Seminars in Ophthalmology, Early Online, 1–6, 2015 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2015.1009555

ORIGINAL ARTICLE

Outcomes of Patients Initially Treated with Intravitreal Bevacizumab for Central Retinal Vein Occlusion: Long-Term Follow-Up

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Jasmina Bajric and Sophie J. Bakri Mayo Clinic Department of Ophthalmology, Rochester, Minnesota, USA

ABSTRACT Background and objective: To assess outcomes of visual acuity (VA) and central retinal thickness (RT) in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO) who were initially treated with bevacizumab and followed for up to four years. Study design/Materials and methods: In this observational case series, 51 patients with non-ischemic and ischemic CRVO who had initial treatment with bevacizumab were included. Main outcome measures were VA and RT at one year, with follow-up of up to four years. Results: Mean VA improved from 20/214 at baseline to 20/107 at one year (p = 0.0009) and this improvement was maintained clinically at four years. RT decreased from 595 mm to 339 mm at one year (p = 0.0027) and this was maintained at four years. Conclusion: Patients who received bevacizumab as initial therapy for ME from CRVO maintained VA and RT improvement for up to four years. Keywords: Avastin, bevacizumab, CRVO, optical coherence tomography, retinal vein occlusion

INTRODUCTION

Treatment of macular edema in CRVO has seen much excitement in recent years with the emergence of VEGF inhibitors. The CRUISE trial was the first randomized control trial to show that a VEGF inhibitor, ranibizumab (Lucentis, Genentech Inc., South San Francisco, CA), rapidly improved visual acuity and macular edema at six months in patients with CRVO and that the medication had a good safety profile.7 Following the CRUISE trial, ranibizumab was approved by the Food and Drug Administration for treatment of macular edema in patients with retinal vein occlusions. In clinical practice, VEGF inhibitors are now the first-line treatment offered to patients who have CRVO with macular edema. Bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is another VEGF inhibitor that has been used off-label to treat macular edema. Several studies have demonstrated that bevacizumab is effective in improving vision and decreasing central macular thickness when used in patients with

Central retinal vein occlusion (CRVO) is the second most common cause of blindness from retinal vascular disease, second only to diabetic retinopathy.1 The prevalence of CRVO in a cohort of adults in the United States was noted to be one out of 1,000 individuals.2 This frequent ocular disease causes not only visual impairment, but has also been associated with decreased quality of life.3 The mainstay of current treatment for CRVO has been directed at managing vision-compromising complications of the vein occlusion, which are macular edema and neovascularization. These secondary complications result from retinal ischemia, which promotes the production of pro-inflammatory mediators, including vascular endothelial growth factor (VEGF), which lead to increased vascular permeability and stimulate vascular endothelial cell migration and proliferation.4–6 Studies have demonstrated that VEGF expression is up-regulated in patients with CRVO.5–6

Received 21 September 2014; accepted 14 January 2015; published online 27 April 2015 Correspondence: Sophie J. Bakri, MD, Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA. E-mail: [email protected]

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macular edema due to retinal vein occlusions.8–17 However, unlike the randomized controlled CRUISE trial, studies evaluating bevacizumab have been small population cohort studies, which have lacked followup longer than two years. In addition, many studies have not differentiated the effect of the medication on ischemic versus non-ischemic CRVO subtypes. It was our objective to evaluate the effectiveness of bevacizumab therapy in patients with macular edema secondary to CRVO in a long-term follow-up of up to four years and to evaluate the differences in response between patients with ischemic versus non-ischemic subtypes. We also sought to determine the number of intravitreal injections that patients required annually, a subject infrequently reported in the literature.8,12,16,18

MATERIALS AND METHODS This study was a retrospective, single-center case series. The Mayo Clinic Institutional Review Board approved the study and it was in accordance with HIPAA regulations. We conducted a search of the electronic medical record at Mayo Clinic for patients diagnosed with CRVO who underwent bevacizumab injections for macular edema between July 2005 and July 2011. Patients with CRVO who had initial treatment with bevacizumab were included in the study. Exclusion criteria were prior treatment for macular edema and the presence of rubeosis. After applying these criteria, 51 patients qualified for the study. Patients were divided into non-ischemic and ischemic subtype groups based on best-corrected visual acuity at baseline of less than or greater than 20/200, respectively. Visual acuity was used for subtype classification because it was measured on every patient. Other factors for classification, including afferent papillary defect and amount of retinal non-perfusion on fluorescein angiography, were not utilized since these tests were not performed on all patients at the initial visit. For each patient, data were collected at the time of the initial bevacizumab injection and then at approximately one-, two-, and three-month visits and annually thereafter for up to four years following the first injection. Vision and intraocular pressure were checked at each visit. Central macular thickness was measured using the Spectralis OCT (Heidelberg Engineering, Inc., Carlsbad, CA) and was performed at baseline and at some subsequent follow-up visits. Additionally, the total number of injections and the type of drug treatment received during each visit were recorded. The decision as to the timing and type of treatment received after the first visit was based on the clinical judgment of the treating physician. If patients received treatment other than bevacizumab after the initial injection, it was

recorded. The reasons for loss to follow-up were also noted on all patients. Statistical analysis was performed utilizing the JMP software (Version 9.0, SAS Institute Inc., 2010). Paired t-tests were used to compare the change in vision and central macular thickness between baseline and all follow-up time periods. Statistical significance was set at p50.05.

RESULTS Patient Demographics Baseline patient demographics and ocular characteristics are outlined in Table 1. The mean length of follow-up was 24.0 months (range 2–48 months, SD = 18.4). A total of 36/51 (70.6%) patients received only bevacizumab treatment throughout the duration of follow-up, while 15/51 (29.4%) were transitioned to alternate therapy. All patients had their initial therapy with bevacizumab, but it was at the discretion of the treating physician to determine if the patient would benefit from alternative therapy. Table 2 demonstrates the alternative therapies received. Rationales for changing therapy are noted in Table 3. The reasons for loss to follow-up are noted in Table 4.

TABLE 1. Patient demographics and baseline ocular characteristics (n = 51). Age, years Mean (SD) Median Range Gender Male Female Baseline vision 20/40 20/50-20/200 20/200 CRVO Type Non-ischemic Ischemic IOP (mmHg), mean (SD) Open angle glaucoma Pseudophakic

Number (%) 72.3 (10.9)a 73 41–90 27 (52.9) 24 (47.1) 3 (5.9) 28 (54.9) 20 (39.2) 31 20 16.1 7 13

(60.8) (39.2) (5.9)a (13.7) (25.5)

a

Standard deviation.

TABLE 2. Type of treatments received by patients N (%). Bevacizumab only Other Dexamethasone intravitreal implant Triamcinolone Triamcinolone & dexamethasone intravitreal implant Ranibizumab

36 15 8 3 3

(70.6) (29.4) (53.3) (20.0) (20.0)

1 (6.7) Seminars in Ophthalmology

Intravitreal Bevacizumab

Visual Acuity Visual acuity (VA) improved for all patients after the initial bevacizumab injection from baseline and this improvement was maintained at a statistical significance at month 1 (p50.001), month 2 (p50.0001), month 3 (p50.0001), and one year of follow-up (p50.0009). The improved vision was clinically

TABLE 3. Reason for switching treatment from bevacizumab (%).

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No improvement Visual acuity Macular edema Uveitis following injection Unknown

13 4/13 9/13 1 1

(86.7) (30.8) (69.2) (6.7) (6.7)

TABLE 4. Reason for loss to follow-up (%). No improvement Improvement Death Follow-up elsewhere Adverse reaction Unknown

21 17 7 4 1 1

(41.2) (33.3) (13.7) (7.8) (2.0) (2.0)

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maintained during years 2, 3, and 4 but there was a lack of statistically significant difference from baseline (Figure 1). In the non-ischemic sub-group, VA improved at months 1 (p = 0.0015), 2 (p = 0.0001), 3 (p50.0001), and at one year (p = 0.0176). In the ischemic subgroups, VA improved at months 1 (p50.0001), 2 (p = 0.0003), 3 (p = 0.0004), and at one year (p = 0.0029). The improvement in visual acuity was maintained clinically at years 2, 3, and 4, but there was a lack of statistically significant difference from baseline (Figure 1). Of the patients that received bevacizumab only, clinical and statistical improvement was achieved one month following the bevacizumab injection for both sub-groups (non-ischemic baseline 20/85 to 20/46 at one month (p50.0001) and ischemic baseline 20/950 to 20/452 at one month (p = 0.0015)). The improvement in visual acuity was maintained at months 2, 3, and at one year for both groups when compared to baseline (non-ischemic group: 20/55 (p = 0.0012), 20/53 (p = 0.0007), 20/57 (p = 0.0531), and ischemic group: 20/523 (p = 0.0019), 20/500 (p = 0.0121), 20/532 (p = 0.029), respectively). There was clinical improvement in visual acuity for both sub-groups at years 2

FIGURE 1. Visual acuity in Snellen and logMAR at baseline and all follow-up time points for all patients with CRVO who were initially treated with bevacizumab. The visual acuities for the non-ischemic and ischemic sub-groups are also shown. logMAR = logarithm of the minimal angle of resolution. *p50.05, compared with baseline values. !

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and 3, but there was a lack of statistically significant difference from baseline. In the non-ischemic group, visual acuity was 20/39 at year 4 (p = 0.034). There were no data for year 4 for the ischemic group. Although both subgroups had improvement in visual acuity over time, the ischemic subgroup had worse visual acuity at baseline and at all follow-up time points when compared to the non-ischemic subgroup.

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Retinal Thickness Retinal thickness (RT) improved for all patients at one month following the bevacizumab injection (p50.0001), and this improvement was maintained at two months (p = 0.0011), three months (p = 0.0001), one year (p = 0.0027), two years (p = 0.0027), three years (p = 0.013), and four years (p = 0.0123) (Figure 2). In the non-ischemic group, RT decreased significantly at months 1 (p50.0001), 2 (p = 0.0106), 3 (p = 0.0013), and at years 1 (p = 0.0024), 2 (p = 0.0045), 3 (p = 0.0155), and 4 (p = 0.0261). For the ischemic subgroup, improvement in RT was observed at months 1 (p = 0.0245), 2 (p = 0.0157), and 3 (p = 0.0144). Although the RT remained decreased

at years 1 and 2, it was not statistically different from baseline. There were no data available for the ischemic group in years 3 and 4 (Figure 2). Unlike the improvement in VA, in which the ischemic subgroup had worse VA at baseline and at all follow-up time points, the RT was similar for both subgroups at baseline (610 mm for non-ischemic and 578 mm for ischemic) and had similar improvement increments at each time period, as seen in Figure 2. The RT in patients who only received bevacizumab was 613 mm at baseline for the non-ischemic group and 574 mm for the ischemic group. For the nonischemic group, RT improved to 314 mm at one month (p50.0001), 438 mm at two months (p = 0.0359), 361 mm at three months (p = 0.0025), 327 mm at one year (p = 0037), and 247 mm at two years (p = 0.0115) when compared to baseline. Although the thickness was clinically improved at years 3 and 4 (255 mm and 327 mm, respectively), it was not statistically different when compared to baseline. Similarly, in the ischemic sub-group, the RT improved to 298 mm at one month (p = 0.0007) and 261 mm at two months (p = 0.0065). At month 3, the thickness was 403 mm and at one year it was 543 mm; neither was statistically different from baseline. No data was available for years 2, 3, or 4.

FIGURE 2. Retinal thickness in micrometers (mm) at baseline and all follow-up time points for all patients with CRVO who were initially treated with bevacizumab. The retinal thickness for the non-ischemic and ischemic sub-groups is also shown. *p50.05, compared with baseline values. Seminars in Ophthalmology

Intravitreal Bevacizumab TABLE 5. Mean number of injections per year (n)a. Bevacizumab only Year 1 2 3 4

All 5.9 2.6 2.8 2.2

(27) (16) (8) (5)

Mixed treatment

Non-ischemic Ischemic Bevacizumab 6.0 3.3 3.0 2.8

(19) (12) (7) (4)

5.6 0.3 1.0 0

(8) (4) (1) (1)

5.4 2.3 3.3 2.0

(13) (9) (6) (3)

Other 1.3 2.0 1.9 2.2

(10) (10) (10) (6)

a

Includes only patients with complete year data.

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Number of Injections Table 5 shows the mean number of injections received by patients who received both bevacizumab only as well as combination therapy.

DISCUSSION In this study, we found that patients with macular edema from non-ischemic and ischemic CRVO, who were initially treated with bevacizumab, had improved vision and this improvement was maintained long-term. For the non-ischemic group, vision improved from a baseline of 20/87 to 20/56 at one month (p = 0.0015) and 20/57 (p = 0.0176) at one year. For the ischemic group, VA improved from a baseline of 20/820 to 20/395 at one month (p =50.0001) and 20/391 (p = 0.0029) at one year. Improvement in vision was seen immediately at the one-month follow-up visit, suggesting that only a single injection of bevacizumab may be effective at improving vision. It has been shown that visual improvement after a single bevacizumab injection may be maintained for as long as 12 weeks.13 However, it is unclear exactly how long the effect of just a single injection of bevacizumab may be, and additional bevacizumab injections are needed to maintain the improvement in visual acuity. Although vision remained clinically improved in the non-ischemic and ischemic subgroups at years two, three, and four, there was no statistical difference from baseline. We postulate that there was a lack of statistical significance in these three groups because there was loss to follow-up and thus the groups were underpowered. A recent study found long-term visual acuity improvement in patients with CRVO who were treated with intermittent bevacizumab injections, further supporting that long-term maintenance of vision can be achieved with periodic asneeded intravitreal bevacizumab injections.19 Although patients with ischemic CRVO had worse vision at baseline and throughout the duration of follow-up when compared to non-ischemic patients, they still achieved improvement in vision. Similar to our study, Priglinger et al. found that ischemic CRVO was associated with significantly lower visual acuity !

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than non-ischemic CRVO, but visual acuity gain was similar in both groups.9 Another study from Duke found that, after intravitreal bevacizumab, no significant difference in vision gain was noted between patients with non-ischemic and ischemic CRVO.20 We also confirmed, as has been shown in previous studies, that central macular thickness significantly improved after bevacizumab injection in patients with macular edema from CRVO.8–11,16 In the non-ischemic group, RT improved from 610 mm at baseline to 347 mm at one month (p50.0001) and 325 mm at one year (p = 0.0024). This effect was maintained between years two and four. In the ischemic group, improvement was also noted from baseline 578 mm to 424 mm at one month (p = 0.0245); however, at year one, the RT was not statistically different from baseline (365 mm, p = 0.0845). Other studies have also found that the improvement in central macular thickness can be maintained long-term, up to 18 months.19 It is interesting to note that, although the non-ischemic subgroup had better visual acuity than the ischemic subgroup, both groups had similar retinal thicknesses throughout follow-up. This suggests that visual improvement cannot be attributed to resolution of macular edema alone. This finding is consistent with previously published studies, which demonstrated no difference in improvement in central macular thickness between the ischemic and non-ischemic subgroups.9,20 The annual mean number of bevacizumab injections per patient was 5.9 in the first year, but then declined throughout years two, three, and four to 2.6, 2.8, and 2.2, respectively. This decline in injection rate in subsequent years may be due to improvement with treatment or transition to other therapies secondary to treatment failure. Other studies have found the rate of bevacizumab injections to range between 6 and 8 during the first year of follow-up, correlating closely with our findings.16,19 A subgroup analysis revealed that both the non-ischemic and ischemic subgroups had a similar pattern of high rate of injections in the first year, with subsequent decrease in the number of annual injections thereafter. One limitation of this study is that, after the initial bevacizumab injection, patients had varied clinical management, which in some instances included receiving other treatments. Although this may be a confounding effect to our data analysis, our study remains clinically relevant since this is how patients are treated in the real world. Furthermore, in each subsequent year of follow-up, we had loss of patients in the study pool due to varied circumstances, as previously outlined. Although this limited our statistical power, we feel that our results show clinically relevant patterns. In summary, our data indicate that bevacizumab, when used as the initial therapy for patients with nonischemic and ischemic CRVO, is effective in

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improving vision and decreasing central macular edema up to four years after the initial treatment. In addition, the mean number of injections is highest in the first year, with subsequent annual decline for both ischemic and non-ischemic subtypes.

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8.

ACKNOWLEDGMENTS This article was presented at the 111th Annual Scientific Meeting of the American Academy of Ophthalmology, Chicago, IL, November 2012.

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FUNDING 11.

This work was sponsored by Research to Prevent Blindness, New York, NY. Dr. Bakri has consulted for Genentech and Allergan in the previous 12 months, but neither company has funded this study.

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13.

DECLARATION OF INTEREST 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. Ophthalmology 1998; 105(3):412–416. Brown D, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117(6):1124–1133. Figueroa MS, Contreras I, Noval S, Arruabarrena C. Results of bevacizumab as the primary treatment for retinal vein occlusions. Br J Ophthalmol 2010; 94(8):1052–1056. Priglinger SG, Wolf AH, Kreutzer TC, et al. Intravitreal bevacizumab injections for treatment of central retinal vein occlusion: six-month results of a prospective trial. Retina 2007;27(8):1004–1012. Hoeh AE, Ach T, Schaal KB, et al. Long-term follow-up of OCT-guided bevacizumab treatment of macular edema due to retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2009;247(12):1635–1641. Rensch F, Jonas JB, Spandau HM. Early intravitreal bevacizumab for non-ischaemic central retinal vein occlusion. Acta Ophthalmol 2009;87(1):77–81. Ferrara DC, Koizumi H, Spaide RF. Early bevacizumab treatment of central retinal vein occlusion. Am J Ophthalmol 2007;144(6):864–871. Pai SA, Shetty R, Vijayan PB, et al. Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion. Am J Ophthalmol 2007;143(4):601–606. Hsu J, Kaiser RS, Sivalingam A, et al. Intravitreal bevacizumab (avastin) in central retinal vein occlusion. Retina 2007;27(8):1013–1019. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (avastin) treatment of macular edema in central retinal vein occlusion: A short-term study. Retina 2006;26(3):279–284. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol 2009;93(4):452–456. Algvere PV, Wendt GV, Gudmundsson J, et al. Visual improvement in central retinal vein occlusion (CRVO) following intravitreal injections of bevacizumab (Avastin). Acta Ophthalmol 2010;88(8):836–841. Beutel J, Ziemssen F, Luke M, et al. Intravitreal bevacizumab treatment of macular edema in central retinal vein occlusion: one-year results. Int Ophthalmol 2010; 30(1):15–22. Algvere PV, Epstein D, von Wendt G, et al. Intravitreal bevacizumab in central retinal vein occlusion: 18-month results of a prospective clinical trial. Eur J Ophthalmol 2011; 21(6):789–795. DeCroos FC, Ehlers JP, Stinnett S, Fekrat S. Intravitreal bevacizumab for macular edema due to central retinal vein occlusion: perfused vs. ischemic and early vs. late treatment. Curr Eye Res 2011;36(12):1164–1170.

Seminars in Ophthalmology

Outcomes of Patients Initially Treated with Intravitreal Bevacizumab for Central Retinal Vein Occlusion: Long-Term Follow-Up.

To assess outcomes of visual acuity (VA) and central retinal thickness (RT) in patients with macular edema (ME) secondary to central retinal vein occl...
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