Graefes Arch Clin Exp Ophthalmol (2011) 249:1527 DOI 10.

1007/s00417-010-1452-4

RETINAL DISORDERS

Meta-analysis and review on the effect of bevacizumab in diabetic macular edema

Sunali Goyal & Michael LaValley & Manju L. Subramanian

Received: 19 April 2010 / Revised: 17 June 2010 / Accepted: 4 July 2010 / Published online: 28 July 2010 # Springer-Verlag 2010

Abstract Background Systematic review and meta-analysis to evaluate the effect of bevacizumab (Avastin) in diabetic macular edema (DME) Methods Pertinent publications were identified through systematic searches of PUBMED and Cochrane Central Register of Controlled Trials. Change in central subfield macular thickness (CSMT) in m and best-corrected visual acuity (BCVA) in log MAR equivalents were extracted at 6, 12 and 24 weeks, and results compared between groups receiving intravitreal bevacizumab (IVB), a combination of IVB and intravitreal triamcinolone acetonide (IVT), and macular laser photocoagulation or sham control groups. Results The summary mean difference indicated a statistically significant reduction in CSMT at 6 weeks when treated with bevacizumab compared to control. IVB treatment, however, lost significance at 12 weeks and 24 weeks. The summary mean difference in BCVA for
Financial interest: None Summary Statement Intravitreal bevacizumab appears to be a safe, inexpensive and effective short-term treatment choice for patients with diabetic macular edema, and should be explored as a therapy for diabetic macular edema. S. Goyal : M. L. Subramanian Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA S. Goyal (*) Department of Ophthalmology, University of Arkansas Medical Sciences, 1501 Rahling Road, #1008, Little Rock, AR 72223, USA e-mail: sunali_goyal@hotmail.com M. LaValley Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

IVB group compared to control reached significance only at 6 and 24 weeks. Combination therapy of IVB and IVT did not result in any significant reduction in CSMT or gain in vision compared to treatment with IVB alone at any point in time. Conclusions Current data suggests that IVB is an effective short-term treatment for diabetic macular edema, and that its efficacy wanes after 6 weeks. More trials exploring the therapeutic role of intravitreal bevacizumab in DME need to be conducted to define the role of bevacizumab. Keywords Avastin . Angiogenesis . Anti-VEGF therapy . Bevacizumab . Diabetic macular edema

Introduction Diabetic macular edema (DME), a frequent manifestation of diabetic retinopathy, is the foremost cause of central vision loss, affecting about 75,000 new patients every year in the United States alone [1, 2]. The presence of DME varies with the duration and stage of diabetic retinopathy [3]. The prevalence of DME is 3% in mild non-proliferative retinopathy, and rises to 38% in eyes with moderate to severe non-proliferative retinopathy, eventually reaching 71% in eyes with proliferative retinopathy [4]. If left untreated, 20% to 30% of patients with DME will experience a doubling of the visual angle within 3 years [5]. The pathogenesis of DME is multifactorial. It is predominantly due to generalized breakdown of the inner bloodretinal barrier, leading to accumulation of fluid and plasma constituents, such as lipoproteins, within the intraretinal layers of macula [6, 7]. Factors such as duration of diabetes, insulin dependence, glycosylated hemoglobin levels, proteinuria, and hypertension have all been implicated in the development of DME [5]. Various therapeutic

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Table 1 Study characteristics and result of excluded studies evaluating the effect of bevacizumab in DME [2840]
Major inclusion criteria No. of eyes (n); mean age (years) NA Intervention regimen Results of BCVA (logMAR) Results of CMT (m) Adverse effects Conclusion of the study

Study

Year and place Level of support

Haritoglou et al. [28]

2006, Germany

Prospective consecutive case series

Diffuse DME not 51; 64.1 responding to other treatments

IVB leads to improvement of BCVA and CMT in unresponsive cases of diffuse DME

Arevalo et al. [29]

2007, PanInterventional, America retrospective Collaboramulticenter study tive Retina Study Group 11; 62 8 IVB 1.25 mg monthly x 3 mo Baseline* ETDRS score 59 15, 59 16 at 3 mo, 57 15 at 6 mo (P= 0..398) Baseline CMT 408 NA 77, 453 97 at 3 mo, 454 101 at 6 mo (P=0.172)

DME excluding LPC/ IVT treated, eyes with macular ischemia

78; 59.7 9.3

Baseline 0.860.38 improved to 0.80 Baseline 501163 decreased IVB 1.25 mg 0.37 (not significant), 0.75 0.37 (P= to 425 180 (P=0.002), injections 0.001) at 2 wks and 6 wks. Regression 416 180 (P=0.001), 377 followed by 117 (P=0.001) at 2, 6 second to 0.84 0.41 at 12 wks (not wks, and 12 wks. injection, if significant) needed IVB 1.25 mg or Baseline 0.87 improved to 0.6 Baseline 387.0 182.8 2.5 mg (P<0.0001) at 1 mo and 6 mo decreased to 287.9 102.4 injections (P<0.0001), 275.7 108.3 (P<0.0001) at 1 mo and 6 mo None

IVB (1.25 mg or 2.5 mg) provides stability (41%) or improvement (55%) in BCVA and CMT in DME at 6 mo No change in BCVA and CMT in short-term after IVB for DME in previously vitrectomized eyes Significant decrease in CMT and improvement in BCVA at 3 mo and though statistical improvement from baseline, blunted effect at 6 mo IVB may be effective in refractory DME unresponsive to LPC or IVT

Yanyali et al. [30]

2007, Turkey

Retrospective, DME with interventional nonprevious comparative case vitrectomy series Chronic persistent 20; 59 diffuse DME with previous LPC>6 mo

Kumar et al. 2007, India [31]

Prospective, interventional case series

IVB 1.25 mg: 2 Baseline 1.34 0.46 improved to 1.09 Baseline 492.8 167.2 None injections 6 0.25 (P=0.008), 1.12 0.22 (P= decreased to 377.3 wks apart 0.029) at 3 mo and 6 mo 113.57 (P=0.001), 379 104 (P=0.001) at 3 mo and 6 mo IVB 1.25 mg

Ornek et al. [32]

2008, Turkey

Prospective case series

DME with previous LPC and IVT in all

17; 63.8

Kook et al. [33] IVB 1.25 mg with repeat injections as required

2008, Germany

Prospective, noncomparative case series

BCVA improved in 12 eyes (70%), Eight (8) eyes (47%) revealed NA remained same in 5 eyes (30%). In the a marked improvement of macular edema, 6 eyes 12 eyes, visual acuity improved by one Snellen line in 8 eyes (67%), by two (35%) revealed mild Snellen lines in 1 eye (8%) and by improvement and three three Snellen lines in 3 eyes (25%). eyes (18%) had no change Baseline 0.82 0.37 improved to 0.76 Baseline 463 173 decreased None 0.37 (P<0.05), 0.74 0.33 (P<0.05) to 391 158 (P<0.001), at 6 wks and 6 mo 374 195 (P<0.001) at 6 wks and 6 mo

IVB decreases CMT and improves BCVA in chronic diffuse DME

Roh et al. [34]

2008, Korea

Retrospective case series

Chronic persistent 126; 66.1 diffuse DME with previous treatment at any time>6 mo Clinically 31; 63.19 significant 7.14 DME with or without previous treatment 38; 61.7 13.3 IVB 1.25 mg injections followed by repeated IVB at least 12 wks after the first injection IVB 1 mg injections

BCVA and CMT returned to baseline at 12 wks, suggesting requirement of repeated IVB

Fang et al. [35]

2008, Japan

Prospective nonGroup 1: DME randomized conwithout secutive case series previous treatment. Group 2: DME with previous treatment (>4 mo prior)

Graefes Arch Clin Exp Ophthalmol (2011) 249:1527

IVB is effective in both previously treated and untreated DME. Effect is temporary, requiring repeated injections.

Baseline 455.03 200.0 Increased IOP Baseline* ETDRS score 26.87 14.21 increased by 3.72 8.02 (P=0.019) at decreased by 93.30 (n=2, 6.4%) 6 wks after first injection, and by 210.33 (P=0.022) at 6 wks 3.97 7.46 (P=0.006) at six wks after after first injection, and by second injection. 118.77 178.58 (P=0.001) at six wks after second injection. Group 1: baseline 0.76 0.33 decreased Group 1: baseline 632.4 None to 0.57 0.30 (P=0.02), 0.54 0.27 196.0 decreased to 392.3 (P=0.014) at 2-4 wks, 8 wks 113.6 (P=0.01), 370.4 141.7 (P=0.01) at 2-4 wks, 8 wks Group 2: baseline decreased from 0.62 Group 2: baseline decreased 0.30 to 0.53 0.33 (P<0.01) and was from 583.9 180.7 to unchanged at 2-4 wks and 8/12 wks 404.1 197.9 (P<0.001) and was unchanged at 2-4 wks and 8/12 wks

Table 1 (continued)
Major inclusion criteria No. of eyes (n); mean age (years) IVB 1 mg injections Mean increase in BCVA of 7.3 17 ETDRS letters between baseline and month 4 (P<0.0001) IVB caused moderate reduction in DME Intervention regimen Results of BCVA (logMAR) Results of CMT (m) Adverse effects Conclusion of the study

Study

Year and place Level of support

Soliman et al. [36]

2008, Denmark/ Egypt IVB 1.25 mg injections

Consecutive case series

Seo et al. [37]

2009, Korea

Retrospective consecutive case series

IVB resulted in significant improvement in BCVA and CMT at 1 wk which persisted for 3 mo, but with slight reduction -Systemic effect of IVB seems unlikely

VelezMontoya et al. [38] IVB 2.5 mg injections given in the worst eye

2009, multicenter

Pilot study

Diffuse DME with 10; 59.2 or without previous treatment Clinically 30; 57.9 significant 13.8 DME not responding to previous treatment Bilateral diffuse 23; 62.45 DME with no 8.5 LPC done anytime or antiangiogenic treatment done in the past 3 mo DME excluding LPC/ IVT treated, eyes with macular ischemia 101; 59.7 9.3 IVB 1.25 mg or Baseline 0.87 improved to 0.67 (P< Baseline 401.8 180 2.5 mg 0.0001), 0.77 (P: NA), 0.68 (P<0.001) decreased to 290.2 119.6 injections at 1 mo, 6 mo and 12 mo (P<0.001), 309.3 123.6 (P<0.001), 281.6 105.0 (P< 0.001) at 1 mo, 6 mo and 12 mo

CMT decreased from 447 None 117 to 338 117 between baseline and month 4 (P= 0.03) Baseline 0.73 0.36 improved to 0.63 Baseline 498.96 123.99 None 0.41 (P=0.02), 0.58 0.36 (P=0.003), decreased to 359.06 0.61 0.40 (P=0.006) at 1 wk, 1 mo, 105.97 (P<0.001), 3 mo 334.40 121.76(P<0.001), 421.40 192.76(P=0.035) at 1 wk, 1 mo, 3 mo Treated eye: baseline CMT NA Treated eye: baseline * ETDRS score 22.15 20.21 increased to 26.31 459.46 141.26 decreased 20.89 (P=0.46) at 4 wks to 346.23 121.3 (P= 0.002) at 4 wks Untreated eye: baseline 34.46 17.29 Untreated eye: baseline increased to 37.38 14.59 (P=0.098) 324.77 76.51 decreased at 4 wks to 315.54 78.2 (P=0.142) at 4 wks

Graefes Arch Clin Exp Ophthalmol (2011) 249:1527

Arevalo et al. [39]

2009, PanInterventional, America retrospective Collaboramulticenter study tive Retina Study Group

Bonini-Filho 2009, multiet al. [40] center

Open labeled prospective, nonrandomized

DME with severe capillary loss

10; 59.8 4 IVB 1.25 mg injections

Baseline 0.78 0.38 improved to 0.64 Baseline 472.6 205.2 decreased to 371.4 148.2 0.43 (P=0.008), 0.57 0.37 (P= (P=0.07), 323.9 115.7 0.007), 0.55 0.38 (P=0.005) at 8 wks, 24 wks and 54 wks (P=0.005), 274.6 55.3 (P=0.007) at 8 wks, 24 wks and 54 wks

Transient high - IVB provides stability or blood pressure improvement in BCVA and (1.2%), transient CMT,- No difference increased IOP between 1.25 mg or 2.5 (1%), tractional mg,- At least 3 injections retinal per year required to detachment maintain BCVA (1%) None IVB causes favorable changes in BCVA and CMT in DME with severe capillary loss

* Denotes ETDRS (Early Treatment Diabetic Retinopathy Study) letter score, NA: not available, DM: diabetes mellitus, BCVA: best-corrected visual acuity, CMT: central macular thickness, DME: diabetic macular edema, LPC: laser photocoagulation, IVB: intravitreal bevacizumab, IVT: intravitreal triamcinolone acetonide, IOP: intraocular pressure, wks: weeks, mo: month

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approaches, including laser photocoagulation, pars plana vitrectomy, and intravitreal steroid injections aim to prevent or delay a permanent alteration of the photoreceptors in the central macular region [811]. However, unsatisfactory outcomes are frequent, and have often prompted interest in other treatments options for DME. Vascular endothelial growth factor (VEGF) has been identified as one of the many growth factors causing breakdown of the bloodretinal barrier with increased retinal permeability by affecting the endothelial tight junctions [12]. While the normal human retina contains VEGF, the levels are significantly elevated in eyes with DME, with hypoxia and hyperglycemia acting as important contributing factors [13, 14]. As a result, pharmacologic attenuation of the effects of VEGF using several anti-VEGF therapies like pegaptanib (Macugen; Eyetech Pharmaceuticals, New York, NY, USA) and ranibizumab (Lucentis; Novartis Pharmaceuticals, East Hanover, NJ, USA) have been hypothesized and anecdotally tested as alternative treatments, and all seem to have shown favorable short-term results [15, 16]. Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA), a humanized monoclonal antibody, which encompasses all vascular endothelial growth factor isoforms, was originally approved by the US Food and Drug Administration for the treatment of colorectal cancer in 2004 [17]. The off-label use of bevacizumab has been applied to many neovascular diseases of the eye, particularly age-related macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity, and macular edema secondary to retinal vein occlusions [18, 19]. Although not currently approved by the FDA for intraocular use, the infusion of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity [20]. As far as the authors are aware, no systematic review highlighting the evidence for the therapeutic effect and safety of bevacizumab in diabetic macular edema has been published. In an attempt to gain better perspective of the mentioned issues, we performed a meta-analysis and review of the literature in order to quantify the effect of bevacizumab on visual acuity and central macular thicknesss in DME. Additionally, we report the adverse events described with this therapy.

macular edema, bevacizumab, avastin, anti-VEGF therapy and randomized controlled trials in various combinations. Reference lists of case reports, studies and review articles were also reviewed for any additional citations. Additional information from the Internet search engines, such as Google and Yahoo, was also incorporated. All relevant articles were extracted in print, and final selection was based on a discussion between the observers. Inclusions for analysis were restricted to randomized clinical control trials (RCCTs) that used intravitreal bevacizumab (IVB) as a treatment modality for DME. Seven potential RCCTs were identified [2127]. Of these, only five trials comparing IVB to a non-drug control treatment either macular laser photocoagulation (MPC) or sham were initially considered eligible for the study [2125]. One of the RCCT was published showing interim results of the main trial, so only the final study was selected to avoid duplication of subjects [21, 25]. The Paccola study that compared IVB to intravitreal triamcinolone (IVT), and the Lam study, which compared two different doses of IVB, were excluded from the analysis [26, 27]. Thirteen other studies (seven prospective, uncontrolled studies, five retrospective database studies, and one pilot study) were identified, and their important characteristics were tabulated in detail (Table 1) [2840]. However, due to differences in study methods, they were not subjected to any statistical analysis. Data extraction Data were extracted directly into electronic summary by one investigator. All articles were then verified against a primary paper by a different investigator, and any disparity was resolved by dialogue between all the authors. Means and standard deviations (SDs) of change from baseline in central subfield macular thickness (CSMT) in m and best-corrected visual acuity (BCVA) in log MAR equivalents were extracted from the papers. In one study, medians and 25th and 75th percentiles were presented, and these were converted to means and SDs based on the normal distribution percentiles [22]. Control treatment was considered to be sham injection or macular laser photocoagulation. Results of subjects receiving IVB, a combination of IVB and IVT, or control treatment were extracted and compiled for comparison. Other recorded characteristics of the RCCTs included- name of first author, year and geographical location of the study, major inclusion and exclusion criteria, various intervention groups, number of eyes in various groups, mean age and sex of patients, and follow-up periods. Outcome measures The primary outcomes measured for the meta-analysis were: a) best-corrected visual acuity (BCVA), and b)

Materials and methods Search and selection The authors performed three incremental electronic database searches using PUBMED and Cochrane Central Register of Controlled Trials until July 2009, in order to comprehensively identify English language publications describing the use of bevacizumab in DME. Search terms used were diabetic

Graefes Arch Clin Exp Ophthalmol (2011) 249:1527

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change in central subfield macular thickness (CSMT) from baseline after the proposed intervention. Studies presented results at varying follow-up periods, and we chose to analyze results at 6, 12, and 24 weeks due to their common presence in most study reports. In one study, the 16-week results were used as a proxy for 12-week results [24]. In another study BCVA was not reported in log MAR, but instead a letter score was used to measure vision change [22]. So while this study is included with the other RCCTs for CSMT outcomes, visual outcomes are instead reported using standardized mean differences (mean differences divided by the pooled standard deviation) to allow combination of results measured on different scales [41]. Secondary outcomes reported are ocular or systemic adverse effects noticed after treatment administration. Quality assessment The RCCTs were analyzed for their quality based on the Delphi list for quality assessment of randomized clinical trials (Table 2) [42]. For each trial, a quality score was calculated, where yes was scored as one point for a certain quality item and no and dont know were scored as zero points. Quality of individual study was then determined by giving a total additive score to each study. Statistical analysis Inverse-variance pooling was used to meta-analyze the within-study mean differences between IVB and control subjects (or IVB + IVT subjects and IVB subjects) to provide a weighted summary estimate and its 95% confidence interval. Cochrans Q-test was used to test for the presence of excess variation between study mean differences (heterogeneity), and the I2 statistic was used to quantify the percentage of variation in study results due to heterogeneity [43]. The random effects weighted estimate and its 95% confidence interval were calculated using the SAS MIXED procedure and presented in the

results, due to the presence of substantial heterogeneity (I2 >50%) in most analyses [44]. Forest plots are used to display the study estimates and the summary weighted estimates by outcome (CSMT or BCVA), comparison (IVB vs control or IVB+IVT vs IVB), and time point (6, 12 or 24 weeks). The SAS statistical analysis software version 9.1.3 was used for all analyses.

Results Study characteristics Figure 1 shows in a flow chart format the process of filtering articles to determine their appropriate value for inclusion in the meta-analysis and review. Ultimately, four RCCTs with a total of 484 DME eyes undergoing different interventions were included in this review. The total number of eyes was fairly consistent in each of the studies, ranging from 109 to 150. The RCCTs were each given a quality score as described (Table 2). All four RCCTs were of reasonable to good quality, with the Soheilian study scoring the best in terms of quality. Detailed characteristics of the included trials are described in Table 3. Both male and female participants were involved in almost equal proportion. Clinical heterogeneity was, however, seen in several areas, including specific characteristics of DME and differing treatment protocols. As an example, Ahmadieh et al. included cases with refractory clinically significant diabetic macular edema (CSME) unresponsive to previous MPC [23]. In contrast, Faghihi et al. and Soheilian et al. included CSME cases with no previous treatment [24, 25]. The Diabetic Retinopathy Clinical Research Network (DRCN) included those subjects with CSME with no previous treatment in the last 3 months [22]. The duration of diabetes, type or duration of diabetic retinopathy, duration of macular edema, type of DME (focal versus diffuse), hemoglobin A1C levels, baseline intra-ocular pressures were not

Table 2 Quality assessment of randomized trials based on Delphi list for quality assessment of randomized clinical trials [42]
Study Randomization Allocation Baseline Eligibility Blinded Care provider Patient Point estimates and Intention to Total concealment group similarity criteria specified outcome assessor blinded blinded measure of variability treat analysis score presented Yes Yes Yes DNK Yes Yes No Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes No DNK DNK Yes 5 7 7 9

DRCRN [22]

Ahmadieh et al. Yes [23] Faghihi et al. Yes [24] Soheilian et al. Yes [25]

DNK: do not know

20 Fig. 1 Flow chart depicting the selection of articles. DME: Diabetic Macular Edema, RCCT: Randomize Case Controlled Trial, IVB: Intravitreal Bevacizumab, IVT: Intravitreal triamcinolone acetonide

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Step 1: 72 citations identified after search with key words

Step 2: 52 citations excluded diseases other than DME basic science or experimental studies, kinetics or dosage studies, Adverse events as primary goal of study outcome Step 3: 20 full text articles retrieved for detailed evaluation

Step 4: 13 articles excluded Prospective Consecutive Case Series (7) Retrospective Case Series (5) Step 5: 7 RCCTs retrieved for detailed evaluation Pilot Study (1)

Step 6: 3 RCCTs excluded 1 RCCT compared 2 doses of IVB 1 RCCT compared IVB to IVT 1 RCCT showed interim results of the final study Step 7: 4 RCCTs included in the study

consistently reported in the publications, and hence were not analyzed. Intervention arms Three of the studies had consistent treatment arms comparing 1.25 mg/0.05 ml of IVB to either a combination of IVB and intravitreal triamcinolone acetonide (IVT 2 mg/0.05 ml) or with macular photocoagulation (MPC) or sham (control group) [23 25]. The Faghihi and Soheilian studies provided one-time treatment at baseline, but Ahmadieh allowed for repeated, subsequent interventions at weeks 6 and 12 (Table 3). The DRCN, however, compared IVB (1.25 mg/0.05 ml and 2.5 mg/0.1 ml) to MPC without use of IVT at any time [22]. To keep the arms consistent, we pooled eyes in subgroups of selected studies, particularly 2, 3 and 4 in DRCN (all using IVB), and compared them to group 1 that used MPC for treatment.

Intervention outcome The studies reported outcome at different follow-up intervals after intervention. All four studies assessed change in CSMT and BCVA at early (week 6) and late (12-16 week) time frame. Only two studies (Ahmadieh and Soheilian) had results described at 24 weeks [23, 25]. Comparing IVB to control Central subfield macular thickness The difference in mean change in CSMT (in m) for each study, along with its standard error and 95% confidence interval (CI) bounds, is outlined in the forest plot displayed in Fig. 2. The dots show the mean difference estimates, and the whiskers extending from the dots show the associated 95% confidence intervals. Values to the left of the vertical line at 0

Table 3 Study characteristics of the four randomized controlled trials evaluating effect of bevacizumab in DME [2225]
Major exclusion criteria Number of eyes Intervention groups Mean age (years) Percentage Follow- up of males visits (in weeks) 3,6,9,12

Study

Year and place

Major inclusion criteria

DRCRN [22]

2007, USA

-Type I or Type II DM, -BCVA20/320 and20/32, - definite central macular thickening clinically, - CMT275 m, - No previous treatment for DME within last 3 months

Group 1. n=19 Group 2. n=22 Group 3. n=24 Group 4. n=22 Group 5. n=22 Total: 109

65 (Median: 57, 61 Group 1. MPC at baseline Quartiles: 73) Group 2. IVB (1.25 mg)- baseline, week 6 Group 3. IVB (2.5 mg)- baseline, week 6 Group 4. IVB (1.25 mg)- baseline, sham at week 6 Group 5. IVB (1.25 mg)-baseline & week 6, MPC at week 3

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Ahmadieh et al. [23]

2008, Iran

- CSME unresponsive to previous MPC (> 3 months),

Group 1. n=41 Group 2. n=37 Group 3. n=37 Total: 115

Group 1. IVB (1.25 mg)- baseline, week 6, 59.78.3 week 12 Group 2. IVB (1.25 mg)+IVT (2 mg) at baseline, IVB (1.25 mg) week 6, week 12 Group 3. sham

49.5

6, 12, 18, 24

Faghihi et al. [24] Group 1. n=42 Group 2. n=41, Group 3. n=47 Total: 110

2008, Iran

-Type II DM with DME, -BCVA20/40, - CMT250 m

Group 1. IVB (1.25 mg) Group 2. IVB (1.25 mg)+IVT (2 mg) Group 3. MPC

577

49

6,16

Soheilian et al. [25]

2009, Iran

- CSME with no previous treatment

- Macular edema due to other causes, - inflammatory ocular disease, - any treatment for DME in the previous 3 months, - PRP in the previous 4 months, - Major ocular surgery in the previous 6 months, - history of PPV, - aphakia, uncontrolled glaucoma, - hypertension - BCVA20/40, - Cataract surgery in the last six months, - Previous intraocular injections or vitrectomy, - Glaucoma, - PDR, Vitreous hemorrhage, macular traction, - Monocularity, Pregnancy, Serum Creatinine>3 mg/dl -Macular edema due to other causes, - vitreous traction, - any previous treatment for DR, - anticipated PRP in next 6 months, - uncontrolled glaucoma, - history of arterial thromboembolic event, - poorly controlled hypertension - History of glaucoma, - prior intraocular injection or surgery, - BCVA20/40 or20/300, - Iris neovascularization, - PDR, - monocularity, pregnancy, serum creatinine>3 mg/dl - previous PRP or focal laser photocoagulation, Group 1. n=50 Group 2. n=50 Group 3. n=50 Total: 150 Group 1. IVB (1.25 mg)- baseline, Group 2. IVB (1.25 mg)+IVT (2 mg) at baseline Group 3. MPC group 61.26.1 52.7

6,12,24,36

DRCRN: Diabetic Retinopathy Clinical Research Network, DM: diabetes mellitus, BCVA: best-corrected visual acuity, PPV: pars plana vitrectomy, CMT: central macular thickness, DME: diabetic macular edema, CSME: clinically significant macular edema, MPC: macular photocoagulation, PDR: proliferative diabetic retinopathy, IVB: intravitreal bevacizumab, IVT: intravitreal triamcinolone acetonide

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22 Fig. 2 This forest plot shows the study mean differences in central subfield macular thickness in m along with their associated 95% confidence intervals, comparing IVB treatment to control at 6, 12, and 24 weeks. The random effects pooled mean difference for each time is shown underneath the study results on the subtotal lines. Negative values in this plot favor IVB treatment over control; positive values favor control over IVB treatment

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show greater change in CSMT in the subjects treated with IVB, and values to the right of the vertical line show greater change in control subjects. The subtotal rows show the metaanalysis summary values for each time point. Confidence intervals that do not intersect with the vertical line at 0 indicate a result that is statistically significant at the 0.05 significance level. At 6 weeks, all studies except the DRCN showed significant reduction in CSMT from baseline in the IVBtreated group. The summary mean difference for all studies at 6 weeks was statistically significant [-48.2 m (95% CI 86.2 to 10.2)] in favor of IVB treatment with significant heterogeneity (Q-test p-value=0.01 and I2 =71.4%). At 12 weeks, the combined mean difference in CSMT showed a favorable response to IVB (22.3 m), but this reduction
Fig. 3 This forest plot shows the study mean differences in best-corrected visual acuity in log MAR along with their associated 95% confidence intervals, comparing IVB treatment to control at 6, 12, and 24 months. The random effects pooled mean difference for each time is shown underneath the study results on the subtotal lines. Negative values in this plot favor IVB treatment over control; positive values favor control over IVB treatment

was not statistically significant (95% CI 57.9 to 13.3 m) and the heterogeneity was significant (Q-test p-value=0.03 and I2 =65.8%). Only two studies expressed results at 24 weeks, with a combined mean difference in CSMT as 67.7 m. The results were not statistically significant (95% CI 186.75 to 51.4) mainly due to large amount of heterogeneity between the two studies (Q-test p-value=<0.001 and I2 =91.3%). Visual acuity Figure 3 shows the forest plot of BCVA results comparing IVB to control. This figure is interpreted in a similar manner as Fig. 2, with the exception that the results are on the log MAR scale.

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At 6 weeks, all studies in the combined analysis consistently showed improvement in BCVA in patients who received bevacizumab. The summary mean difference in study patients, when compared to controls, at week 6 was statistically significant (0.13 log MAR ; 95% CI 0.23 to 0.02) with significant heterogeneity (Q-test p-value=0.001 and I2 =85.1%). However, similar to the outcomes we report on central subfield thickness, visual outcomes at 12 weeks showed a difference of 0.10 log MAR in favor of IVB treatment, but it was not statistically significant (95% CI 0.26 to 0.07) with significant heterogeneity (Q-test p-value<0.001 and I2 =90.8%). However, at 24 weeks the combined mean difference in BCVA from two studies (Ahmadieh and Soheilian) also showed statistically significant improvement for the IVB-treated group compared to the control group (0.191 log MAR with 95% CI 0.28 to 0.10) but without statistically significant heterogeneity (Qtest p-value=0.29 and I2 =11.0%). When the letter score results were combined with the BCVA results using standardized mean differences, the results (not shown in figure) showed a similar trend at 6 weeks (0.69 with 95% CI 1.07 to 0.31) and 12 weeks (0.43 with 95% CI 0.94 to 0.09) with significant heterogeneity at both time points (Q-test p-values and I2 were 0.03 and 64.5%, and 0.001 and 82.3% respectively). There were no letter scores for 24 weeks, so the results are similar to the BCVA results. Comparing combination therapy (IVB+IVT) to sole IVB therapy Central subfield macular thickness Three studies used a combination of IVB and IVT as a treatment arm (Fig. 4). Among group comparisons, no
Fig. 4 This forest plot shows the study mean differences in central subfield macular thickness in m along with their associated 95% confidence intervals, comparing combined IVB and IVT treatment to IVB treatment at 6, 12, and 24 weeks. The random effects pooled mean difference for each time is shown underneath the study results on the subtotal lines. Negative values in this plot favor combined IVB and IVT treatment over IVB; positive values favor IVB treatment over the combined IVB and IVT treatment

significant reduction in CSMT was shown with addition of IVT at week 6 (5.6 m with 95% CI as 31.3 to 20.1), week 12 (36.5 m with 95% CI as 80.3 and 7.3) or at week 24 (8.15 m with 95% CI as 28 and 44). Study results did not show significant heterogeneity at any of these follow-up periods (6 weeks, Q-test p-value=0.87 and I2 =0%; 12 weeks, Q-test p-value=0.06, and I2 =65%; 24 weeks, Q-test p-value=0.86 and I2 =0%). Visual acuity Figure 5 shows the forest plot of BCVA results comparing treatment with both IVB and IVT to treatment with only IVB. The group comparison showed that combination therapy did not result in any significant gain in vision (log MAR) compared to treatment with IVB alone at week 6 (0.00 with 95% CI as 0.08 to 0.09), week 12 (0.02 with 95% CI as 0.14 to 0.09) or at week 24 (0.06 with 95% CI as 0.12 to 0.25). Unlike the CSMT findings, there was significant heterogeneity at all of these time points (6 weeks, Q-test p-value=0.04 and I2 =69.1%; 12 weeks, Q-test p-value=0.006, and I2 =80.4%; 24 weeks, Q-test pvalue=0.01 and I2 =84.5%). Adverse effects Adequate data about complications occurring at different follow-up intervals could not be determined from the studies, thus limiting performance of a meta-analysis to assess side-effects. Significant adverse effects reported in different studies in each treatment arm are presented in Table 4. Anterior chamber reaction was the most frequently observed side-effect, with 18 to 20% of treated patients experiencing this, with almost equal incidence reported in both the IVB and combined IVB and IVT groups.

24

Graefes Arch Clin Exp Ophthalmol (2011) 249:1527

Fig. 5 This forest plot shows the study mean differences in bestcorrected visual acuity in log MAR along with their associated 95% confidence intervals, comparing combined IVB and IVT treatment to IVB treatment at 6, 12, and 24 months. The random effects pooled

mean difference for each time is shown underneath the study results on the subtotal lines. Negative values in this plot favor combined IVB and IVT treatment over IVB treatment; positive values favor IVB treatment over the combined IVB and IVT treatment

Increased intraocular pressure was also seen, with incidence ranging from 8 to 16% primarily in the group receiving IVT. Interestingly, endophthalmitis was reported in only one eye in the DRCN study [22]. Systemic adverse effects, related to cardiovascular (MI, CHF) and renal dysfunction (hypertension, worsening renal function), were reported by the DRCN study only, all of which occurred in the context of pre-existing medical conditions [22].
Table 4 Adverse effects reported in various trials [2225]
Intervention Study group Anterior chamber reaction Increase Lens Retinal NV, in IOP opacities vitreous hage, TRD 1

Discussion Diabetic macular edema has long been recognized as an important cause of vision loss in patients with diabetes. Extensive research has been underway for decades to understand the precise pathogenesis and potential treatment modalities to improve, stabilize and prevent DME. Laser photocoagulation has been the gold standard of treatment of DME, and its merits were proven by the Early

Progression Endophthalmitis Systemic events of retinopathy 1* 2 MI, 1 CHF, 3 hypertension, 1 death d/t pancreatic cancer, 1 PVD, 1 syncope, 3 worsening of renal function, 4 anemia -

IVB

DRCRN [22]

Ahmadieh et al. [23] Faghihi et al. [24] Soheilian et al. [25] IVB+IVT Ahmadieh et al. [23] Faghihi et al. [24] Soheilian 9 (18%) et al. [25] MPC/sham DRCRN [22] Ahmadieh et al. [23] Faghihi et al. [24] Soheilian et al. [25]

8 (19.5%) 10 (20%) 7 (18.9%) 8(16%) -

3 4 (8%) -

1 (2.4%) 4 (8%) (8.1%)

5 (10%) 2 (4.8%) 6 (12%)

1 (2.7%) -

2 (4%) 1 (2%)

7 (14%) 3 (6%)

1 anemia, 2 PVD, 1 hypertension, 1 worsening of renal function -

DRCN: Diabetic Retinopathy Clinical Research Network, MPC: macular photocoagulation, IVB: intravitreal bevacizumab, IVT: intravitreal triamcinolone acetonide, IOP: intra-ocular pressure, TRD: tractional retinal detachment, NV: neovascularization, Hage: hemorrhage, *: denotes exclusion from study, : group not specified

Graefes Arch Clin Exp Ophthalmol (2011) 249:1527

25

Treatment Diabetic Retinopathy Study [8]. Intravitreal triamcinolone acetonide has been used by vitreoretinal specialists to treat unresponsive cases but are often associated with well-recognized side-effects, such as cataract and glaucoma [10]. Despite these treatments, many patients do not respond and will continue to lose vision. As more studies have supported the role of VEGF in influencing structural and functional changes in diabetic retinopathy and macular edema, it is increasingly being used as an off-label therapeutic option for DME. Our meta-analysis of randomized clinical trials done to date substantiates the short-term beneficial effects of IVB compared to standard laser therapy. IVB caused significant reduction in CSMT and improvement in visual acuity at 6 weeks when compared to macular photocoagulation. However, there was no statistically meaningful difference in CSMT or visual acuity between the study and control groups at 12 weeks. At 24 weeks, the combined results from two trials showed a significant improvement in vision without significant decrease in CSMT. Furthermore, our analysis suggests that there is no significant benefit of adding steroids to bevacizumab for improving either anatomical (CSMT) or functional (visual acuity) aspect of DME at any time. The use of IVT should be guarded against because of cumulative side-effects such as cataract and glaucoma, and potential toxicity of the drug itself. The half-life of intravitreal injection of 1.25 mg of IVB into a rabbit eye has been shown to be 4.32 days in the vitreous cavity [45]. Most studies have shown that CSMT reduction in IVB either plateaus or starts decreasing in most eyes between 36 weeks [22, 25, 28, 35]. This may argue for a need for repeat injections. The emerging popularity of anti-VEGF agents is also raising concerns about safety with long-term use of these agents. Because bevacizumab is a full-length immunoglobulin, it remains in systemic circulation significantly longer than its Fab offspring, ranibizumab, raising the possibility of both local and systemic overdosage, particularly with an already compromised bloodretinal barrier [46, 47]. Bevacizumab, as a pan-VEGF blocker, has the potential to inhibit important physiological functions of VEGF such as wound healing and development of collaterals deemed significant in myocardial or peripheral ischemia, thus potentially causing systemic adverse events [48]. Although a meta-analysis for side effects of IVB was not performed in our study, anterior chamber reaction resolving with topical steroids was noted as the most common ocular sideeffect. Recent studies have shown that bevacizumab treatment did not cause any detectable retinal damage, and appears to be safe and well-tolerated as long as 12 months follow-up [49, 50]. In short, our meta-analysis suggests that IVB appears to be a more efficacious treatment for diabetic macular edema

than MPC during the short term or early (6-week) followup period. However, the benefits of IVB appear to wane over longer follow-up periods. Accordingly, one could argue that the best treatment for DME is still the "gold standard" of laser photocoagulation. However, the potential destructive effect of laser therapy cannot be overlooked, and there is increasing evidence for benefit with combination therapy in DME. Accordingly, other authors have pointed out the short-term effect of anti-angiogenic agents and have suggested using one or two intravitreal injections of anti-angiogenic agents to reduce central macular thickness, followed by focal or grid laser to give a sustained response as an alternative to treatment in DME [51]. The primary limitation to this study is the small number of trials eligible for our meta-analysis. It is worth mentioning that three of the four RCCTs in the current analysis are from Iran. Though, there have been no studies done to identify the differences in the diabetic and normal population between the two countries, such a possibility cannot be excluded. In addition, the inherent heterogeneity in methodology of the RCCTs in this study also presented a challenge. We were unable to use regression or stratification of study results to explore study-level factors that might have explained some of the heterogeneity that was detected using the Q-test and the I2 statistic. While a significantly larger number of studies would be required to validly explore the heterogeneity using statistical analyses, we did account for the presence of heterogeneity in our study results by using the random effects approach to meta-analysis. As far as the authors are aware, this is the first study to consolidate and review current knowledge of published data regarding the use of bevacizumab in DME, and despite the aforementioned limitations, the authors feel that the results of this meta-analysis is clinically useful and can offer some valuable, preliminary data on this subject. Our data suggests that bevacizumab yields better visual outcomes and achieves greater reduction in macular thickness in DME eyes compared to laser photocoagulation during the early follow-up period. However, the current literature does not seem to provide sufficient evidence for its longterm efficacy when used either singly or in combination with other therapies to treat DME. Further studies, perhaps in the form of multi-center controlled trials, could help elucidate the long-term effects of bevacizumab in DME.

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