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research-article2015
AOPXXX10.1177/1060028014568006Annals of PharmacotherapyJin et al
Research Report (Original research/clinical trials)
Comparative Effectiveness of Intravitreal Bevacizumab With or Without Triamcinolone Acetonide for Treatment of Diabetic Macular Edema
Annals of Pharmacotherapy 1–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014568006 aop.sagepub.com
Enzhong Jin, MD, MS1, Ling Luo, MD, PhD2, Yujing Bai, MD, PhD1, and Mingwei Zhao, MD, PhD1
Abstract Background: Bevacizumab and triamcinolone acetonide (TA) are both common choices for treatment of diabetic macular edema (DME), but the comparative efficacy of combined or separate applications is still not determined. Objectives: To compare the treatment efficacy of intravitreal bevacizumab (IVB) and the combination of IVB and intravitreal triamcinolone (IVT) for DME patients. Methods: PubMed, EMBASE, and the Cochrane library were systematically reviewed for randomized controlled trials comparing IVB with IVB/IVT. Data on visual acuity (VA) and central macular thickness (CMT) changes at 3 and 6 months were extracted and data on adverse events were collected. A meta-analysis was performed using the software RevMan 5.3. The methodological quality and bias risks were also evaluated. Results: VA improved more significantly in the IVB/IVT group compared with the IVB group at 3 months (mean difference [MD] = 0.07; 95% CI = 0.01 to 0.13), whereas there was no significant difference at 6 months (MD = −0.01; 95%CI = −0.11 to 0.09). The CMT reduction in the IVB/IVT group was significantly greater than that in the IVB group at 3 months (MD = 48.40; 95%CI = 30.23 to 66.57), but no statistically significant difference was found at 6 months (MD = 0.47; 95%CI = −24.11 to 25.04). Ocular hypertension was detected in 9/243 eyes in the IVB/IVT group but none of the IVB eyes. Conclusion: IVB/IVT is more effective for improving VA and decreasing CMT at 3 months in DME. A single injection of TA along with the first IVB could improve outcome within 3 months, but this is not sustained at 6 months. Continuous IVT/IVB treatment should be performed in further trials to clarify its long-term potential efficacy. Keywords diabetes, ophthalmology, drug utilization review, meta-analysis, evidence-based medicine
Introduction Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM), with high morbidity globally, and is considered to be the leading cause of vision loss and blindness in the working-age population.1 Diabetic macular edema (DME), an advanced vision-limiting complication of DR, induces swelling of the central macular area and affects a high proportion (up to 29%) of patients who have had DM for more than 20 years.2 DME tends to be a chronic disease, and spontaneous recovery seldom happens. If left untreated, 25% to 30% of patients go on to suffer moderate vision loss, and many of them may suffer severe vision loss or even blindness.3 Focal or diffuse photocoagulation has been considered as the standard treatment for DME since the 1980s.4 However, the cessation of vision loss or improvements in visual acuity (VA) are rarely observed.5 Therefore, a reliably safe and effective treatment for DME is required. Recently, there has been encouraging evidence regarding the use of anti-vascular endothelial growth factor (anti-VEGF)
agents in DME. Bevacizumab is a full-length monoclonal antibody blocking all isoforms of VEGF, and many studies have demonstrated its effectiveness as a pharmacotherapy for DME.6 Current studies have also indicated that 1
Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory for the Diagnosis and Treatment of Retinal and Choroid Diseases, Department of Ophthalmology, Peking University People’s Hospital, Beijing, People’s Republic of China 2 The 306th Hospital of PLA, Beijing, People’s Republic of China Corresponding Authors: Mingwei Zhao, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory for the Diagnosis and Treatment of Retinal and Choroid Diseases, Department of Ophthalmology, Peking University People’s Hospital, No. 11 Xizhimen South St, Xicheng District Beijing, 100044, People’s Republic of China. Email: [email protected] Ling Luo, The 306th Hospital of PLA, No.9, An Xiang North Lane, Deshengmen Wai, Chao Yang District, Beijing, 100101, People’s Republic of China. Email: [email protected]
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intravitreal injection of triamcinolone acetonide (TA) is effective and leads to anatomical and functional improvements in DME patients.7,8 It plays a significant role because of its antiangiogenic, anti-inflammatory, and blood–retinal barrier stabilizing effects.9 But the effectiveness of intravitreal triamcinolone (IVT) was only shown in the short term and was found to be transient; the recurrence of DME and potential complications of IVT have also been highlighted by other studies.9-11 In recent years, there is growing evidence that the combination of anti-VEGF agents and TA may be better for reducing macular edema and preventing the loss of visual acuity caused by DME.10,12,13 Previous meta-analyses dealing with treatment for DME compared a variety of anti-VEGF agents with photocoagulation or IVT, or a combination of them.14-16 To our knowledge, there is no meta-analysis that compares the effectiveness and safety of intravitreal bevacizumab (IVB) and IVB/IVT for DME both at 3 and 6 months. The present study focused on the treatment effectiveness and complications in randomized trials of IVB and IVB/IVT in DME patients.
Methods
on the discussion result. For duplicated publications or several reports of one trial, only the articles containing complete data at 3 months and 6 months were included. In studies utilizing additional injections, only those employing identical IVB dosage and interval use between both groups were enrolled. If the additional IVB was only performed in the IVB group during the first trimester but not in the IVB/IVT group, the study could also be enrolled.
Data Extraction Data extraction was conducted by 2 individual investigators according to the predesigned data extraction form. Study characteristics, such as the title, author, year of publication, and study design were extracted, and participant characteristics, such as age, gender, number of patients, and eyes, were also recorded. The interventions and details, primary and secondary outcomes, and ocular and systematic adverse events mentioned were recorded exactly. When extracting the VA data, the EDTRS letters assessment was converted into the logarithm of the minimal angle of resolution (log MAR) form.17
Quality Assessment
Search Strategy A computerized literature search was performed through PubMed, EMBASE, and the Cochrane library, from which the literature before August 2014 was chosen with no lower date limit or language restriction. The search was restricted to randomized controlled trials (RCTs). The articles and references were also screened for potentially eligible articles. Searches comprised various combinations of the following keywords: diabetic macular edema, DME, macular edema in diabetes, bevacizumab, Avastin, intravitreal, steroid, triamcinolone, triamcinolone acetonide, randomized controlled trial, RCT, double blind procedure, and single blind procedure.
Enrollment and Exclusion Criteria The inclusion criteria were the following: (1) study designed as a RCT, (2) study participants comprising patients with any type of DME, (3) study comparing IVB and IVB/IVT, (4) study indicating outcome of VA and central macular thickness (CMT), (5) follow-up longer than 3 months, (6) same dose of IVB (1.25 mg) and IVT (2 mg) used in both IVB and IVB/IVT groups, and (7) single injection of TA in the IVB/IVT group. Exclusion criteria were the following: (1) macular edema that was not caused by DR and (2) studies with completion rate lower than 80%. The electronic searches were examined by 2 independent reviewers, and only the reports meeting the inclusion criteria were selected. When disagreements occurred, they were resolved by discussion, and the final selection was based
The quality of RCTs was evaluated using the Jadad Scale according to 3 major study characteristics: randomization, blinding, and participant withdrawals and dropouts.18 The methodological quality was taken to be high when the Jadad score (range = 0-5) was 3 points or higher. The sensitivity analyses were performed with only the high-quality studies (Jadad score = 3-5) to determine the impact of excluded studies with a lower methodological quality. The bias of the selected articles was analyzed by 2 review authors according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions. The following parameters were assessed: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessments (detection bias); incomplete outcome data (attrition bias); selective reporting (reporting bias); other sources of bias, including an extreme baseline imbalance; risk of bias related to the specific study design used; and trial stopped early because of some data-dependent process. An answer of “yes” for the above parameters indicated low risk of bias; “no” indicated high risk of bias; and “unclear” indicated unclear or unknown risk of bias.19 The publication bias was estimated with a funnel plot, and trials sponsored by any industry funds were also reported.
Statistical Analysis We used the meta-analysis program of the Cochrane Collaboration (Review Manager 5.3) to calculate the
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Characteristics of Included Studies
Figure 1. Flow diagram of study screening and selection.
summary statistic for each component study. The primary and secondary outcomes were analyzed as continuous or dichotomized variables using a random-effect model or a fixed-effect model. Statistical heterogeneity was assessed using the χ2 and I2 tests. A value of I2 >50% was considered to represent substantial heterogeneity, and P 18 years past 6 months, presence of traction on the macula, glaucoma or ocular hypertension, significant media opacity, contraindications for bevacizumab or TA, pregnancy, not able to give informed consent
Major Inclusion Criteria Number of Patients
Mean age (years)
•• Group 1: IVB (1.25 mg) •• Group 1: n = 21 •• Group 1: 54.19 ± 9.90 •• Group 2: IVB/IVT (1.25 •• Group 2: n = 19 •• Group 2: 52.11 ± mg/2 mg) 12.54
•• Group 1: n = 41 59.7 ± 8.3 •• Group 1: IVB (3 injections of 1.25 mg at •• Group 2: n = 37 •• Group 3: n = 37 6-week intervals) •• Group 2: IVB/IVT (1.25 mg/2 mg) + IVB (2 injections of 1.25 mg at 6-week intervals) •• Group 3: sham injection
Intervention Group
Not mentioned
CMT of Baseline
•• Group 1: 525.76 •• Group 1: ± 184.10 41.76 ± 15.59 •• Group 2: 554.50 •• Group 2: ± 169.05 39.89 ± 12.27
Not mentioned
VA of Baseline
4, 6, 12
6, 12, 18, 24
1
5
Duration of Follow-up Jadad (weeks) Score
Abbreviation: BCVA, best-corrected visual acuity; CMT, central macular thickness; CRT: central retinal thickness; DM, diabetes mellitus; DME, diabetic macular edema; IVB, intravitreal bevacizumab injection; IVT, intravitreal triamcinolone acetonide injection; IVB/IVT, intravitreal injection of bevacizumab combined with triamcinolone actronide; LP, light perception; ME, macular edema; MPC, macular laser photocoagulation; OCT, optical coherence tomography; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation; TA, triamcinolone acetonide; VA, visual acuity.
2008, Iran
Ahmadieh et al12
Study
Publication Date and Country
Table 1. (continued)
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Figure 2. Comparison of IVB versus IVB/IVT in visual acuity: A. Comparison of IVB versus IVB/IVT in visual acuity at 3 months. The forest plot shows the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 3-month follow-up. The mean difference for included studies is shown in the total line. The random effects were used for analysis. B. Comparison of IVB versus IVB/IVT in visual acuity at 6 months: The forest plot reveals the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 6-month follow-up. The mean difference for included studies is shown in the total line. Random effects were used for analysis. Abbreviation: IVB, intravitreal bevacizumab injection; IVT, intravitreal triamcinolone acetonide injection; IVB/IVT, intravitreal injection of bevacizumab combined with triamcinolone actronide; VA, visual acuity.
Figure 3. Comparison of IVB versus IVB/IVT in central macular thickness: A. Comparison of IVB versus IVB/IVT in central macular thickness at 3 months. The forest plot reveals the mean difference in CMT along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 3-month follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis. B. Comparison of IVB versus IVB/IVT in central macular thickness at 6 months. The forest plot presents the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 6-month follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis. Abbreviation: IVB, intravitreal bevacizumab injection; IVT, intravitreal triamcinolone acetonide injection; IVB/IVT, intravitreal injection of bevacizumab combined with triamcinolone actronide; VA, visual acuity.
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Jin et al (MD = 48.40; 95% CI = 30.23 to 66.57; Figure 3A). But there was no statistically significant difference between the 2 groups for the CMT reduction (MD = 0.47; 95%CI = −24.11 to 25.04; P = 0.97) at 6 months (Figure 3B). A sensitivity analysis was conducted as well as VA, and the statistical results did not change17,21,23-25 (Figures A.4 and A.5). Unlike the VA findings, there was no significant heterogeneity at 3 months (P < 0.00001; I2 = 27%) or 6 months (P = 0.97; I2 = 0%).
Adverse Events Of the 7 trials, which included 546 eyes, 5 reported ocular and nonocular adverse events. Ocular hypertension (intraocular pressure [IOP] >21 mm Hg) was detected in 9 eyes, with a rate ranging from 0% to 8.3%, across the trials in the IVB/IVT group, but there was no case among the IVB treated eyes. Rise in IOP can be controlled with topical IOP-lowering medications. Progression of fibrous proliferation was noticed in 1 eye in the IVB group, with no sign of retinal traction.12 No other ocular complications such as progression of cataract, vitreous hemorrhage, endophthalmitis, or retinal detachment were observed. No systemic adverse events such as significant increase in blood pressure or thromboembolic events such as myocardial infarction or heart failure were found during the studies. Two patients in the IVB/IVT group and 3 patients in the control or macular laser photocoagulation group died during follow-up.12,22
Quality Assessment Two of the included studies with Jadad score lower than 3 points were removed for sensitivity analysis, and the pooled results did not yield any significant difference (Figures A.2-A.5). A funnel plot for publication bias estimate was performed and showed symmetry, indicating no obvious evidence of publication bias (Figure A.6). None of the included trials was sponsored by any industry funds.
Discussion DME has long been recognized as the major cause of vision loss and blindness in adults with DM. Epidemiological studies show that the 10-year cumulative incidence of DME could be as high as 20.1% and 25.4%, respectively, among type 1 and type 2 diabetes patients treated with insulin.26 Besides laser photocoagulation, several anti-VEGF agents and steroids have been introduced as potential therapeutic choices for DME patients. At present, ranibizumab, bevacizumab, and triamcinolone acetonide are frequently used in the treatment of DME and are thought to have considerable
value. IVB and IVT have been studied by several authors for their effects in improving VA and reducing CMT in DME.8,10,12,13,20-22 Some authors have demonstrated the superiority of triamcinolone compared with bevacizumab, whereas others showed that bevacizumab was more efficient.8,20,27,28 However, in a study performed by Rensch et al,29 results for IVT and IVB did not differ markedly. Two meta-analyses have been performed to compare the efficacy of both therapies in DME, and they concluded that the relatively longer half-life and better 3-month efficacy in terms of anatomical and functional improvements of TA suggested that IVT was superior to IVB in DME treatment.14,15 The combination of IVB and IVT has been frequently used to improve the efficacy of monotherapy in recent years. In the study by Faghihi et al,21 the response was stable for the IVB/IVT group, but the IVB group showed significant relapse (P < 0.001). The response to bevacizumab alone was thought to be shorter lived. For several other trials, no significant difference between IVB/IVT and IVB was demonstrated, but there was a trend toward earlier functional effects with combined treatment.8,12 VA improvement in the IVB/IVT group was shorter in duration when compared with the IVB group (12 vs 36 weeks).22 The question of how and how much the combination therapy affected the anatomical and functional outcomes remains controversial. In a recent published meta-analysis, the efficacy of IVB and IVB/IVT was compared at 3 months by analyzing the end point VA and CMT; no significant difference in VA outcome was seen, but better CMT was found in IVB/IVT group.16 But the authors did not analyze the change of VA or CMT, which is much more reasonable and precise for efficacy comparison. In the present study, we compared the efficacy of IVB/IVT and IVB in DME by analyzing the changing value of VA and CMT at 3 and 6 months. VA is the primary measurement indicator of treatment efficacy and progression of DME. In our meta-analysis, it was shown that IVB with or without IVT could improve the VA at 3 and 6 months. The VA improvement at 3 months was significantly superior in the IVB/IVT group compared with the IVB group. But at 6 months, the VA improvement in the IVB group tended to surpass that in the combination group, though the difference had no significance. The overall tendency for comparison of VA improvement for the 2 groups was consistent except in 1 trial.22 In this trial, 14 and 10 retreatments were performed in the IVB and IVB/ IVT groups, which may affect the result. Additionally, 6 and 12 cases of incomplete data in the IVB and IVB/IVT groups, respectively, may have also interfered with the outcome. As an important anatomical indicator, the decrease in CMT was also measured. Both IVB and IVB/IVT treatment
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decreased the CMT of DME eyes at 3 and 6 months. The 3-month CMT decrease was more significant in the IVB/ IVT group compared with the IVB group, which may be attributed to the impact of TA in the vitreous. But there was no superiority at 6 months. The anatomical outcome was quite consistent with the VA change. Although Browning et al23 had proposed that age, hemoglobin A1C level, and severity of fluorescein leakage all affect the change in VA, it is still considered that decrease in CMT may play a major role. It is well known that TA has a relatively longer half-life than bevacizumab, as long as 18.6 days, and the measurable concentration was expected to last nearly 3 months (93 ± 28 days).24 This may explain the better outcome for the combination group at 3 months. At 6 months, no effect of TA was left, and the VA was almost attributed to bevacizumab. Thus, no significant difference was found. The most important and common complication of IVT was elevation of IOP.25 For IVB, systemic adverse events were also occasionally reported.30 We reviewed all the ocular and nonocular events reported in the included trials. Although 0% to 8.3% of patients developed ocular hypertension in the IVB/IVT group, the IOP rise could be well controlled. No serious ocular and systemic adverse events were reported in these 7 articles. Two deaths occurred in the IVB/IVT group but were not identified to be associated with IVB or IVT.22 Our results indicated that both single and combined use of IVB and IVT for treating DME were safe. All the articles analyzed were RCTs, which improved the quality of our meta-analysis. The analysis focused on 2 relatively inexpensive drugs used in the majority of DME patients, which means that the results of this study may be of great importance for clinical practice. However, there are also limitations that need to be taken into account. First, the major limitation is the small sample of the included trials. Second, although inclusion and exclusion criteria were defined, the design processes were different. Several studies performed additional injections with certain intervals for the IVB group alone or along with the IVB/IVT group after initial treatment.19,21,23 Third, the results of VA were limited by heterogeneity, which may be associated with sample size and additional injections. Fourth, the follow-up time was too short to yield more information about the long-term effectiveness and safety issues. Among the included studies, only the Lim et al8 study analyzed the results at 48 weeks; thus, the metaanalysis could not be performed for the 1-year followup.23 Because all the included trials only performed an adjunctive injection of TA along with the first injection of bevacizumab, we could not collect sufficient data to judge the possible efficacy of a continuous combination of IVT
with IVB. Thus, further studies on the persisting combination of IVT with IVB for DME patients are needed to assess the long-term efficacy. The present meta-analysis specially reviewed published information of the efficacy comparisons between IVB and IVB/IVT in DME. From this study, we conclude that a single injection of TA along with the first injection of bevacizumab could improve the results of VA and CMT within 3 months, but this did not last for 6 months. The VA improvement and CMT decrease were highly correlated. The single dose of TA with concentration attenuation and relatively short half-life may explain its limited long-term effectiveness. Further studies of continuous injection of TA along with bevacizumab still need to be performed, which may sustain the improvements in VA and CMT outcomes for a longer time and provide a more effective route for the treatment of DME.
Appendix A
Figure A.1. Assessment of review authors’ judgment about each risk of bias item for each included study: +, low risk of bias; ?, unclear risk of bias.
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Figure A.2. Comparison of IVB versus IVB/IVT in visual acuity (VA) at 3 months, after excluding the studies with low methodological quality for sensitivity analysis. The forest plot reveals the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 3 months’ follow-up. The mean difference for included studies is shown in the total line. Random effects were used for analysis.
Figure A.3. Comparison of IVB versus IVB/IVT in visual acuity (VA) at 6 months after excluding the studies with low methodological quality for sensitivity analysis. The forest plot presents the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 6 months’ follow-up. The mean difference for included studies is shown in the total line. Random effects were used for analysis.
Figure A.4. Comparison of IVB versus IVB/IVT in central macular thickness at 3 months after excluding the studies with low methodological quality for sensitivity analysis. The forest plot reveals the mean difference in CMT along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 3 months’ follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis.
Figure A.5. Comparison of IVB versus IVB/IVT in central macular thickness at 6 months after excluding the studies with low methodological quality for sensitivity analysis. The forest plot reveals the mean difference in CMT along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 6 months’ follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis.
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Figure A.6. Funnel plot to assess for evidence of publication bias: the funnel plot was used to assess whether publication bias was potentially present in our meta-analysis. Abbreviations: MD, mean difference; SE, standard error.
Acknowledgments The authors thank the researchers whose studies were involved in this meta-analysis and who provided useful data to us.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant Number 81470651 and Grant Number 81271016).
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5. Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse diabetic macular edema: long-term visual results. Ophthalmology. 1991;98:1594-1602. 6. Goyal S, Lavalley M, Subramanian ML. Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2011;249:15-27. 7. Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebocontrolled, randomized clinical trial. Ophthalmology. 2006;113:1533-1538. 8. Lim JW, Lee HK, Shin MC. Comparison of intravitreal bevacizumab alone or combined with triamcinolone versus triamcinolone in diabetic macular edema: a randomized clinical trial. Ophthalmologica. 2012;227:100-106. 9. Al Dhibi HA, Arevalo JF. Clinical trials on corticosteroids for diabetic macular edema. World J Diabetes. 2013;4:295-302. 10. Synek S, Vojniković B. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular oedema. Coll Antropol. 2010;34(suppl 2):99-103. 11. Marey HM, Ellakwa AF. Intravitreal bevacizumab alone or combined with triamcinolone acetonide as the primary treatment for diabetic macular edema. Clin Ophthalmol. 2011;5:1011-1106. 12. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema: a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008;246:483-489. 13. Wang YS, Li X, Wang HY, Zhang ZF, Li MH, Su XN. Intravitreal bevacizumab combined with/without triamcinolone acetonide in single injection for treatment of diabetic macular edema. Chin Med J. 2011;124:352-358.
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Jin et al 14. Zhang XL, Chen J, Zhang RJ, Wang WJ, Zhou Q, Qin XY. Intravitreal triamcinolone versus intravitreal bevacizumab for diabetic macular edema: a meta-analysis. Int J Ophthalmol. 2013;18:546-552. 15. Zhang Y, Ma J, Meng N, Li H, Qu Y. Comparison of intravitreal triamcinolone acetonide with intravitreal bevacizumab for treatment of diabetic macular edema: a meta-analysis. Curr Eye Res. 2013;38:578-587. 16. Liu X, Zhou X, Wang Z, Li T, Jiang B. Intravitreal bevacizumab with or without triamcinolone acetonide for diabetic macular edema: a meta-analysis of randomized controlled trials. Chin Med J (Engl). 2014;127:3471-3476. 17. Thomson D. VA testing in optometric practice: part 2. Newer chart designs. Optometry Today. 2005;45:22-24. 18. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12. 19. Higgins J, Green S. Assessing risk of bias in included studies. In: Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.0 ed. Oxford, UK: Cochrane Collaboration; 2008:672. 20. Marey HM, Ellakwa AF. Intravitreal bevacizumab alone or combined with triamcinolone acetonide as the primary treatment for diabetic macular edema. Clin Ophthalmol. 2011;5:1011-1016. 21. Faghihi H, Roohipoor R, Mohammadi SF, et al. Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol. 2008;18:941-948. 22. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116:1142-1150.
23. Browning DJ, Glassman AR, Aiello LP, et al. Relationship between optical coherence tomography-measured central retinal thickness and VA in diabetic macular edema. Ophthalmology. 2007;114:525-536. 24. Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB III, Miller M. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology. 2003;110:681-686. 25. Sonmez K, Ozturk F. Complications of intravitreal triamcinolone acetonide for macular edema and predictive factors for intraocular pressure elevation. Int J Ophthalmol. 2012;5: 719-725. 26. Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XV. The long-term incidence of macular edema. Ophthalmology. 1995;102:7-16. 27. Chakrabarti M, John SR, Chakrabarti A. Intravitreal monotherapy with bevacizumab (IVB) and triamcinolone acetonide (IVTA) versus combination therapy (IVB and IVTA) for recalcitrant diabetic macular edema. Kerala J Ophthalmol. 2009;21:139-148. 28. Isaac DL, Abud MB, Frantz KA, Rassi AR, Avila M. Comparing intravitreal triamcinolone acetonide and bevacizumab injections for the treatment of diabetic macular oedema: a randomized double-blind study. Acta Ophthalmol. 2012;90:56-60. 29. Rensch F, Spandau UH, Wickenhauser A, Jonas JB. Diffuse diabetic macular oedema treated with intravitreal bevacizumab or triamcinolone acetonide. Acta Opthalmologica. 2010;88:e36-e37. 30. Jyothi S, Chowdhury H, Elagouz M, Sivaprasad S. Intravitreal bevacizumab (Avastin) for age-related macular degeneration: a critical analysis of literature. Eye (Lond). 2010;24:816-824.
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research-article2015
AOPXXX10.1177/1060028014568006Annals of PharmacotherapyJin et al
Research Report (Original research/clinical trials)
Comparative Effectiveness of Intravitreal Bevacizumab With or Without Triamcinolone Acetonide for Treatment of Diabetic Macular Edema
Annals of Pharmacotherapy 1–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014568006 aop.sagepub.com
Enzhong Jin, MD, MS1, Ling Luo, MD, PhD2, Yujing Bai, MD, PhD1, and Mingwei Zhao, MD, PhD1
Abstract Background: Bevacizumab and triamcinolone acetonide (TA) are both common choices for treatment of diabetic macular edema (DME), but the comparative efficacy of combined or separate applications is still not determined. Objectives: To compare the treatment efficacy of intravitreal bevacizumab (IVB) and the combination of IVB and intravitreal triamcinolone (IVT) for DME patients. Methods: PubMed, EMBASE, and the Cochrane library were systematically reviewed for randomized controlled trials comparing IVB with IVB/IVT. Data on visual acuity (VA) and central macular thickness (CMT) changes at 3 and 6 months were extracted and data on adverse events were collected. A meta-analysis was performed using the software RevMan 5.3. The methodological quality and bias risks were also evaluated. Results: VA improved more significantly in the IVB/IVT group compared with the IVB group at 3 months (mean difference [MD] = 0.07; 95% CI = 0.01 to 0.13), whereas there was no significant difference at 6 months (MD = −0.01; 95%CI = −0.11 to 0.09). The CMT reduction in the IVB/IVT group was significantly greater than that in the IVB group at 3 months (MD = 48.40; 95%CI = 30.23 to 66.57), but no statistically significant difference was found at 6 months (MD = 0.47; 95%CI = −24.11 to 25.04). Ocular hypertension was detected in 9/243 eyes in the IVB/IVT group but none of the IVB eyes. Conclusion: IVB/IVT is more effective for improving VA and decreasing CMT at 3 months in DME. A single injection of TA along with the first IVB could improve outcome within 3 months, but this is not sustained at 6 months. Continuous IVT/IVB treatment should be performed in further trials to clarify its long-term potential efficacy. Keywords diabetes, ophthalmology, drug utilization review, meta-analysis, evidence-based medicine
Introduction Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM), with high morbidity globally, and is considered to be the leading cause of vision loss and blindness in the working-age population.1 Diabetic macular edema (DME), an advanced vision-limiting complication of DR, induces swelling of the central macular area and affects a high proportion (up to 29%) of patients who have had DM for more than 20 years.2 DME tends to be a chronic disease, and spontaneous recovery seldom happens. If left untreated, 25% to 30% of patients go on to suffer moderate vision loss, and many of them may suffer severe vision loss or even blindness.3 Focal or diffuse photocoagulation has been considered as the standard treatment for DME since the 1980s.4 However, the cessation of vision loss or improvements in visual acuity (VA) are rarely observed.5 Therefore, a reliably safe and effective treatment for DME is required. Recently, there has been encouraging evidence regarding the use of anti-vascular endothelial growth factor (anti-VEGF)
agents in DME. Bevacizumab is a full-length monoclonal antibody blocking all isoforms of VEGF, and many studies have demonstrated its effectiveness as a pharmacotherapy for DME.6 Current studies have also indicated that 1
Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory for the Diagnosis and Treatment of Retinal and Choroid Diseases, Department of Ophthalmology, Peking University People’s Hospital, Beijing, People’s Republic of China 2 The 306th Hospital of PLA, Beijing, People’s Republic of China Corresponding Authors: Mingwei Zhao, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing Key Laboratory for the Diagnosis and Treatment of Retinal and Choroid Diseases, Department of Ophthalmology, Peking University People’s Hospital, No. 11 Xizhimen South St, Xicheng District Beijing, 100044, People’s Republic of China. Email: [email protected] Ling Luo, The 306th Hospital of PLA, No.9, An Xiang North Lane, Deshengmen Wai, Chao Yang District, Beijing, 100101, People’s Republic of China. Email: [email protected]
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intravitreal injection of triamcinolone acetonide (TA) is effective and leads to anatomical and functional improvements in DME patients.7,8 It plays a significant role because of its antiangiogenic, anti-inflammatory, and blood–retinal barrier stabilizing effects.9 But the effectiveness of intravitreal triamcinolone (IVT) was only shown in the short term and was found to be transient; the recurrence of DME and potential complications of IVT have also been highlighted by other studies.9-11 In recent years, there is growing evidence that the combination of anti-VEGF agents and TA may be better for reducing macular edema and preventing the loss of visual acuity caused by DME.10,12,13 Previous meta-analyses dealing with treatment for DME compared a variety of anti-VEGF agents with photocoagulation or IVT, or a combination of them.14-16 To our knowledge, there is no meta-analysis that compares the effectiveness and safety of intravitreal bevacizumab (IVB) and IVB/IVT for DME both at 3 and 6 months. The present study focused on the treatment effectiveness and complications in randomized trials of IVB and IVB/IVT in DME patients.
Methods
on the discussion result. For duplicated publications or several reports of one trial, only the articles containing complete data at 3 months and 6 months were included. In studies utilizing additional injections, only those employing identical IVB dosage and interval use between both groups were enrolled. If the additional IVB was only performed in the IVB group during the first trimester but not in the IVB/IVT group, the study could also be enrolled.
Data Extraction Data extraction was conducted by 2 individual investigators according to the predesigned data extraction form. Study characteristics, such as the title, author, year of publication, and study design were extracted, and participant characteristics, such as age, gender, number of patients, and eyes, were also recorded. The interventions and details, primary and secondary outcomes, and ocular and systematic adverse events mentioned were recorded exactly. When extracting the VA data, the EDTRS letters assessment was converted into the logarithm of the minimal angle of resolution (log MAR) form.17
Quality Assessment
Search Strategy A computerized literature search was performed through PubMed, EMBASE, and the Cochrane library, from which the literature before August 2014 was chosen with no lower date limit or language restriction. The search was restricted to randomized controlled trials (RCTs). The articles and references were also screened for potentially eligible articles. Searches comprised various combinations of the following keywords: diabetic macular edema, DME, macular edema in diabetes, bevacizumab, Avastin, intravitreal, steroid, triamcinolone, triamcinolone acetonide, randomized controlled trial, RCT, double blind procedure, and single blind procedure.
Enrollment and Exclusion Criteria The inclusion criteria were the following: (1) study designed as a RCT, (2) study participants comprising patients with any type of DME, (3) study comparing IVB and IVB/IVT, (4) study indicating outcome of VA and central macular thickness (CMT), (5) follow-up longer than 3 months, (6) same dose of IVB (1.25 mg) and IVT (2 mg) used in both IVB and IVB/IVT groups, and (7) single injection of TA in the IVB/IVT group. Exclusion criteria were the following: (1) macular edema that was not caused by DR and (2) studies with completion rate lower than 80%. The electronic searches were examined by 2 independent reviewers, and only the reports meeting the inclusion criteria were selected. When disagreements occurred, they were resolved by discussion, and the final selection was based
The quality of RCTs was evaluated using the Jadad Scale according to 3 major study characteristics: randomization, blinding, and participant withdrawals and dropouts.18 The methodological quality was taken to be high when the Jadad score (range = 0-5) was 3 points or higher. The sensitivity analyses were performed with only the high-quality studies (Jadad score = 3-5) to determine the impact of excluded studies with a lower methodological quality. The bias of the selected articles was analyzed by 2 review authors according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions. The following parameters were assessed: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessments (detection bias); incomplete outcome data (attrition bias); selective reporting (reporting bias); other sources of bias, including an extreme baseline imbalance; risk of bias related to the specific study design used; and trial stopped early because of some data-dependent process. An answer of “yes” for the above parameters indicated low risk of bias; “no” indicated high risk of bias; and “unclear” indicated unclear or unknown risk of bias.19 The publication bias was estimated with a funnel plot, and trials sponsored by any industry funds were also reported.
Statistical Analysis We used the meta-analysis program of the Cochrane Collaboration (Review Manager 5.3) to calculate the
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Characteristics of Included Studies
Figure 1. Flow diagram of study screening and selection.
summary statistic for each component study. The primary and secondary outcomes were analyzed as continuous or dichotomized variables using a random-effect model or a fixed-effect model. Statistical heterogeneity was assessed using the χ2 and I2 tests. A value of I2 >50% was considered to represent substantial heterogeneity, and P 18 years past 6 months, presence of traction on the macula, glaucoma or ocular hypertension, significant media opacity, contraindications for bevacizumab or TA, pregnancy, not able to give informed consent
Major Inclusion Criteria Number of Patients
Mean age (years)
•• Group 1: IVB (1.25 mg) •• Group 1: n = 21 •• Group 1: 54.19 ± 9.90 •• Group 2: IVB/IVT (1.25 •• Group 2: n = 19 •• Group 2: 52.11 ± mg/2 mg) 12.54
•• Group 1: n = 41 59.7 ± 8.3 •• Group 1: IVB (3 injections of 1.25 mg at •• Group 2: n = 37 •• Group 3: n = 37 6-week intervals) •• Group 2: IVB/IVT (1.25 mg/2 mg) + IVB (2 injections of 1.25 mg at 6-week intervals) •• Group 3: sham injection
Intervention Group
Not mentioned
CMT of Baseline
•• Group 1: 525.76 •• Group 1: ± 184.10 41.76 ± 15.59 •• Group 2: 554.50 •• Group 2: ± 169.05 39.89 ± 12.27
Not mentioned
VA of Baseline
4, 6, 12
6, 12, 18, 24
1
5
Duration of Follow-up Jadad (weeks) Score
Abbreviation: BCVA, best-corrected visual acuity; CMT, central macular thickness; CRT: central retinal thickness; DM, diabetes mellitus; DME, diabetic macular edema; IVB, intravitreal bevacizumab injection; IVT, intravitreal triamcinolone acetonide injection; IVB/IVT, intravitreal injection of bevacizumab combined with triamcinolone actronide; LP, light perception; ME, macular edema; MPC, macular laser photocoagulation; OCT, optical coherence tomography; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation; TA, triamcinolone acetonide; VA, visual acuity.
2008, Iran
Ahmadieh et al12
Study
Publication Date and Country
Table 1. (continued)
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Figure 2. Comparison of IVB versus IVB/IVT in visual acuity: A. Comparison of IVB versus IVB/IVT in visual acuity at 3 months. The forest plot shows the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 3-month follow-up. The mean difference for included studies is shown in the total line. The random effects were used for analysis. B. Comparison of IVB versus IVB/IVT in visual acuity at 6 months: The forest plot reveals the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 6-month follow-up. The mean difference for included studies is shown in the total line. Random effects were used for analysis. Abbreviation: IVB, intravitreal bevacizumab injection; IVT, intravitreal triamcinolone acetonide injection; IVB/IVT, intravitreal injection of bevacizumab combined with triamcinolone actronide; VA, visual acuity.
Figure 3. Comparison of IVB versus IVB/IVT in central macular thickness: A. Comparison of IVB versus IVB/IVT in central macular thickness at 3 months. The forest plot reveals the mean difference in CMT along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 3-month follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis. B. Comparison of IVB versus IVB/IVT in central macular thickness at 6 months. The forest plot presents the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at the 6-month follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis. Abbreviation: IVB, intravitreal bevacizumab injection; IVT, intravitreal triamcinolone acetonide injection; IVB/IVT, intravitreal injection of bevacizumab combined with triamcinolone actronide; VA, visual acuity.
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Jin et al (MD = 48.40; 95% CI = 30.23 to 66.57; Figure 3A). But there was no statistically significant difference between the 2 groups for the CMT reduction (MD = 0.47; 95%CI = −24.11 to 25.04; P = 0.97) at 6 months (Figure 3B). A sensitivity analysis was conducted as well as VA, and the statistical results did not change17,21,23-25 (Figures A.4 and A.5). Unlike the VA findings, there was no significant heterogeneity at 3 months (P < 0.00001; I2 = 27%) or 6 months (P = 0.97; I2 = 0%).
Adverse Events Of the 7 trials, which included 546 eyes, 5 reported ocular and nonocular adverse events. Ocular hypertension (intraocular pressure [IOP] >21 mm Hg) was detected in 9 eyes, with a rate ranging from 0% to 8.3%, across the trials in the IVB/IVT group, but there was no case among the IVB treated eyes. Rise in IOP can be controlled with topical IOP-lowering medications. Progression of fibrous proliferation was noticed in 1 eye in the IVB group, with no sign of retinal traction.12 No other ocular complications such as progression of cataract, vitreous hemorrhage, endophthalmitis, or retinal detachment were observed. No systemic adverse events such as significant increase in blood pressure or thromboembolic events such as myocardial infarction or heart failure were found during the studies. Two patients in the IVB/IVT group and 3 patients in the control or macular laser photocoagulation group died during follow-up.12,22
Quality Assessment Two of the included studies with Jadad score lower than 3 points were removed for sensitivity analysis, and the pooled results did not yield any significant difference (Figures A.2-A.5). A funnel plot for publication bias estimate was performed and showed symmetry, indicating no obvious evidence of publication bias (Figure A.6). None of the included trials was sponsored by any industry funds.
Discussion DME has long been recognized as the major cause of vision loss and blindness in adults with DM. Epidemiological studies show that the 10-year cumulative incidence of DME could be as high as 20.1% and 25.4%, respectively, among type 1 and type 2 diabetes patients treated with insulin.26 Besides laser photocoagulation, several anti-VEGF agents and steroids have been introduced as potential therapeutic choices for DME patients. At present, ranibizumab, bevacizumab, and triamcinolone acetonide are frequently used in the treatment of DME and are thought to have considerable
value. IVB and IVT have been studied by several authors for their effects in improving VA and reducing CMT in DME.8,10,12,13,20-22 Some authors have demonstrated the superiority of triamcinolone compared with bevacizumab, whereas others showed that bevacizumab was more efficient.8,20,27,28 However, in a study performed by Rensch et al,29 results for IVT and IVB did not differ markedly. Two meta-analyses have been performed to compare the efficacy of both therapies in DME, and they concluded that the relatively longer half-life and better 3-month efficacy in terms of anatomical and functional improvements of TA suggested that IVT was superior to IVB in DME treatment.14,15 The combination of IVB and IVT has been frequently used to improve the efficacy of monotherapy in recent years. In the study by Faghihi et al,21 the response was stable for the IVB/IVT group, but the IVB group showed significant relapse (P < 0.001). The response to bevacizumab alone was thought to be shorter lived. For several other trials, no significant difference between IVB/IVT and IVB was demonstrated, but there was a trend toward earlier functional effects with combined treatment.8,12 VA improvement in the IVB/IVT group was shorter in duration when compared with the IVB group (12 vs 36 weeks).22 The question of how and how much the combination therapy affected the anatomical and functional outcomes remains controversial. In a recent published meta-analysis, the efficacy of IVB and IVB/IVT was compared at 3 months by analyzing the end point VA and CMT; no significant difference in VA outcome was seen, but better CMT was found in IVB/IVT group.16 But the authors did not analyze the change of VA or CMT, which is much more reasonable and precise for efficacy comparison. In the present study, we compared the efficacy of IVB/IVT and IVB in DME by analyzing the changing value of VA and CMT at 3 and 6 months. VA is the primary measurement indicator of treatment efficacy and progression of DME. In our meta-analysis, it was shown that IVB with or without IVT could improve the VA at 3 and 6 months. The VA improvement at 3 months was significantly superior in the IVB/IVT group compared with the IVB group. But at 6 months, the VA improvement in the IVB group tended to surpass that in the combination group, though the difference had no significance. The overall tendency for comparison of VA improvement for the 2 groups was consistent except in 1 trial.22 In this trial, 14 and 10 retreatments were performed in the IVB and IVB/ IVT groups, which may affect the result. Additionally, 6 and 12 cases of incomplete data in the IVB and IVB/IVT groups, respectively, may have also interfered with the outcome. As an important anatomical indicator, the decrease in CMT was also measured. Both IVB and IVB/IVT treatment
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decreased the CMT of DME eyes at 3 and 6 months. The 3-month CMT decrease was more significant in the IVB/ IVT group compared with the IVB group, which may be attributed to the impact of TA in the vitreous. But there was no superiority at 6 months. The anatomical outcome was quite consistent with the VA change. Although Browning et al23 had proposed that age, hemoglobin A1C level, and severity of fluorescein leakage all affect the change in VA, it is still considered that decrease in CMT may play a major role. It is well known that TA has a relatively longer half-life than bevacizumab, as long as 18.6 days, and the measurable concentration was expected to last nearly 3 months (93 ± 28 days).24 This may explain the better outcome for the combination group at 3 months. At 6 months, no effect of TA was left, and the VA was almost attributed to bevacizumab. Thus, no significant difference was found. The most important and common complication of IVT was elevation of IOP.25 For IVB, systemic adverse events were also occasionally reported.30 We reviewed all the ocular and nonocular events reported in the included trials. Although 0% to 8.3% of patients developed ocular hypertension in the IVB/IVT group, the IOP rise could be well controlled. No serious ocular and systemic adverse events were reported in these 7 articles. Two deaths occurred in the IVB/IVT group but were not identified to be associated with IVB or IVT.22 Our results indicated that both single and combined use of IVB and IVT for treating DME were safe. All the articles analyzed were RCTs, which improved the quality of our meta-analysis. The analysis focused on 2 relatively inexpensive drugs used in the majority of DME patients, which means that the results of this study may be of great importance for clinical practice. However, there are also limitations that need to be taken into account. First, the major limitation is the small sample of the included trials. Second, although inclusion and exclusion criteria were defined, the design processes were different. Several studies performed additional injections with certain intervals for the IVB group alone or along with the IVB/IVT group after initial treatment.19,21,23 Third, the results of VA were limited by heterogeneity, which may be associated with sample size and additional injections. Fourth, the follow-up time was too short to yield more information about the long-term effectiveness and safety issues. Among the included studies, only the Lim et al8 study analyzed the results at 48 weeks; thus, the metaanalysis could not be performed for the 1-year followup.23 Because all the included trials only performed an adjunctive injection of TA along with the first injection of bevacizumab, we could not collect sufficient data to judge the possible efficacy of a continuous combination of IVT
with IVB. Thus, further studies on the persisting combination of IVT with IVB for DME patients are needed to assess the long-term efficacy. The present meta-analysis specially reviewed published information of the efficacy comparisons between IVB and IVB/IVT in DME. From this study, we conclude that a single injection of TA along with the first injection of bevacizumab could improve the results of VA and CMT within 3 months, but this did not last for 6 months. The VA improvement and CMT decrease were highly correlated. The single dose of TA with concentration attenuation and relatively short half-life may explain its limited long-term effectiveness. Further studies of continuous injection of TA along with bevacizumab still need to be performed, which may sustain the improvements in VA and CMT outcomes for a longer time and provide a more effective route for the treatment of DME.
Appendix A
Figure A.1. Assessment of review authors’ judgment about each risk of bias item for each included study: +, low risk of bias; ?, unclear risk of bias.
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Figure A.2. Comparison of IVB versus IVB/IVT in visual acuity (VA) at 3 months, after excluding the studies with low methodological quality for sensitivity analysis. The forest plot reveals the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 3 months’ follow-up. The mean difference for included studies is shown in the total line. Random effects were used for analysis.
Figure A.3. Comparison of IVB versus IVB/IVT in visual acuity (VA) at 6 months after excluding the studies with low methodological quality for sensitivity analysis. The forest plot presents the mean difference in VA along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 6 months’ follow-up. The mean difference for included studies is shown in the total line. Random effects were used for analysis.
Figure A.4. Comparison of IVB versus IVB/IVT in central macular thickness at 3 months after excluding the studies with low methodological quality for sensitivity analysis. The forest plot reveals the mean difference in CMT along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 3 months’ follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis.
Figure A.5. Comparison of IVB versus IVB/IVT in central macular thickness at 6 months after excluding the studies with low methodological quality for sensitivity analysis. The forest plot reveals the mean difference in CMT along with the associated 95% CI comparing the IVB group with the IVB/IVT group at 6 months’ follow-up. The mean difference for included studies is shown in the total line. Fixed effects were used for analysis.
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Figure A.6. Funnel plot to assess for evidence of publication bias: the funnel plot was used to assess whether publication bias was potentially present in our meta-analysis. Abbreviations: MD, mean difference; SE, standard error.
Acknowledgments The authors thank the researchers whose studies were involved in this meta-analysis and who provided useful data to us.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant Number 81470651 and Grant Number 81271016).
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