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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������_�	���bjbj4�bb�V&�������$$������������8�t@|��eN��"������eeeeeee$�g��j�2e9������2e�����ke[/[/[/��
�����\[/�e[/[/�>��?�����p�ˊ7�����y,��>�\�e0�e�>�kg-��k(�?�?��k�~B\��[/�����2e2ea.�����e�������������������������������������������������������������������������k���������$"F:	Intravitreal Bevacizumab Improves Macular Edema of the Contralateral Eye - A comparative study of two Anti-VEGFs

Running Title: Comparison of Anti-VEGF for Contralateral DME
Abstract
Purpose: To compare the effects of bevacizumab and ranibizumab on the visual function and macular thickness in the contralateral (untreated) eye of patients with bilateral diabetic macular edema (DME).
Methods: Thirty-nine patients with bilateral DME who had been treated with both bevacizumab and ranibizumab, were considered for this study. The best corrected visual acuity (BCVA) assessment with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, and the central subfield macular thickness (CSMT) measurement of the contralateral, uninjected eye before and at 4 weeks after the injections were recorded as outcome measurements.
Results: The median BCVA of the uninjected eye was 50 ETDRS letters, and the median CSMT was 459 �m, preceding the bevacizumab injection. At the 4th week control appointment following the injection, the median BCVA increased to 52 letters (P=0.098), and the median CSMT decreased to 390 �m (P=0.036). The mean interval between the bevacizumab and ranibizumab treatments was 4.79 � 1.52 months. The measurements of the untreated eye after the ranibizumab treatment showed that the median BCVA decreased from 55 to 52 letters, and the median CSMT increased from 361 �m to a level of 418 �m (P=0.148 and P=0.109, respectively).   
Conclusions: In contrast to the ranibizumab, the intravitreal administration of bevacizumab resulted in a statistically significant decrease in macular thickness in the untreated eye in patients with bilateral DME.

Key words: Bevacizumab; Ranibizumab; Macular edema; Diabetic retinopathy; Anti VEGF treatment; Intravitreal injection 







Introduction
   One of the main causes for the loss of vision in patients diagnosed with diabetes is due to the development of diabetic macular edema (DME) [1, 2]. DME is associated with high levels of vascular endothelial growth factor (VEGF) in the vitreous humour [3]. Currently, research studies have been focusing on anti-VEGF medications for the treatment of DME, and bevacizumab (Avastin) (Genentech, San Francisco, CA) and ranibizumab (Lucentis) (Genentech, San Francisco, CA) are the two VEGF inhibitors that are most widely used [3-6]. Bevacizumab is a full-length antibody of 149 kDa that binds to all of the subtypes of the VEGF. On the other hand, ranibizumab is a fragment antigen-binding (Fab) fragment of a humanized monoclonal antibody with a molecular weight of 48 kDa that also binds all of the isoforms of VEGF [2, 3]. The differences in the molecular weight and structure of bevacizumab and ranibizumab influence their penetration, half-lives, and efficacy. 
   The plasma levels of VEGF in patients are found to be significantly reduced after the intravitreal injection of bevacizumab [7, 8]. This finding suggested that the body clears the anti-VEGF after intravitreal administration, which brings up the question of whether or not there is an effect on the contralateral eye after intravitreal use. However, there are few studies regarding the pharmacokinetics and distribution of these agents after intravitreal injection, particularly in human eyes.
   In a pilot study, the intravitreal administration of bevacizumab was found to have no significant effect on the contralateral eye in patients with bilateral DME [9]. However, in some cases with macular edema, an effect on the contralateral eye has been observed after the intravitreal anti-VEGF injection [10-13]. Since the pharmacokinetic properties of an intravitreally administered drug, and the function of the blood-retinal barrier may vary from one person to another (and change with the presence of ocular disease), it is difficult to assess and compare the crossover effect of these two agents when used intravitreally. Therefore, we performed this study in order to compare the visual and structural outcomes on the contralateral, uninjected eye after 1 dose of the intravitreal injection of bevacizumab and ranibizumab to the treated (same) eye of patients with bilateral DME at selected points in time.
Materials and Methods
   This retrospective review was carried out on patients who were in the follow-up stage of a diagnosis of DME at the retina service. Data was collected from January 2012 until April 2013, and patients with bilateral DME who received a single dose (injection) of bevacizumab, and who did not attend the scheduled repeat intravitreal bevacizumab injections, were considered for enrollment. Among them, the patients who visited the Retina Service after at least 3 months, and planned to receive monthly intravitreal ranibizumab injections for their DME were included in the study. The local ethics committee approved this study, which was conducted in accordance with the Declaration of Helsinki.
   Exclusion criteria were (a) those with a history or evidence of a macular pathology such as age-related macular degeneration (ARMD), or a vascular occlusive disease affecting the macula; (b) treatment with any other intravitreal drug injections or laser photocoagulation within 3 months (previously) to either eye; (c) any associated pathology such as an epiretinal membrane or vitreomacular traction; or (d) any history of retinal surgery.
Intravitreal injection protocol for the ranibizumab and bevacizumab injections
   The exclusion criteria for the injections of ranibizumab and bevacizumab included any history of a myocardial infarction or cerebrovascular incident, or evidence of a severe cardiac disease, history of stroke, history of a chronic ocular or periocular infection, uncontrolled hypertension, or pregnancy. All patients were informed about the potential side effects and complications of intravitreal bevacizumab and ranibizumab. The intravitreal injections were administered to the eye according to the severity of the macular edema, and these injections were performed according to a standard protocol. Intravitreal injections were performed at the same institution by the same ophthalmologists (BB, BTO). A topical anesthetic was applied to the eye, followed by an application of 5% povidone-iodine to the lower fornix. By using a sterile lid speculum, 0.05 mg (0.05 mL) of ranibizumab or 1.25 mg (0.05 mL) of bevacizumab was injected 3.5 mm to 4 mm posterior to the limbus, through the pars plana, and pressure was applied subsequently to the injection site using a sterile cotton swab. Patients were then instructed to apply topical antibiotics to the injected eye four times a day for 5 days. 
Outcomes
   The preinjection, best-corrected visual acuities (BCVA) were determined by using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (at 4 and 1 m), intraocular pressure measurements, slit-lamp and fundus examination findings, and central subfield macular thickness (CSMT) measurements (using optical coherence tomography-3) (OCT-3, Carl Zeiss Meditec, San Leandro, CA). The examination findings during the control visits after 1 day and 4 weeks following the injections were reviewed as well. The first visit was done to assess any complications and included intraocular pressure (IOP) measurements with an air-puff tonometer, a slit-lamp examination, and a dilated fundus examination. However, during the second visit, the BCVA and OCT measurements were also performed. The primary outcome variables included any BCVA and CSMT changes in either eye after the single dose injection of bevacizumab and ranibizumab.
Statistical analysis
   A statistical analysis was carried out using the Statistical Package for Social Science (SPSS) program (15.0, Windows) (SPSS Inc., Chicago, IL). The visual acuities and CSMT values were compared using the nonparametric Mann-Whitney U test and the Wilcoxon signed-rank test. A probability (P) value of less than 0.05 was considered to be statistically significant.
Results
Baseline characteristics
   A review of all of the patients with diabetic macular edema, who met the inclusion criteria, yielded a total of 39 patients. The mean age of these 39 patients (16 males and 23 females; 41.1% and 58.9%, respectively) was 56.9 � 11.58 years old. Five patients had type 1 diabetes mellitus (DM) and the remaining 34 were diagnosed with type 2 DM.
   Eleven patients (28.2%) exhibited nephropathy as a DM-related complication, and twenty-five patients (64.1%) had controlled hypertension. The diabetic retinopathy was in the preproliferative stage in 21 of the patients (53.8%). 
   No complications, including issues such as endophthalmitis, traumatic lens injury, raised IOP, or retinal detachment, were associated with the intravitreal injections. Before the bevacizumab injection, the median (baseline) BCVA (for the treated eyes) was 48 (18�68) ETDRS letters, which increased to 52 (18-76) ETDRS letters after the injections. The median CSMT of 473 (297-682) �m before the bevacizumab injection decreased to 337 (249-566) �m after the treatment. These changes in the BCVA and CSMT in the eyes treated with bevacizumab were found to be statistically significant (P=0.029 and P=0.005, respectively).
   In the uninjected (fellow) eyes, the median BCVA was 50 ETDRS letters, and the median CSMT was 459 �m preceding the bevacizumab injection. At the 4th week control follow-up after the injection, the median BCVA had increased to 52 ETDRS letters, and the median CSMT decreased to 390 �m. There was no statistically significant change in the BCVA (P=0.098); however, the decrease in the CSMT was found to be statistically significant at P=0.036 (Figure 1, Table 1).
   Intravitreal ranibizumab was administered to the same eye after a mean period of 4.79 � 1.52 (3�6) months. In the treated eye, the pretreatment median BCVA of 46 (20�73) ETDRS letters increased to 53 (22�78) ETDRS letters after the treatment, and the preinjection median CSMT of 483 (298-670) �m declined to a level of 265 (214-563) �m after the treatment. Statistical analyses revealed significant changes in both the BCVA and CSMT (P=0.008 and P<0.001, respectively).
   The measurements of the untreated (fellow) eye after the ranibizumab treatment showed that the median BCVA decreased from 55 to 52 ETDRS letters, and the median CSMT increased from 361 �m to a level of 418 �m. The changes in the BCVA and CSMT were found to be statistically insignificant (P=0.148 and P=0.109, respectively) (Table 2).
Discussion
   The vascular endothelial growth factor plays an important role in the pathogenesis of diabetic macular edema [5,6,14]. Several reviews have been conducted on the efficacy of the two anti-VEGFs, bevacizumab and ranibizumab, in the treatment of DME [1-3, 5]. Bevacizumab is a full-length humanized antibody that binds all types of VEGF. It is approved by the Food and Drug Administration for the treatment of various cancers, but is used off-label intravitreally to treat ocular diseases, including proliferative diabetic retinopathy and diabetic macular edema. Ranibizumab, a recombinant humanized monoclonal IgG1 antibody is approved for choroidal neovascularization in the context of age related macular degeneration and diabetic macular edema. Despite the widespread clinical applications, the pharmacokinetics of intravitreal bevacizumab and ranibizumab concerning the untreated eye has not been extensively studied.
   In the present study, we found a statistically-significant decrease in the CSMT in the untreated eyes after the injection of bevacizumab, but not ranibizumab. This finding suggests that there is a systemic penetration of bevacizumab from the human eye injections, and supports the previous study which demonstrated a significant reduction in the plasma VEGF after an intravitreal injection with bevacizumab, but not ranibizumab [7, 8].
In an experimental study, Bakri et al. [15] found small amounts of bevacizumab in the serum and in the (fellow) uninjected eye. Avery et al. [12] reported that some of their patients with bilateral proliferative diabetic retinopathy had a regression of neovascularization in both eyes, when injected with intravitreal bevacizumab in only one eye. Similar results were observed after unilateral intravitreal bevacizumab injections, in the cases of bilateral persistent diffuse diabetic macular edema or bilateral uveitic cystoid macular edema [11, 16]. A pilot study on bilateral DME suggested no significant effects in the contralateral, uninjected eye; however, they emphasized the small sample size and low confidence in their own study [9].
   In this study, the intravitreal ranibizumab administration in patients with DME was found to have no statistically significant change on the BCVA and CSMT in the contralateral (uninjected) eye. We also compared these results (in which a statistically significant decrease in CSMT was found) to the untreated eyes after the treatment with bevacizumab in the same patients.
There are conflicting results in the literature regarding the contralateral eye effects of intravitreal ranibizumab injections. A retrospective observational study has demonstrated a visual improvement in the contralateral eyes of patients with ARMD after an intravitreal ranibizumab injection [17]. Acharya et al. [13] observed the beneficial effect of ranibizumab in both eyes of patients (2 of 3 patients) who were treated unilaterally for uveitis-related CME. However, Bakri et al. [18] found no ranibizumab in either the serum or the fellow uninjected eye after a 0.5 mg intravitreal injection. Similarly, Gamulescu and Helbig [19] observed no therapeutic effect of ranibizumab in the untreated fellow eye in patients with ARMD. A Phase III clinical trial of ranibizumab for ARMD also showed no effect on the rate of choroidal neovascularization development in the untreated eyes [20].
   We are unaware of any previous studies that have evaluated a crossover effect (in the eye contralateral to the treatment eye) of bevacizumab and ranibizumab in patients with bilateral diabetic macular edema. The effects of both agents in the treated eyes of our patients support the previous studies that bevacizumab and ranibizumab effectively reduced the macular thickness and improved the visual acuity in the treated eyes [1-3]. However, this result raises the question of why only the bevacizumab administration affected the untreated eye. The exact mechanism of how intravitreally administered anti-VEGFs affect the uninjected eye has not been elucidated thus far. One possible mechanism for this is that the anti-VEGF enters the bloodstream via the choroidal blood flow [12, 13]. In contrast, others researchers have suggested that bevacizumab enters the eye from the systemic circulation through the anterior route, where it diffuses into the vitreous humour [9]. Ranibizumab has a smaller molecular weight when compared with bevacizumab, so it is possible that it may pass to the fellow eye more easily. However, experimental studies using rabbits have demonstrated that no ranibizumab was detected in the serum or the fellow eye; whereas the bevacizumab was found in both the serum and the fellow eye [15, 18]. Nevertheless, the rabbit retina is less vascular than a human�s, which may result in altered pharmacokinetics when compared with the human condition. Another reason that bevacizumab might give a contralateral effect and ranibizumab does not concerns the systemic half-lives of the 2 drugs. Longer half-life increases the exposure in the contralateral eye, improves penetration, and enables a possible clinical effect. 
   Our previous study using 55 patients with bilateral DME demonstrated that, compared with ranibizumab, the intravitreal administration of bevacizumab resulted in a greater decrease in the macular thickness of the untreated eye in patients with bilateral DME [21]. However, in that study we administered bevacizumab or ranibizumab in two different groups of patients. Since the pharmacokinetic properties of an intravitreally administered anti-VEGF, and the blood-retinal barrier function may vary from one person to another, and change with the presence of an ocular disease, we compared the crossover effect of the agents in same patients for this study. Further investigation, including the analysis of the serum and vitreous levels of the anti-VEGF agents, will be the best study design for the comparison.
   In summary, we found that, in contrast to ranibizumab, the intravitreal administration of bevacizumab resulted in a statistically significant decrease in the macular thickness of the untreated eye in patients with bilateral DME.
   	


























References
Ford JA, Elders A, Shyangdan D, Royle P, Waugh N (2012) The relative clinical effectiveness of ranibizumab and bevacizumab in diabetic macular oedema: an indirect comparison in a systematic review. BMJ 345: e5182. 
Zechmeister-Koss I, Huic M (2012) Vascular endothelial growth factor inhibitors (anti-VEGF) in the management of diabetic macular oedema: a systematic review. Br J Ophthalmol 96: 167-78. 
Ozturk BT, Kerimoglu H, Bozkurt B, Okudan S (2011) Comparison of intravitreal bevacizumab and ranibizumab treatment for diabetic macular edema. J Ocul Pharmacol Ther 27: 373-7. 
Goyal S, Lavalley M, Subramanian ML (2011) Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 249: 15-27. 
Singh R, Ramasamy K, Abraham C, Gupta V, Gupta A (2008) Diabetic retinopathy: an update. Indian J Ophthalmol 56: 178-88. 
Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM (2006) A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 113: 1706-12. 
Carneiro AM, Costa R, Falc�o MS, Barthelmes D, Mendon�a LS, et al. (2012) Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Acta Ophthalmol 90: e25-30.
Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach GF (2013) Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol 97: 454-9.
Velez-Montoya R, Fromow-Guerra J, Burgos O, Landers MB 3rd, Morales-Cat�n V, et al. (2009) The effect of unilateral intravitreal bevacizumab (avastin), in the treatment of diffuse bilateral diabetic macular edema: a pilot study. Retina 29: 20-6.
Wu Z, Sadda SR (2008) Effects on the contralateral eye after intravitreal bevacizumab and ranibizumab injections: a case report. Ann Acad Med Singapore 37: 591-3. 
Al-Dhibi H, Khan AO (2009) Bilateral response following unilateral intravitreal bevacizumab injection in a child with uveitic cystoid macular edema. J AAPOS 13: 400-2. 
Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, et al. (2006) Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 113: 1695.e1-15.
Acharya NR, Sittivarakul W, Qian Y, Hong KC, Lee SM (2011) Bilateral effect of unilateral ranibizumab in patients with uveitis-related macular edema. Retina 31: 1871-6. 
Selim KM, Sahan D, Muhittin T, Osman C, Mustafa O (2010) Increased levels of vascular endothelial growth factor in the aqueous humor of patients with diabetic retinopathy. Indian J Ophthalmol 58: 375-9.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ (2007) Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 114: 855-9. 
Scartozzi R, Chao JR, Walsh AC, Eliott D (2009) Bilateral improvement of persistent diffuse diabetic macular oedema after unilateral intravitreal bevacizumab (Avastin) injection. Eye (Lond) 23: 1229. 
Rouvas A, Liarakos VS, Theodossiadis P, Papathanassiou M, Petrou P, et al. (2009) The effect of intravitreal ranibizumab on the fellow untreated eye with subfoveal scarring due to exudative age-related macular degeneration. Ophthalmologica 223: 383-9. 
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, et al. (2007) Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 114: 2179-82.
Gamulescu MA, Helbig H (2010) Lack of therapeutic effect of ranibizumab in fellow eyes after intravitreal administration. J Ocul Pharmacol Ther 26: 213-6. 
Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, et al. (2010) Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials. Am J Ophthalmol 149: 939-946.
Bakbak B, Ozturk TB, Gonul S, Yilmaz M, Gedik S (2013) Comparison of the effect of unilateral intravitreal bevacizumab and ranibizumab injection on diabetic macular edema of the fellow eye. J Ocul Pharmacol Ther 29: 728-32.







Table 1:
Pre-treatmentAt 4 weeksP valueBCVAM�SD47.72�19.8348.96�20.270.098Median5052Range21-6322-69CSMTM�SD427.90�112.37383.51�121.630.036*Median459390Range308-610255-533

Table 1: Visual acuity and central subfield macular thickness values of untreated eyes before and after bevacizumab injection. 
BCVA: Best corrected visual acuity (Letters)
CSMT: Central subfield macular thickness (�m)
M�SD: Mean � Standard Deviation
*Statistically significant














Table 2:
Pre-treatmentAt 4 weeksP valueBCVAM�SD53.12�17.1849.76�22.630.148Median5552Range19-67        18-65CSMTM�SD354.49�119.36399.08�137.410.109Median361418Range327-646320-715
Table 2: Visual acuity and central subfield macular thickness values of untreated eyes before and after ranibizumab injection. 
BCVA: Best corrected visual acuity (Letters)
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M�SD: Mean � Standard Deviation
















Figure Legend
Figure 1: A comparison of the changes in the macular thickness in treated and untreated eyes of the same patients, before (baseline) and at
4 weeks after the intravitreal bevacizumab and ranibizumab injections. Note that a statistically significant decrease in the CSMT was seen with the
bevacizumab administration, but not with the ranibizumab.
�m=microns









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