First Author: S.Régnier SWITZERLAND
Co Author(s): W. Malcolm F. Allen J. Wright 0 0 0 0 0 0 0 0 0
Back to previous
Diabetic macular edema (DME) is one of the main ocular complications associated with diabetes mellitus and can lead to visual impairment (VI) and, if left untreated, blindness. Treatment options are evolving as new anti-vascular endothelial growth factor (anti-VEGF) therapies become available. This systematic review and network meta-analysis compares the efficacy of anti-VEGF therapies (ranibizumab and aflibercept) with laser photocoagulation and sham in the treatment of VI due to DME. The objective of the study is to inform treatment and resource allocation decisions.
Data sources were identified in a systematic review of MEDLINE, Embase, the Cochrane Library, ophthalmology congress abstracts, the ClinicalTrials.gov registry and Novartis data on file (to be submitted for publication).
A systematic review using the above data sources was conducted to identify relevant randomized clinical trials (RCTs). Studies reporting 6- or 12-month results of RCTs evaluating the efficacy of at least two of ranibizumab 0.5 mg, aflibercept 2.0 mg bi-monthly, laser photocoagulation therapy or sham were included. The outcome of interest was improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining at least 10 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. The outcome of interest was chosen because NICE accepted a Markov model using 10-letter states in the assessment of ranibizumab for the treatment of DME. Studies with single treatment arms were excluded. Studies focusing on a specific ethnic group were not included in the base case but were included in sensitivity analyses. Study quality was assessed based on the use of treatment allocation concealment, masking and methodologies to address incomplete outcomes. Comparisons of efficacy were made using a Bayesian network meta-analysis (random and fixed treatment effects) adjusting for baseline BCVA. The relative treatment effect was the odds ratio (OR) for the percentage of patients experiencing an improvement in BCVA of at least 10 letters on the ETDRS scale.
The analysis included 1978 patients from eight relevant high quality RCTs. Baseline BCVA of patient populations differed among the included RCTs: for example, the inclusion criteria for baseline BCVA in the VIVID and VISTA trials was 24–73 letters compared with 39–78 letters in RESTORE. In the random treatment effects model, ranibizumab was non-significantly favoured over aflibercept (OR, 1.59; 95% credible interval [CrI], 0.61–5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy OR 5.50 (95% CrI, 2.73–13.16; p<0.05) and OR 3.45 (95% CrI, 1.62–6.84; p<0.05) respectively. The probability that ranibizumab 0.5 mg monotherapy is the most efficacious treatment in the network, for the outcome of interest, was 73%, versus 14% for aflibercept, 12% for ranibizumab plus laser and 0% for laser monotherapy. The results for the fixed effects model were similar: ranibizumab was non-significantly favoured over aflibercept (OR, 1.49; 95% CrI, 0.80–2.80). The probability that ranibizumab monotherapy is the most efficacious treatment in the network was 86%. One study (REVEAL) was excluded from the base case because it only included Asian patients. In sensitivity analyses, the inclusion of this study did not significantly modify the random-effect results (OR, 1.35; 95% CrI, 0.62–3.48).
Given the substantial burden of VI due to DME and the evolving options for treatment, it is important to compare the relative efficacy of the available first-line therapies. To our knowledge, this systematic review and network meta-analysis is the first to include Phase III data for aflibercept. This is important because aflibercept was submitted for EU approval for the treatment of VI due to DME in November 2013. The results of this analysis confirm the findings of RCTs indicating statistical superiority of anti-VEGF monotherapy over laser monotherapy in the treatment of VI due to DME. Ranibizumab and aflibercept monotherapies had a statistically higher efficacy than laser monotherapy. Laser therapy had a zero probability of being the most efficacious treatment in the network, compared with 73% for ranibizumab and 14% for aflibercept. Furthermore, it cannot be proven that adding laser to ranibizumab provides additional benefits over ranibizumab monotherapy; combination therapy had only a 12% probability of being the most efficacious treatment. Comparison of the efficacy of anti-VEGF therapies in both the random and fixed effects models indicated that the efficacy of ranibizumab was numerically, but not statistically significantly, superior to aflibercept.