp and fundus biomicroscopic examinations were performed in all patients. Best-corrected visual acuity (BCVA) testing was performed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual chart (CC-100, Topcon Corporation, Tokyo, Japan), and the intraocular pressure was determined using rebound tonometry (Icare; Icare Finland Oy, Helsinki, Finland) followed by Goldmann applanation tonometry if ocular hypertension or glaucoma was suspected. Spectral domain optical coherence tomography (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany) scanning was performed in all eyes using eye-tracking for follow-up measurements to maximize intersession repeatability.8 Foveal center point thickness (CPT) was assessed using the manufacturer’s proprietary software (Heidelberg Eye Explorer 1.7.1.0). Fluorescein angiography was not routinely performed and neither was the assessment of the presence of an afferent papillary defect. The duration of symptoms was defined as the patients’ subjective assessment of symptom duration by the initiation of anti-VEGF therapy. Serous macular detachment was defined as the presence of fluid under the neuroretina but above the retinal pigment epithelium layer determined by spectral domain optical coherence tomography. We considered a gain of 15 ETDRS letters or more as functional success,9 and reaching a CPT below 275 mm—with Heidelberg equipment—as anatomical success.10 Patient Management Treatment, monitoring, and decision regarding retreatment or discontinuation of treatment followed the Danish National guidelines set forward by the Danish Ophthalmological Society. Intravitreal anti-VEGF was initiated in all patients with visual impairment deemed to result from subfoveal edema secondary to RVO. All patients were treated promptly after diagnosis. An exception was BRVO patients with initial BCVA of
2014 VOLUME 34 NUMBER 8
more than 70 ETDRS letters who were observed for 3 months for spontaneous resolution. Anti-VEGF treatment was usually initiated as a series of 3 intravitreal injections of 0.5 mg ranibizumab each month for 3 months followed by a follow-up examination 1 to 2 months after the third injection. We continued with 1 to 3 monthly injections if there was an improvement in the BCVA or on spectral domain optical coherence tomography, unless the macula was devoid of edema. Causes of discontinuation were unchanged/decreased BCVA and/or lack of improvement on spectral domain optical coherence tomography. In BRVO, adjuvant central photocoagulation was applied in the case of unsatisfactory response to intravitreal therapy at the investigators discretion. Panretinal laser photocoagulation was applied if retinal neovascularizations developed. Data Analysis The changes in both BCVA and CPT followed a normal distribution, and a paired student’s t-test was performed comparing baseline BCVA and CPT to 5 months and baseline to 12 months for both BRVO and CRVO. Multiple linear regression analysis with backward elimination was performed pooled for all patients with change in BCVA or CPT as dependent variables. The data were analyzed using SAS 9.3 (SAS Institute Inc, Cary, NC). A P value less than 0.05 was considered significant. Results Patients One hundred and twenty patients had attended the first follow-up visit. Fourteen patients were excluded (2 had diabetic macular edema, 1 had severe vitreomacular traction, 10 had received an intravitreal sustained release implant before ranibizumab treatment, and 1 underwent cataract surgery during the treatment period). Seventy-four of the remaining 106 patients had follow-up through at least 9 months and were included for the 12-month analysis. The baseline data are shown in Table 1. Patients with BRVO had received a median of 5 (interquartile range, 3–5.5) injections whereas patients with CRVO had received a median of 6 (interquartile range, 3–6) injections. Four patients received bilateral treatment. Six patients were discontinued before 9 months of follow-up because of: nonresponse and change to dexamethasone implant therapy (n = 2), nonresponse in patients with very poor baseline visual acuity (n = 2), or development of neovascular glaucoma (n = 2). Five patients had received macular laser before initiating intravitreal ranibizmab, and one patient had central grid laser
RANIBIZUMAB FOR RVO IN CLINICAL PRACTICE BRYNSKOV ET AL Table 1. Baseline Data
Eyes, n Age, mean (SD), years Male, n (%) Symptom duration, months, median (IQR) Ocular tension, mmHg, mean (SD) Serous macular detachment, n (%) BCVA Mean number of ETDRS letters (SD) #34, n (%) 35–54, n (%) $55, n (%) CPT, mean (SD), mm
BRVO
CRVO
57 67 (13) 31 (54) 3 (1–6)
49 71 (10) 34 (69) 6 (3–9)
16 (3)
16 (3)
23 (40)
22 (45)
54.7 (16.1) 51.2 (18.5) 6 20 31 638
(11) (35) (54) (208)
11 11 27 615
(22) (22) (55) (208)
BRVO, branch vein occlusion; CRVO, central vein occlusion; SD, standard deviation; IQR, interquartile range; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CPT, foveal centre point thickness.
performed after ranibizumab treatment was initiated. Median follow-up was 9.7 months (interquartile range, 5.1–12.8) for BRVO patients and 11.2 months (interquartile range, 6.5–13.0) for CRVO patients. Functional Outcome Patients with BRVO improved a mean of 9.4 (P , 0.0001) ETDRS letters at Month 5 and 11.6 letters
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at Month 12 (P , 0.0001). Patients with CRVO improved a mean of 5.7 letters (P , 0.0001) at Month 5 and 1.8 letters at Month 12 (P = 0.50) (Table 2). In BRVO, 31.6% gained 15 ETDRS letters or more at 5 months and 26.3% at 12 months. An additional 28.9% gained 10 to 14 letters at 12 months. Only 1.8% and 0% lost 15 letters or more at 5 months and 12 months, respectively (Figure 1). In CRVO, 24.5% gained 15 letters or more at 5 months, but only 16.7% by 12 months, and just 11.1% gained 10 to 14 letters. A total of 6.1% and 8.3% lost 15 ETDRS letters or more by 5 months and 12 months, respectively (Figure 2). We performed a multiple linear regression analysis for all patients combined, adjusting for age, gender, type of retinal occlusion, ocular tension, presence of serous macular detachment, subjective duration of ocular symptoms, BCVA, and CPT. Younger patients gained 0.45 ETDRS letter (95% confidence interval [CI], 0.13–0.71, P , 0.0001) per year of age. Patients with lower baseline BCVA gained 0.21 ETDRS letters (95% CI, 0.05–0.37, P = 0.01) per affected letter at baseline. At 5 months, there was no significant difference between patients with CRVO and BRVO (P = 0.1). By 12 months, BRVO patients had an adjusted 8.8 ETDRS letters (95% CI, 3.4–14.3, P = 0.002) improvement over CRVO patients. Patients with serous macular detachment improved 7.3 ETDRS letters at 5 months (95% CI, 2.2–12.6, P = 0.006), but the difference was −2.0 letters at 12 months (95% CI, −7.6 to 3.6, P = 0.49).
Table 2. Treatment Outcome After Initiation of Intravitreal Injections With Ranibizumab BRVO
P
CRVO
P
n Baseline 5 months 12 months BCVA, ETDRS letters, mean ± SEM Baseline 5 months 12 months BCVA change,* ETDRS letter, mean ± SEM 0–5 months 0–12 months CPT, mm, mean ± SEM Baseline 5 months 12 months CPT change,* mm, mean ± SEM 0–5 months 0–12 months
57 57 38
49 49 36
54.7 ± 2.1 64.1 ± 2.0 66.0 ± 2.8
51.2 ± 2.6 56.9 ± 2.8 52.9 ± 2.9
9.4 ± 1.8 11.6 ± 2.2
,0.0001 ,0.0001
638 ± 28 421 ± 31 373 ± 35 −217 ± 29 −248 ± 38
5.7 ± 2.1 1.8 ± 2.5
0.009 0.50
617 ± 30 435 ± 36 416 ± 34 ,0.0001 ,0.0001
−192 ± 39 −222 ± 34
,0.0001 ,0.0001
*Paired difference, 12 months compared only for patients with follow-up through 12 months. BRVO, branch vein occlusion; CRVO, central vein occlusion; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CPT, foveal centre point thickness. SEM, standard error of the mean.
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success. There was no clear pattern between achieving functional success and the corresponding anatomical status. The proportion of patients who achieved neither success criteria was 45% to 53%. Safety
Fig. 1. Distribution of change in visual acuity for branch vein occlusions 5 months and 12 months after initiation of intravitreal injections with ranibizumab.
A total of 617 injections have been given for RVO at our department including patients treated beyond 12 months and patients excluded for the efficacy analysis. No sight-threatening ocular adverse events were recorded. One patient experienced a nonfatal ischemic stroke 3 days after his third ranibizumab injection. A computer tomography of the cerebrum however only revealed signs of older minor infarctions.
Anatomical Outcome In BRVO, there was a reduction in CPT of 217 mm at 5 months (P , 0.0001) and of 248 mm at 12 months (P , 0.0001). In CRVO, the reduction in CPT was 192 mm (P , 0.0001) and 222 mm (P , 0.0001), respectively (Table 2). We performed a multiple linear regression analysis for CPT adjusting for the same factors as in the functional outcome. Younger patients improved 5 mm (95% CI, 1.1–9.2, P = 0.01) more in CPT per year of age at 12 months, and patients with thicker retina improved 0.5 mm (95% CI, 0.26–0.74, P = 0.0001) per micrometer of CPT at baseline. There was no difference between BRVO versus CRVO at 5 (P = 0.77) or 12 months (P = 0.85). Serous macular detachment at baseline led to an adjusted improved reduction in CPT of 99.4 mm (95% CI, 5–194, P = 0.04) at 12 months. Functional and Anatomical Outcome Combined We compared the functional and anatomical success criteria in Table 3. In total, 22% to 31% reached the anatomical success without accompanying functional
Fig. 2. Distribution of change in visual acuity for central vein occlusions 5 months and 12 months after initiation of intravitreal injections with ranibizumab.
Discussion We found our BCVA results for BRVO to be within our expectations, but for CRVO, the mean improvement of 1.8 letters at 12 months was below our expectations. The reduction in CPT was satisfactory for both groups, but the visual gain did not appear to mirror the decreased macular edema as 22% to 31% reached the anatomical success criteria without an accompanying significant improvement in BCVA. Daily clinical practice is different from the setting of randomized controlled clinical trials. First, the inclusion criteria of BRAVO and CRUISE differed from our study. The randomized trials did not include patients with BCVA above 70 ETDRS letters (0.5 Snellen equivalents), a group of patients with less potential to improve vision by 15 ETDRS letters or more because of ceiling effect. Patients with baseline visual acuity below 20/400 (approximately 20 ETDRS letters) were not included in BRAVO and CRUISE, a group of patients so severely affected that improvement is less likely. In Table 4, we have compared our patients with baseline BCVA between 20 and 70 letters with the randomized trials. This subgroup has slightly better results, but both in BRVO and CRVO, our results were superior to the sham arms and inferior to the 2 treatment arms of the randomized trials. BRAVO and CRUISE did not have a sham or 0.3 ranibizumab arm at 12 months because those patients were converted to a 0.5-mg ranibizumab dosing regimen. Second, BRAVO and CRUISE had several exclusion criteria that we did not. For instance, patients with brisk afferent pupillary defect or previous RVO were excluded in those studies. Pupillary defect is often caused by extensive capillary nonperfusion, and such patients would be expected to improve less. We have no reliable estimation of the number of patients with afferent pupillary defect in our cohort, and
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RANIBIZUMAB FOR RVO IN CLINICAL PRACTICE BRYNSKOV ET AL Table 3. Correlation of Functional and Anatomical Success After Intravitreal Ranibizumab in BRVO +Anatomical Success*
−Anatomical Success*
Total
14/18 22/29 36/47
17/8 47/45 64/53
31/26 69/74 100/100
13/6 28/31 41/36
11/11 48/53 59/64
24/17 76/83 100/100
BRVO +Functional success† (5/12 months, %) −Functional success† (5/12 months, %) Total BRVO (5/12 months, %) CRVO + Functional success† (5/12 months, %) −Functional success† (5/12 months, %) Total CRVO (5/12 months, %)
Three patients with missing baseline measures of centre point thickness were excluded from this analysis. *Foveal centre point thickness reduced to less than 275 mm. †Best-corrected visual acuity improving at least 15 ETDRS letters or more compared with baseline.
we did not perform fluorescein angiography routinely. A high degree of retinal ischemia in our CRVO patients could have negatively affected our results. Third, our patients were solely white and older than the ethnically mixed participants of BRAVO and CRUISE. Older age has been found to be a risk factor for poorer visual prognosis in untreated CRVO,11 and we also found this association in our regression analysis. Fourth, the treatment regimen differed. The therapy in BRAVO and CRUISE was initiated with an injection each month for 6 consecutive months followed by injections as needed, whereas we usually initiated
therapy with 3 injections 1 month apart followed by usually 8 weeks of observation before further observation and retreatment. Eight weeks of follow-up compares with 4 weeks in the randomized controlled trials, and the edema may have returned in the interim period. Although we endeavor a 4-week to 6-week interval for follow-up, our department is time constrained because of a constant rise in the number of patients undergoing antiVEGF treatment. Because of all these differences between randomized controlled clinical trials and our daily clinical practice, it is to be expected that our results are less impressive. However, the level of
Table 4. Comparison of Visual Outcome in Randomized Clinical Trials and the Present Study BRVO
BRAVO sham6 5–6 months n Mean change* $15 letters (%)† #15 letters (%)‡ 12 months n Mean change* $15 letters (%)† #15 letters (%)‡
CRVO
BRAVO 0.3 BRAVO 0.5 mg6 mg6
This Study, Baseline BCVA 20-70 letters
CRUISE sham7
CRUISE 0.3 mg7
CRUISE 0.5 mg7
This Study, Baseline BCVA 20-70 letters
132 7.3
134 16.6
131 18.3
47 11.0
130 0.8
132 12.7
130 14.9
38 6.6
28.8
55.2
61.1
36.3
16.9
46.2
47.7
28.9
4.5
0
1.5
2.1
15.4
3.8
1.5
7.9
§ §
§ §
131 18.3
31 12.8
§ §
§ §
130 13.9
29 2.6
§
§
60.3
29.0
§
§
50.8
17.2
§
§
2.3
0
§
§
2.3
6.9
*Mean change in ETDRS letters from baseline. †Percentage of patients gaining 15 ETDRS letters or more. ‡Percentage of patients losing 15 ETDRS letters or more. §No data, the patients were converted to treatment with 0.5 mg ranibizumab.
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difference for CRVO at 12 months remains discouraging. Nevertheless, our results are superior to conventional laser treatment and sham at both 5 months to 6 months and 12 months when comparing with the sham and laser arms of other randomized clinical trials,12–14 and only few of our patients had a decrease in BCVA. The results of the present study have prompted us to change our local treatment guidelines to address concerns of undertreatment and undermonitoring and more closely follow the BRAVO and CRUISE regimen. Our study does not address the role of dexamethasone implants in RVO. Six (46%) of the 13 patients with hemicentral retinal vein occlusion gained at least 15 ETDRS letters. As in BRAVO, these patients were included in the BRVO group, but hemicentral vein occlusion should ideally be considered a separate disease entity.15 Our results for this subgroup of patients are encouraging. Changes in BCVA were only little to moderately related to quality of life changes in BRAVO and CRUISE.16 This is also our clinical experience, although we have not systematically assessed quality of life changes. Our CPT measurements were performed with Heidelberg equipment, and the absolute thickness cannot be directly compared with other manufacturer’s equipment8 such as the Stratus (Zeiss) equipment used in the BRAVO and CRUISE studies. The change in CPT should however be similar, and our reduction of 217 mm for BRVO at 5 months compares with 339 mm and 345 mm for the 0.3-mg and 0.5-mg arm versus 158 mm for the sham arm in BRAVO.6 Similarly, the mean reduction of 192 mm for our CRVO patients at 5 months compares with 435 mm and 453 mm for the 0.3 mg and 0.5 mg ranibizumab versus 168 mm for the sham arm in CRUISE.7 Similar to the BCVA results, our results are superior to the sham arm and inferior to the treatment arm of BRAVO and CRUISE. The improved response in younger patients for both CPT and BCVA and with worse baseline BCVA or CPT is consistent with the findings of other studies of ranibizumab for diabetic macular edema17 and agerelated macular degeneration.18,19 To the best of our knowledge, subgroup analysis for this parameter has not yet been published for the BRAVO and CRUISE trials. Other studies on the role of serous macular detachment have been contradicting: One study found an improved treatment effect in patients with serous macular detachment,20 whereas subgroup analysis of the BRAVO and CRUISE data did not find the presence of submacular fluid to influence visual outcome.21 We found that serous macular detachment was related to a slower improvement in visual function, but at
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12 months, the visual outcome was similar to patients without serous macular detachment. Strengths of this study are that almost every patient treated in our daily clinical setting through more than 2 years has been included for analysis. A limitation of this study is the nonrandomized design, and we were unable to control for the natural course of BRVO and CRVO. Though we have made attempts to compare our results with the sham and laser arms of clinical trials, we acknowledge that such comparisons have numerous caveats. In conclusion, in our daily clinical practice, intravitreal ranibizumab for BRVO led to 12-month visual improvements that were comparable with those of the BRAVO trial that led to the approval of the therapy for BRVO. However, our visual results for CRVO at 12 months failed to reproduce the results of the CRUISE trial that led to the approval of the therapy for CRVO. In both BRVO and CRVO, we found a significant reduction of foveal CPT, but the anatomical outcome did not mirror the functional outcome. Younger and more severely affected patients responded more favourably to the treatment. No safety issues were identified. These results have prompted us to a closer adherence to the treatment protocol of the CRUISE trial for CRVO patients. Key words: anti-VEGF, branch vein occlusion, central vein occlusion, clinical practice, macular edema, ranibizumab, retinal vein occlusion. References 1. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094–1101.e5. 2. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1113–1123.e15. 3. Hahn P, Fekrat S. Best practices for treatment of retinal vein occlusion. Curr Opin Ophthalmol 2012;23:175–181. 4. Funk M, Kriechbaum K, Prager F, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci 2008;50:1025–1032. 5. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487. 6. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology 2011;118:1594–1602. 7. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118:2041–2049. 8. Wolf-Schnurrbusch UEK, Ceklic L, Brinkmann CK, et al. Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci 2009;50:3432–3437.
RANIBIZUMAB FOR RVO IN CLINICAL PRACTICE BRYNSKOV ET AL 9. Shah N, Laidlaw DAH, Shah SP, et al. Computerized repeating and averaging improve the test-retest variability of ETDRS visual acuity measurements: implications for sensitivity and specificity. Invest Ophthalmol Vis Sci 2011;52:9397–9402. 10. Grover S, Murthy RK, Brar VS, et al. Comparison of retinal thickness in normal eyes using stratus and spectralis optical coherence tomography. Invest Ophthalmol Vis Sci 2010;51: 2644–2647. 11. Chen JC, Klein ML, Watzke RC, et al. Natural course of perfused central retinal vein occlusion. Can J Ophthalmol 1995;30:21–24. 12. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127:1115–1128. 13. Ip MS, Scott IU, VanVeldhuisen PC, 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. 14. CVOS Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein
15. 16.
17.
18.
19.
20.
21.
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Occlusion Study Group M report. Ophthalmology 1995;102: 1425–1433. Hayreh SS, Zimmerman MB. Hemicentral retinal vein occlusion: natural history of visual outcome. Retina 2012;32:68–76. Varma R, Bressler NM, Suñer I, et al. Improved vision-related function after ranibizumab for macular edema after retinal vein occlusion. Ophthalmology 2012;119:2108–2118. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol 2012;130:1153–1161. Kaiser PK, Brown DM, Zhang K, et al. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol 2007;144:850–857. Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007;114:246–252. Gallego-Pinazo R, Dolz-Marco R, Pardo-López D, et al. Ranibizumab for serous macular detachment in branch retinal vein occlusions. Graefes Arch Clin Exp Ophthalmol 2013;251:9–14. Bhisitkul RB, Campochiaro PA, Shapiro H, et al. Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography. Ophthalmology 2013;120:1057–1063.
R
CRUISE7—two large randomized multicenter studies— recently found ranibizumab (Lucentis; Novartis, Basel, Switzerland) beneficial for BRVO and CRVO, and the Danish Health and Medicines Authority approved intravitreal injections with ranibizumab for RVO in January 2011. Daily clinical practice is often different from the setting of randomized clinical trials. We, therefore, prospectively collected treatment data of all patients receiving intravitreal ranibizumab for CRVO and BRVO at our department to evaluate and compare the efficacy and safety with the randomized controlled trials that led to the introduction of the therapy.
etinal vein occlusion (RVO) is a vascular disease that is caused by an obstruction in either a branch retinal vein (BRVO) or in the central retinal vein (CRVO). This leads to a retinal edema that can seriously reduce visual acuity when the fovea is involved. Branch retinal vein occlusion can improve spontaneously but can also deteriorate further whereas CRVO rarely improves spontaneously and often deteriorates without treatment.1,2 Treatment of macular edema in RVO has long posed a challenge to clinicians. Until recently, the guiding principle for the management of unresolving BRVO was central grid laser, whereas no treatment was available for CRVO.3 Intraocular vascular endothelial growth factor (VEGF) is highly elevated in RVO,4,5 and novel therapeutic approaches have emerged for the management of macular edema in RVO such as intravitreal corticosteroid injections and intravitreal anti-VEGF injections. BRAVO6 and
Material and Methods Patients We consecutively included all patients with RVO who received intravitreal ranibizumab from January 2011 to April 2013. Patient data were continuously updated in a database. We excluded patients with diabetic macular edema, severe macular traction, previous injection with dexamethasone implant, or cataract surgery during the treatment period. The first visit
From the *Department of Ophthalmology, Copenhagen University Hospital Roskilde, Roskilde, Denmark; and †Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Troels Brynskov, MD, Department of Ophthalmology, Copenhagen University Hospital Roskilde, Køgevej 7-13, Roskilde DK-4000, Denmark; e-mail: [email protected]
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after the initiation of ranibizumab therapy was defined as the 5-month follow-up. The visit in the range 9 to 15 months closest to 12 months was defined as the 12-month follow-up. If a patient was discontinued from further treatment before 9 months, the last observation was carried forward for the 12-month analysis. Patients diagnosed with hemicentral vein occlusion were considered as BRVO in line with the criteria for the BRAVO study.7 All patients who had received a minimum of one intravitreal injection with ranibizumab for RVO were included in the safety analysis. Clinical Examination and Outcome Measures At the first visit, a full medical history was taken. Slit-lamp and fundus biomicroscopic examinations were performed in all patients. Best-corrected visual acuity (BCVA) testing was performed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual chart (CC-100, Topcon Corporation, Tokyo, Japan), and the intraocular pressure was determined using rebound tonometry (Icare; Icare Finland Oy, Helsinki, Finland) followed by Goldmann applanation tonometry if ocular hypertension or glaucoma was suspected. Spectral domain optical coherence tomography (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany) scanning was performed in all eyes using eye-tracking for follow-up measurements to maximize intersession repeatability.8 Foveal center point thickness (CPT) was assessed using the manufacturer’s proprietary software (Heidelberg Eye Explorer 1.7.1.0). Fluorescein angiography was not routinely performed and neither was the assessment of the presence of an afferent papillary defect. The duration of symptoms was defined as the patients’ subjective assessment of symptom duration by the initiation of anti-VEGF therapy. Serous macular detachment was defined as the presence of fluid under the neuroretina but above the retinal pigment epithelium layer determined by spectral domain optical coherence tomography. We considered a gain of 15 ETDRS letters or more as functional success,9 and reaching a CPT below 275 mm—with Heidelberg equipment—as anatomical success.10 Patient Management Treatment, monitoring, and decision regarding retreatment or discontinuation of treatment followed the Danish National guidelines set forward by the Danish Ophthalmological Society. Intravitreal anti-VEGF was initiated in all patients with visual impairment deemed to result from subfoveal edema secondary to RVO. All patients were treated promptly after diagnosis. An exception was BRVO patients with initial BCVA of
2014 VOLUME 34 NUMBER 8
more than 70 ETDRS letters who were observed for 3 months for spontaneous resolution. Anti-VEGF treatment was usually initiated as a series of 3 intravitreal injections of 0.5 mg ranibizumab each month for 3 months followed by a follow-up examination 1 to 2 months after the third injection. We continued with 1 to 3 monthly injections if there was an improvement in the BCVA or on spectral domain optical coherence tomography, unless the macula was devoid of edema. Causes of discontinuation were unchanged/decreased BCVA and/or lack of improvement on spectral domain optical coherence tomography. In BRVO, adjuvant central photocoagulation was applied in the case of unsatisfactory response to intravitreal therapy at the investigators discretion. Panretinal laser photocoagulation was applied if retinal neovascularizations developed. Data Analysis The changes in both BCVA and CPT followed a normal distribution, and a paired student’s t-test was performed comparing baseline BCVA and CPT to 5 months and baseline to 12 months for both BRVO and CRVO. Multiple linear regression analysis with backward elimination was performed pooled for all patients with change in BCVA or CPT as dependent variables. The data were analyzed using SAS 9.3 (SAS Institute Inc, Cary, NC). A P value less than 0.05 was considered significant. Results Patients One hundred and twenty patients had attended the first follow-up visit. Fourteen patients were excluded (2 had diabetic macular edema, 1 had severe vitreomacular traction, 10 had received an intravitreal sustained release implant before ranibizumab treatment, and 1 underwent cataract surgery during the treatment period). Seventy-four of the remaining 106 patients had follow-up through at least 9 months and were included for the 12-month analysis. The baseline data are shown in Table 1. Patients with BRVO had received a median of 5 (interquartile range, 3–5.5) injections whereas patients with CRVO had received a median of 6 (interquartile range, 3–6) injections. Four patients received bilateral treatment. Six patients were discontinued before 9 months of follow-up because of: nonresponse and change to dexamethasone implant therapy (n = 2), nonresponse in patients with very poor baseline visual acuity (n = 2), or development of neovascular glaucoma (n = 2). Five patients had received macular laser before initiating intravitreal ranibizmab, and one patient had central grid laser
RANIBIZUMAB FOR RVO IN CLINICAL PRACTICE BRYNSKOV ET AL Table 1. Baseline Data
Eyes, n Age, mean (SD), years Male, n (%) Symptom duration, months, median (IQR) Ocular tension, mmHg, mean (SD) Serous macular detachment, n (%) BCVA Mean number of ETDRS letters (SD) #34, n (%) 35–54, n (%) $55, n (%) CPT, mean (SD), mm
BRVO
CRVO
57 67 (13) 31 (54) 3 (1–6)
49 71 (10) 34 (69) 6 (3–9)
16 (3)
16 (3)
23 (40)
22 (45)
54.7 (16.1) 51.2 (18.5) 6 20 31 638
(11) (35) (54) (208)
11 11 27 615
(22) (22) (55) (208)
BRVO, branch vein occlusion; CRVO, central vein occlusion; SD, standard deviation; IQR, interquartile range; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CPT, foveal centre point thickness.
performed after ranibizumab treatment was initiated. Median follow-up was 9.7 months (interquartile range, 5.1–12.8) for BRVO patients and 11.2 months (interquartile range, 6.5–13.0) for CRVO patients. Functional Outcome Patients with BRVO improved a mean of 9.4 (P , 0.0001) ETDRS letters at Month 5 and 11.6 letters
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at Month 12 (P , 0.0001). Patients with CRVO improved a mean of 5.7 letters (P , 0.0001) at Month 5 and 1.8 letters at Month 12 (P = 0.50) (Table 2). In BRVO, 31.6% gained 15 ETDRS letters or more at 5 months and 26.3% at 12 months. An additional 28.9% gained 10 to 14 letters at 12 months. Only 1.8% and 0% lost 15 letters or more at 5 months and 12 months, respectively (Figure 1). In CRVO, 24.5% gained 15 letters or more at 5 months, but only 16.7% by 12 months, and just 11.1% gained 10 to 14 letters. A total of 6.1% and 8.3% lost 15 ETDRS letters or more by 5 months and 12 months, respectively (Figure 2). We performed a multiple linear regression analysis for all patients combined, adjusting for age, gender, type of retinal occlusion, ocular tension, presence of serous macular detachment, subjective duration of ocular symptoms, BCVA, and CPT. Younger patients gained 0.45 ETDRS letter (95% confidence interval [CI], 0.13–0.71, P , 0.0001) per year of age. Patients with lower baseline BCVA gained 0.21 ETDRS letters (95% CI, 0.05–0.37, P = 0.01) per affected letter at baseline. At 5 months, there was no significant difference between patients with CRVO and BRVO (P = 0.1). By 12 months, BRVO patients had an adjusted 8.8 ETDRS letters (95% CI, 3.4–14.3, P = 0.002) improvement over CRVO patients. Patients with serous macular detachment improved 7.3 ETDRS letters at 5 months (95% CI, 2.2–12.6, P = 0.006), but the difference was −2.0 letters at 12 months (95% CI, −7.6 to 3.6, P = 0.49).
Table 2. Treatment Outcome After Initiation of Intravitreal Injections With Ranibizumab BRVO
P
CRVO
P
n Baseline 5 months 12 months BCVA, ETDRS letters, mean ± SEM Baseline 5 months 12 months BCVA change,* ETDRS letter, mean ± SEM 0–5 months 0–12 months CPT, mm, mean ± SEM Baseline 5 months 12 months CPT change,* mm, mean ± SEM 0–5 months 0–12 months
57 57 38
49 49 36
54.7 ± 2.1 64.1 ± 2.0 66.0 ± 2.8
51.2 ± 2.6 56.9 ± 2.8 52.9 ± 2.9
9.4 ± 1.8 11.6 ± 2.2
,0.0001 ,0.0001
638 ± 28 421 ± 31 373 ± 35 −217 ± 29 −248 ± 38
5.7 ± 2.1 1.8 ± 2.5
0.009 0.50
617 ± 30 435 ± 36 416 ± 34 ,0.0001 ,0.0001
−192 ± 39 −222 ± 34
,0.0001 ,0.0001
*Paired difference, 12 months compared only for patients with follow-up through 12 months. BRVO, branch vein occlusion; CRVO, central vein occlusion; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CPT, foveal centre point thickness. SEM, standard error of the mean.
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2014 VOLUME 34 NUMBER 8
success. There was no clear pattern between achieving functional success and the corresponding anatomical status. The proportion of patients who achieved neither success criteria was 45% to 53%. Safety
Fig. 1. Distribution of change in visual acuity for branch vein occlusions 5 months and 12 months after initiation of intravitreal injections with ranibizumab.
A total of 617 injections have been given for RVO at our department including patients treated beyond 12 months and patients excluded for the efficacy analysis. No sight-threatening ocular adverse events were recorded. One patient experienced a nonfatal ischemic stroke 3 days after his third ranibizumab injection. A computer tomography of the cerebrum however only revealed signs of older minor infarctions.
Anatomical Outcome In BRVO, there was a reduction in CPT of 217 mm at 5 months (P , 0.0001) and of 248 mm at 12 months (P , 0.0001). In CRVO, the reduction in CPT was 192 mm (P , 0.0001) and 222 mm (P , 0.0001), respectively (Table 2). We performed a multiple linear regression analysis for CPT adjusting for the same factors as in the functional outcome. Younger patients improved 5 mm (95% CI, 1.1–9.2, P = 0.01) more in CPT per year of age at 12 months, and patients with thicker retina improved 0.5 mm (95% CI, 0.26–0.74, P = 0.0001) per micrometer of CPT at baseline. There was no difference between BRVO versus CRVO at 5 (P = 0.77) or 12 months (P = 0.85). Serous macular detachment at baseline led to an adjusted improved reduction in CPT of 99.4 mm (95% CI, 5–194, P = 0.04) at 12 months. Functional and Anatomical Outcome Combined We compared the functional and anatomical success criteria in Table 3. In total, 22% to 31% reached the anatomical success without accompanying functional
Fig. 2. Distribution of change in visual acuity for central vein occlusions 5 months and 12 months after initiation of intravitreal injections with ranibizumab.
Discussion We found our BCVA results for BRVO to be within our expectations, but for CRVO, the mean improvement of 1.8 letters at 12 months was below our expectations. The reduction in CPT was satisfactory for both groups, but the visual gain did not appear to mirror the decreased macular edema as 22% to 31% reached the anatomical success criteria without an accompanying significant improvement in BCVA. Daily clinical practice is different from the setting of randomized controlled clinical trials. First, the inclusion criteria of BRAVO and CRUISE differed from our study. The randomized trials did not include patients with BCVA above 70 ETDRS letters (0.5 Snellen equivalents), a group of patients with less potential to improve vision by 15 ETDRS letters or more because of ceiling effect. Patients with baseline visual acuity below 20/400 (approximately 20 ETDRS letters) were not included in BRAVO and CRUISE, a group of patients so severely affected that improvement is less likely. In Table 4, we have compared our patients with baseline BCVA between 20 and 70 letters with the randomized trials. This subgroup has slightly better results, but both in BRVO and CRVO, our results were superior to the sham arms and inferior to the 2 treatment arms of the randomized trials. BRAVO and CRUISE did not have a sham or 0.3 ranibizumab arm at 12 months because those patients were converted to a 0.5-mg ranibizumab dosing regimen. Second, BRAVO and CRUISE had several exclusion criteria that we did not. For instance, patients with brisk afferent pupillary defect or previous RVO were excluded in those studies. Pupillary defect is often caused by extensive capillary nonperfusion, and such patients would be expected to improve less. We have no reliable estimation of the number of patients with afferent pupillary defect in our cohort, and
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RANIBIZUMAB FOR RVO IN CLINICAL PRACTICE BRYNSKOV ET AL Table 3. Correlation of Functional and Anatomical Success After Intravitreal Ranibizumab in BRVO +Anatomical Success*
−Anatomical Success*
Total
14/18 22/29 36/47
17/8 47/45 64/53
31/26 69/74 100/100
13/6 28/31 41/36
11/11 48/53 59/64
24/17 76/83 100/100
BRVO +Functional success† (5/12 months, %) −Functional success† (5/12 months, %) Total BRVO (5/12 months, %) CRVO + Functional success† (5/12 months, %) −Functional success† (5/12 months, %) Total CRVO (5/12 months, %)
Three patients with missing baseline measures of centre point thickness were excluded from this analysis. *Foveal centre point thickness reduced to less than 275 mm. †Best-corrected visual acuity improving at least 15 ETDRS letters or more compared with baseline.
we did not perform fluorescein angiography routinely. A high degree of retinal ischemia in our CRVO patients could have negatively affected our results. Third, our patients were solely white and older than the ethnically mixed participants of BRAVO and CRUISE. Older age has been found to be a risk factor for poorer visual prognosis in untreated CRVO,11 and we also found this association in our regression analysis. Fourth, the treatment regimen differed. The therapy in BRAVO and CRUISE was initiated with an injection each month for 6 consecutive months followed by injections as needed, whereas we usually initiated
therapy with 3 injections 1 month apart followed by usually 8 weeks of observation before further observation and retreatment. Eight weeks of follow-up compares with 4 weeks in the randomized controlled trials, and the edema may have returned in the interim period. Although we endeavor a 4-week to 6-week interval for follow-up, our department is time constrained because of a constant rise in the number of patients undergoing antiVEGF treatment. Because of all these differences between randomized controlled clinical trials and our daily clinical practice, it is to be expected that our results are less impressive. However, the level of
Table 4. Comparison of Visual Outcome in Randomized Clinical Trials and the Present Study BRVO
BRAVO sham6 5–6 months n Mean change* $15 letters (%)† #15 letters (%)‡ 12 months n Mean change* $15 letters (%)† #15 letters (%)‡
CRVO
BRAVO 0.3 BRAVO 0.5 mg6 mg6
This Study, Baseline BCVA 20-70 letters
CRUISE sham7
CRUISE 0.3 mg7
CRUISE 0.5 mg7
This Study, Baseline BCVA 20-70 letters
132 7.3
134 16.6
131 18.3
47 11.0
130 0.8
132 12.7
130 14.9
38 6.6
28.8
55.2
61.1
36.3
16.9
46.2
47.7
28.9
4.5
0
1.5
2.1
15.4
3.8
1.5
7.9
§ §
§ §
131 18.3
31 12.8
§ §
§ §
130 13.9
29 2.6
§
§
60.3
29.0
§
§
50.8
17.2
§
§
2.3
0
§
§
2.3
6.9
*Mean change in ETDRS letters from baseline. †Percentage of patients gaining 15 ETDRS letters or more. ‡Percentage of patients losing 15 ETDRS letters or more. §No data, the patients were converted to treatment with 0.5 mg ranibizumab.
1642 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
difference for CRVO at 12 months remains discouraging. Nevertheless, our results are superior to conventional laser treatment and sham at both 5 months to 6 months and 12 months when comparing with the sham and laser arms of other randomized clinical trials,12–14 and only few of our patients had a decrease in BCVA. The results of the present study have prompted us to change our local treatment guidelines to address concerns of undertreatment and undermonitoring and more closely follow the BRAVO and CRUISE regimen. Our study does not address the role of dexamethasone implants in RVO. Six (46%) of the 13 patients with hemicentral retinal vein occlusion gained at least 15 ETDRS letters. As in BRAVO, these patients were included in the BRVO group, but hemicentral vein occlusion should ideally be considered a separate disease entity.15 Our results for this subgroup of patients are encouraging. Changes in BCVA were only little to moderately related to quality of life changes in BRAVO and CRUISE.16 This is also our clinical experience, although we have not systematically assessed quality of life changes. Our CPT measurements were performed with Heidelberg equipment, and the absolute thickness cannot be directly compared with other manufacturer’s equipment8 such as the Stratus (Zeiss) equipment used in the BRAVO and CRUISE studies. The change in CPT should however be similar, and our reduction of 217 mm for BRVO at 5 months compares with 339 mm and 345 mm for the 0.3-mg and 0.5-mg arm versus 158 mm for the sham arm in BRAVO.6 Similarly, the mean reduction of 192 mm for our CRVO patients at 5 months compares with 435 mm and 453 mm for the 0.3 mg and 0.5 mg ranibizumab versus 168 mm for the sham arm in CRUISE.7 Similar to the BCVA results, our results are superior to the sham arm and inferior to the treatment arm of BRAVO and CRUISE. The improved response in younger patients for both CPT and BCVA and with worse baseline BCVA or CPT is consistent with the findings of other studies of ranibizumab for diabetic macular edema17 and agerelated macular degeneration.18,19 To the best of our knowledge, subgroup analysis for this parameter has not yet been published for the BRAVO and CRUISE trials. Other studies on the role of serous macular detachment have been contradicting: One study found an improved treatment effect in patients with serous macular detachment,20 whereas subgroup analysis of the BRAVO and CRUISE data did not find the presence of submacular fluid to influence visual outcome.21 We found that serous macular detachment was related to a slower improvement in visual function, but at
2014 VOLUME 34 NUMBER 8
12 months, the visual outcome was similar to patients without serous macular detachment. Strengths of this study are that almost every patient treated in our daily clinical setting through more than 2 years has been included for analysis. A limitation of this study is the nonrandomized design, and we were unable to control for the natural course of BRVO and CRVO. Though we have made attempts to compare our results with the sham and laser arms of clinical trials, we acknowledge that such comparisons have numerous caveats. In conclusion, in our daily clinical practice, intravitreal ranibizumab for BRVO led to 12-month visual improvements that were comparable with those of the BRAVO trial that led to the approval of the therapy for BRVO. However, our visual results for CRVO at 12 months failed to reproduce the results of the CRUISE trial that led to the approval of the therapy for CRVO. In both BRVO and CRVO, we found a significant reduction of foveal CPT, but the anatomical outcome did not mirror the functional outcome. Younger and more severely affected patients responded more favourably to the treatment. No safety issues were identified. These results have prompted us to a closer adherence to the treatment protocol of the CRUISE trial for CRVO patients. Key words: anti-VEGF, branch vein occlusion, central vein occlusion, clinical practice, macular edema, ranibizumab, retinal vein occlusion. References 1. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094–1101.e5. 2. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1113–1123.e15. 3. Hahn P, Fekrat S. Best practices for treatment of retinal vein occlusion. Curr Opin Ophthalmol 2012;23:175–181. 4. Funk M, Kriechbaum K, Prager F, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci 2008;50:1025–1032. 5. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487. 6. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology 2011;118:1594–1602. 7. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118:2041–2049. 8. Wolf-Schnurrbusch UEK, Ceklic L, Brinkmann CK, et al. Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci 2009;50:3432–3437.
RANIBIZUMAB FOR RVO IN CLINICAL PRACTICE BRYNSKOV ET AL 9. Shah N, Laidlaw DAH, Shah SP, et al. Computerized repeating and averaging improve the test-retest variability of ETDRS visual acuity measurements: implications for sensitivity and specificity. Invest Ophthalmol Vis Sci 2011;52:9397–9402. 10. Grover S, Murthy RK, Brar VS, et al. Comparison of retinal thickness in normal eyes using stratus and spectralis optical coherence tomography. Invest Ophthalmol Vis Sci 2010;51: 2644–2647. 11. Chen JC, Klein ML, Watzke RC, et al. Natural course of perfused central retinal vein occlusion. Can J Ophthalmol 1995;30:21–24. 12. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127:1115–1128. 13. Ip MS, Scott IU, VanVeldhuisen PC, 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. 14. CVOS Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein
15. 16.
17.
18.
19.
20.
21.
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Occlusion Study Group M report. Ophthalmology 1995;102: 1425–1433. Hayreh SS, Zimmerman MB. Hemicentral retinal vein occlusion: natural history of visual outcome. Retina 2012;32:68–76. Varma R, Bressler NM, Suñer I, et al. Improved vision-related function after ranibizumab for macular edema after retinal vein occlusion. Ophthalmology 2012;119:2108–2118. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol 2012;130:1153–1161. Kaiser PK, Brown DM, Zhang K, et al. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol 2007;144:850–857. Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007;114:246–252. Gallego-Pinazo R, Dolz-Marco R, Pardo-López D, et al. Ranibizumab for serous macular detachment in branch retinal vein occlusions. Graefes Arch Clin Exp Ophthalmol 2013;251:9–14. Bhisitkul RB, Campochiaro PA, Shapiro H, et al. Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography. Ophthalmology 2013;120:1057–1063.
