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Intravitreal conbercept improves outcome in patients undergoing vitrectomy for proliferative diabetic retinopathy: A systematic review and meta-analysis.
Pranata, R, Vania, A
Journal of evidence-based medicine. 2020;(2):116-124
Abstract
OBJECTIVES To evaluate the latest evidence concerning the efficacy of conbercept on vitrectomy for proliferative diabetic retinopathy (PDR) and its efficacy compared to control and other antivascular endothelial growth factor. METHODS We performed a systematic literature search on topics that assess the role of conbercept in patients undergoing vitrectomy for PDR from inception to November 2019, using PubMed, EuropePMC, Cochrane Central Database, ProQuest, ScienceDirect, and Clinicaltrials.gov. Two researchers independently searched literature, extracted data, and evaluated the risk of bias. RevMan 5.3 and StataMP 16 software were used to perform data analysis. RESULTS There were 699 cases (eyes) from eight studies. Baseline best-corrected visual acuity (BCVA) was better in the control group compared to conbercept group (mean difference [MD] = 0.13, I2 = 0%). A greater BCVA improvement was observed in the conbercept group after 1-month (MD = -0.27, I2 = 1%), 3-month (MD = -0.28, I2 = 0%), and 6-month (MD = -0.20, I2 = 78%) follow-up. The need for endodiathermy (odds ratio [OR] = 0.20, I2 = 0%) and silicone oil tamponade use (OR = 0.59, I2 = 72%) and intraoperative bleeding (OR = 0.11, I2 = 33%) was lower in conbercept group. Postoperative early (OR = 0.22, I2 = 0%) and late (OR = 0.47, I2 = 0%) vitreous hemorrhage was lower in conbercept group. There was no significant difference in BCVA improvement and intraoperative outcome between conbercept and ranibizumab. CONCLUSIONS Intravitreal conbercept was associated with a more significant BCVA improvement, better intraoperative outcome, and less postoperative vitreous hemorrhage compared to no conbercept.
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Efficacy and Treatment Burden of Intravitreal Aflibercept Versus Intravitreal Ranibizumab Treat-and-Extend Regimens at 2 Years: Network Meta-Analysis Incorporating Individual Patient Data Meta-Regression and Matching-Adjusted Indirect Comparison.
Ohji, M, Lanzetta, P, Korobelnik, JF, Wojciechowski, P, Taieb, V, Deschaseaux, C, Janer, D, Tuckmantel, C
Advances in therapy. 2020;(5):2184-2198
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PURPOSE To compare visual outcomes and treatment burden between intravitreally administered aflibercept (IVT-AFL) and ranibizumab (RBZ) treat-and-extend (T&E) regimens in patients with wet age-related macular degeneration (wAMD) at 2 years. METHODS A systematic literature review was carried out in Medline, EMBASE, and CENTRAL in October 2018. Matching-adjusted indirect comparison (MAIC) and/or individual patient data meta-regression was used to connect ALTAIR (assessing IVT-AFL T&E) with other studies, adjusting for between-trial differences in baseline visual acuity and age or baseline visual acuity, age, and polypoidal choroidal vasculopathy (PCV) status. Sensitivity analyses were conducted to test the robustness of the results, including direct MAIC between IVT-AFL T&E (ALTAIR) and RBZ T&E (CANTREAT and TREX-AMD trials). RESULTS Six randomized controlled trials (RCTs) (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX) were included in the analysis. IVT-AFL T&E was assessed in one study, ALTAIR (n = 255), while RBZ T&E was assessed in two trials (n = 327). At 2 years, the median difference (95% credibility interval) between IVT-AFL T&E and RBZ T&E regarding the numbers of Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained was not significant (M1: - 2.29 [- 8.10, 3.58]; M2: - 0.55 [- 6.34, 5.29]). IVT-AFL T&E was associated with significantly fewer injections than RBZ-T&E (M1: - 6.12 [- 7.60, - 4.65]; M2: - 5.93 [- 7.42, - 4.45]). Results of the sensitivity analyses were consistent with the main scenarios. CONCLUSION Patients with wAMD receiving an IVT-AFL T&E regimen achieved and maintained improvement in visual acuity with fewer injections over 2 years compared with RBZ T&E. IVT-AFL T&E may therefore serve as the optimal therapy for wAMD, as it was associated with clinical efficacy and minimized treatment burden.
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The Clinical Effectiveness of Ranibizumab Treat and Extend Regimen in nAMD: Systematic Review and Network Meta-Analysis.
Danyliv, A, Glanville, J, McCool, R, Ferreira, A, Skelly, A, Jacob, RP
Advances in therapy. 2017;(3):611-619
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INTRODUCTION Neovascular age-related macular degeneration (nAMD) is a chronic eye condition that causes severe deterioration of vision and ultimately blindness. Two vascular endothelial growth factor inhibitors are approved for nAMD treatment in Europe: ranibizumab and aflibercept. The European license for ranibizumab was updated with an individualized "treat and extend" (T&E) regimen, which involves more proactive treatment based on changes in best corrected visual acuity (BCVA) and/or anatomical outcomes. The aim of this publication is to compare the efficacy of the ranibizumab T&E regimen with other approved dosing regimens for nAMD on the basis of outcomes identified from a systematic review and subsequent NMA. METHODS Following a systematic search of publications, to identify relevant studies, a repeated-measures network meta-analysis (NMA) was performed to estimate the relative effectiveness of ranibizumab T&E versus approved dosing regimens of ranibizumab and aflibercept. The analysis focused on licensed treatment regimens for nAMD. We examined mean change from baseline in BCVA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. RESULTS The systematic literature review identified 22,949 records, of which 23 studies were included in the NMA. At 12 months, the ranibizumab T&E dosing regimen vs ranibizumab pro re nata (PRN) was associated with small differences in change in BCVA, between 1.86 letter gain at 12 months and 2.35 letter gain at 24 months. A similar difference was observed in the aflibercept dosing regimen versus ranibizumab T&E ; 1.94 letter gain at 12 months and 3.31 letter gain at 24 months. All doses of ranibizumab and aflibercept showed similar effectiveness, and the differences between treatment options were not significant. CONCLUSION This study used novel repeated-measures NMA to synthesize efficacy results when treatment effects were reported at multiple follow-up times. This repeated-measures NMA suggests that treating patients with the ranibizumab T&E regimen yields similar effectiveness compared to other approved ranibizumab and aflibercept dosing regimens for nAMD treatment. FUNDING Novartis Pharmaceuticals UK Ltd, Surrey, UK.
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The Efficacy and Safety of Current Treatments in Diabetic Macular Edema: A Systematic Review and Network Meta-Analysis.
Zhang, L, Wang, W, Gao, Y, Lan, J, Xie, L
PloS one. 2016;(7):e0159553
Abstract
PURPOSE To compare the efficacy and safety of current treatments in diabetic macular edema (DME). METHODS PubMed, Embase and CENTRAL were systematically reviewed for randomized controlled trials of current treatments in DME through August 2015. Data on the mean change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were extracted, and adverse events (AEs) were collected. RESULTS A total of 21 trials were included in our network meta-analysis. Intravitreal ranibizumab improved BCVA most significantly (OR: +7.01 95%CI (2.56 to 11.39)) in 6 months and intravitreal aflibercept (+8.19 (5.07 to 11.96)) in 12 months. Intravitreal triamcinolone combined with LASER decreased CMT most significantly (-111.34 (-254.61 to 37.93)) in 6 months and intravitreal aflibercept (-110.83 (-190.25 to -35.27)) in 12 months. Compared with the relatively high rate of ocular AEs in the groups with administration of steroids, systematic AEs occurred more frequently in the groups with vascular endothelial growth factor inhibitors involved. CONCLUSIONS Our analysis confirms that intravitreal aflibercept is most favorable with both BCVA improvement and CMT decrease than other current therapies in the management of DME within 12 months. Vascular endothelial growth factor inhibitors for DME should be used with caution due to systematic AEs. Combined intravitreal triamcinolone with LASER has a stronger efficacy in decreasing CMT than the other interventions in the early stage after injection. More high-quality randomized controlled trials will be necessary.
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Aflibercept for neovascular age-related macular degeneration.
Sarwar, S, Clearfield, E, Soliman, MK, Sadiq, MA, Baldwin, AJ, Hanout, M, Agarwal, A, Sepah, YJ, Do, DV, Nguyen, QD
The Cochrane database of systematic reviews. 2016;(2):CD011346
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BACKGROUND Central vision loss caused by age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Neovascular AMD is characterized by choroidal neovascularization (CNV). Growth of new blood vessels in patients with neovascular AMD is driven by a complex process that involves a signal protein called vascular endothelial growth factor A (VEGF-A). Anti-VEGF drugs that block this protein include ranibizumab, bevacizumab, and aflibercept. OBJECTIVES To assess and compare the effectiveness and safety of intravitreal injections of aflibercept versus ranibizumab, bevacizumab, or sham for treatment of patients with neovascular AMD. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (Issue 11, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched December 4, 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on November 30, 2015. SELECTION CRITERIA We included randomized controlled trials (RCTs) in which aflibercept monotherapy was compared with ranibizumab, bevacizumab, or sham for participants with neovascular AMD who were treatment-naive. DATA COLLECTION AND ANALYSIS We used standard methodological procedures of The Cochrane Collaboration for screening, data abstraction, and study assessment. Two review authors independently screened records, abstracted data, and assessed risk of bias of included studies; we resolved discrepancies by discussion or with the help of a third review author when needed. MAIN RESULTS We included two RCTs (total of 2457 participants, 2457 eyes). Trial participants had neovascular AMD with active subfoveal choroidal neovascular lesions. Both trials followed the same protocol and compared aflibercept at various doses versus ranibizumab, but they were carried out in different countries. One trial enrolled participants from the United States and Canada, and the second trial was conducted at 172 sites in Europe, Asia Pacific, Latin America, and the Middle East. The overall quality of the evidence was high, and included trials were at low risk for most bias domains assessed; however, both trials were funded by the manufacturers of aflibercept. For the purposes of analysis, we combined aflibercept groups regardless of dosing and analyzed them as a single group.Visual acuity outcomes were similar between aflibercept and ranibizumab groups; at one year, participants in the aflibercept groups showed mean change in best-corrected visual acuity (BCVA) from baseline similar to that of participants in the ranibizumab groups (mean difference (MD) -0.15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (95% CI) -1.47 to 1.17; high-quality evidence). At two years, the mean change in BCVA from baseline was 7.2 ETDRS letters for aflibercept groups versus 7.9 for ranibizumab groups. Sufficient data were not available for calculation of confidence intervals.The proportion of participants who gained 15 or more letters of BCVA by one year of follow-up was approximately 32% for both aflibercept and ranibizumab (RR 0.97, 95% CI 0.85 to 1.11; high-quality evidence), and by two years of follow-up was approximately 31% (RR 0.98, 95% CI 0.85 to 1.12; high-quality evidence). Similar small proportions of participants in the aflibercept and ranibizumab groups lost 15 or more letters of BCVA at one year (RR 0.89, 95% CI 0.61 to 1.30; high-quality evidence); this outcome was not reported for two-year follow-up. Data were not reported on the proportion of participants with BCVA worse than 20/200 at one- or two-year follow-up.Participants treated with aflibercept or ranibizumab showed similar improvement in morphological outcomes, as assessed from images (central retinal thickness and CNV size). At one year, the proportion of eyes that achieved dry retina was similar between aflibercept and ranibizumab groups (absence of cystic intraretinal fluid and subretinal fluid on optical coherence tomography (OCT); RR 1.06, 95% CI 0.98 to 1.14; high-quality evidence). In addition, investigators reported no difference in reduction of CNV area between aflibercept- and ranibizumab-treated eyes at one year (MD -0.24 mm(2), 95% CI -0.78 to 0.29; high-quality evidence). Data were not reported for the proportion of eyes with absence of leakage on fluorescein angiography at one- or two-year follow-up.Overall, occurrence of serious systemic adverse events was similar and comparable in aflibercept- and ranibizumab-treated groups at one year (RR 0.99, 95% CI 0.79 to 1.25). Risk of any serious ocular adverse event was lower in the aflibercept group than in the ranibizumab group, but the risk estimate is imprecise (RR 0.62, 95% CI 0.36 to 1.07). As the result of imprecision, we graded the quality of evidence for all adverse events as moderate. AUTHORS' CONCLUSIONS Results of this review document the comparative effectiveness of aflibercept versus ranibizumab for visual acuity and morphological outcomes in eyes with neovascular AMD. Current available information on adverse effects of each medication suggests that the safety profile of aflibercept is comparable with that of ranibizumab; however, the number of participants who experienced adverse events was small, leading to imprecise estimates of absolute and relative effect sizes. The eight-week dosing regimen of aflibercept represents reduced treatment requirements in comparison with monthly dosing regimens and thus has the potential to reduce treatment burden and risks associated with frequent injections.
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Review and comparison of methodologies for indirect comparison of clinical trial results: an illustration with ranibizumab and aflibercept.
Regnier, SA, Alsop, J, Wright, J, Nixon, R, Staines, H, Fajnkuchen, F
Expert review of pharmacoeconomics & outcomes research. 2016;(6):793-801
Abstract
AIM: To review and compare methods for indirect comparison of aflibercept and ranibizumab in patients with diabetic macular edema. METHODS Post-stratification, inverse probability weighting based on simulated data, weight optimization, and regression model techniques were used to compare pooled individual patient-level data from the RESTORE and RESPOND (ranibizumab 0.5 mg as needed after 3 initial monthly doses) studies with summary-level data from the VIVID and VISTA (aflibercept 2.0 mg every 8 weeks after 5 initial monthly doses, 2q8) studies. The impact of adjusting for up to two baseline characteristics was assessed. RESULTS All methods provided similar results. After adjustment for baseline best-corrected visual acuity and central retinal thickness, no statistically significant difference in average gain in baseline best-corrected visual acuity from baseline at month 12 was found between ranibizumab 0.5 mg and aflibercept 2q8. CONCLUSIONS Weight optimization and regression methods are useful options to adjust for more than one baseline characteristic.
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Systematic review and mixed treatment comparison of intravitreal aflibercept with other therapies for diabetic macular edema (DME).
Korobelnik, JF, Kleijnen, J, Lang, SH, Birnie, R, Leadley, RM, Misso, K, Worthy, G, Muston, D, Do, DV
BMC ophthalmology. 2015;:52
Abstract
BACKGROUND This was an indirect comparison of the effectiveness of intravitreal aflibercept (IVT-AFL) 2 mg every 8 weeks after 5 initial monthly doses (or if different periods, after an initial monthly dosing period) (2q8) and other diabetic macular edema (DME) therapies at doses licensed outside the USA. METHODS A comprehensive search was undertaken to source relevant studies. Feasibility networks were prepared to identify viable comparisons of 12-month outcomes between IVT-AFL 2q8 and therapies licensed outside the USA, which were assessed for clinical and statistical homogeneity. Pooled effect sizes (mean difference [MD] and relative risk/risk ratio [RR]) were calculated using fixed- and random-effects models. Indirect comparisons were performed using Bucher analysis. If at least one 'head-to-head' study was found then a mixed treatment comparison (MTC) was performed using Bayesian methods. Two 12-month comparisons could be undertaken based on indirect analyses: IVT-AFL 2q8 versus intravitreal ranibizumab (IVR) 0.5 mg as needed (PRN) (10 studies) and IVT-AFL 2q8 versus dexamethasone 0.7 mg implants (three studies). RESULTS There was an increase in mean best-corrected visual acuity (BCVA) with IVT-AFL 2q8 over IVR 0.5 mg PRN by 4.67 letters [95% credible interval (CrI): 2.45-6.87] in the fixed-effect MTC model (10 studies) and by 4.82 letters [95% confidence interval (CI): 2.52-7.11] in the Bucher indirect analysis (four studies). IVT-AFL 2q8 doubled the proportion of patients gaining ≥ 10 Early Treatment Diabetic Retinopathy Study letters at 12 months compared with dexamethasone 0.7 mg implants (RR = 2.10 [95% CI: 1.29-3.40]) in the fixed-effect model. There were no significant differences in safety outcomes between IVT-AFL 2q8 and IVR 0.5 mg PRN or dexamethasone 0.7 mg implants. CONCLUSIONS Studies of IVT-AFL 2q8 showed improved 12-month visual acuity measures compared with studies of IVR 0.5 mg PRN and dexamethasone 0.7 mg implants based on indirect comparisons. These analyses are subject to a number of limitations which are inherent in indirect data comparisons.
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Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta-analysis.
Régnier, S, Malcolm, W, Allen, F, Wright, J, Bezlyak, V
PloS one. 2014;(7):e102309
Abstract
OBJECTIVE Compare the efficacy of ranibizumab, aflibercept, laser, and sham in the first-line treatment of diabetic macular edema (DME) to inform technology assessments such as those conducted by the UK National Institute for Health and Care Excellence (NICE). DATA SOURCES MEDLINE, Embase, Cochrane Library, congress abstracts, ClinicalTrials.gov registry and Novartis data on file. INCLUSION CRITERIA Studies reporting 6- or 12-month results of randomized controlled trials (RCTs) evaluating at least two of ranibizumab 0.5 mg pro re nata, aflibercept 2.0 mg bi-monthly, laser photocoagulation or sham. Study quality was assessed based on likelihood of bias in selection, attrition, detection and performance. OUTCOME MEASURE Improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining ≥10 letters on the Early Treatment Diabetic Retinopathy Study scale. The outcome was chosen following acceptance by NICE of a Markov model with 10-letter health states in the assessment of ranibizumab for DME. META-ANALYSIS Bayesian network meta-analyses with fixed and random effects adjusted for differences in baseline BCVA or central retinal thickness. RESULTS The analysis included 1,978 patients from eight RCTs. The random effects model adjusting for baseline BCVA was the best model based on total residual. The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept (odds ratio [OR] 1.59; 95% credible interval [CrI], 0.61-5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy with ORs of 5.50 (2.73-13.16) and 3.45 (1.62-6.84) respectively. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser. LIMITATIONS Three of the eight RCTs included are not yet published. The models did not adjust for all potential effect modifiers. CONCLUSION Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser.