Systematic review and mixed treatment comparison of intravitreal aflibercept with other therapies for diabetic macular edema (DME)

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.

Figure 1

Flow chart of the literature search.

Figure 2

Final feasibility network at 12 months, showing direct comparisons by drug, comparator and dose. IVB, intravitreal bevacizumab; IVR, intravitreal ranibizumab; IVT-AFL, intravitreal aflibercept; IVTA, intravitreal triamcinolone acetonide.

Figure 3

Direct comparison of IVT-AFL 2q8 (plus sham laser) or IVR 0.5 mg PRN (plus sham laser) versus laser (plus sham injection) for mean BCVA change from baseline in key studies. Indirect comparison (IVT-AFL 2q8 vs IVR 0.5 mg PRN) (Bucher analysis) also shown. BCVA, best-corrected visual acuity; CI, confidence interval; IVR, intravitreal ranibizumab; IVT-AFL, intravitreal aflibercept; PRN, as-needed; VEGF, vascular endothelial growth factor.