Aflibercept (3) – Eylea®

• Clinical trials
  • The Aflibercept trials VISTA and VIVID were both ongoing, randomised, double-blind, multicentre Phase III trials.
  • The Ranibizumab trials RESTORE and REVEAL are both randomised, double-blind, multicentre Phase III trials.

Patients with visual impairment due to diabetic macular oedema

• mortality
  • In an indirect comparison, no statistically significant difference in all-cause mortality was observed between aflibercept and ranibizumab, either for the combined study pool (VISTA, VIVID, RESTORE, REVEAL) or in the sensitivity analysis (excluding REVEAL).
  • In the endpoint category of mortality, therefore, the additional benefit of aflibercept compared with ranibizumab is not proven.
• Morbidity – Visual Acuity
  • Visual acuity was assessed in the studies using an ETDRS-standardised visual acuity chart.
  • With regard to the ‘proportion of patients with an improvement in visual acuity of ≥10 ETDRS letters’, no statistically significant difference was observed between aflibercept and ranibizumab, either in the indirect comparison (covering the entire study pool: VISTA, VIVID, RESTORE, REVEAL) nor in the sensitivity analysis (excluding REVEAL).
  • With regard to the ‘proportion of patients with a deterioration in visual acuity of ≥10 ETDRS letters’, based on the relative risk (RR) as a measure of effect, the indirect comparison showed no statistically significant difference between aflibercept and ranibizumab, neither for the entire study pool (VISTA, VIVID, RESTORE, REVEAL) nor in the sensitivity analysis (excluding REVEAL) was a statistically significant difference observed between aflibercept and ranibizumab.
  • The pharmaceutical manufacturer also used further effect measures (odds ratio, absolute risk reduction), which showed statistical significance in the indirect comparison for the entire study pool (OR = 0.28, 95% CI [0.08; 0.99]; ARR = 0.09, 95% CI [0.02; 0.16]). There are therefore no consistent results for the various effect measures (RR, OR, ARR).
  • With regard to the ‘proportion of patients with an improvement in visual acuity of ≥15 ETDRS letters’, the indirect comparison—based on the relative risk (RR) as the effect measure—revealed no statistically significant difference between aflibercept and ranibizumab, neither for the entire study pool (VISTA, VIVID, RESTORE, REVEAL) nor in the sensitivity analysis (excluding REVEAL).
  • Of the other effect measures cited by the pharmaceutical manufacturer (odds ratio, absolute risk reduction), only the absolute risk reduction showed statistical significance in the indirect comparison for the entire study pool (ARR = −0.11, 95% CI [–0.20; –0.03]). There are therefore no consistent results for the various measures of effect.
  • With regard to the ‘proportion of patients with a deterioration in visual acuity of ≥15 ETDRS letters’, the indirect comparison revealed no statistically significant difference between aflibercept and ranibizumab, neither for the entire study pool (VISTA, VIVID, RESTORE, REVEAL) nor in the sensitivity analysis (excluding REVEAL).
  • The ‘mean change in BCVA at 52 weeks compared with baseline (ETDRS letters)’ is the primary endpoint of the aflibercept trials VISTA and VIVID. In the indirect comparison, a mean between-group difference of 4.81 (95% CI [2.52; 7.11]) was observed. In the assessment of the analysis’s statistical significance using Hedges’ g, the calculation derived from the IQWiG’s benefit assessment yields a Hedges’ g of 0.37 (95% CI [0.12; 0.62]). The 95% confidence interval for Hedges’ g is therefore not entirely above the irrelevance threshold of 0.2. A clinically non-relevant effect cannot therefore be ruled out.
  • For the ‘mean change in BCVA from week 4 to week 52 compared with baseline (ETDRS letters)’, an indirect comparison revealed a mean between-group difference of 2.95 (95% CI [1.16; 4.73]). In the assessment of the significance of the analysis using Hedges’ g, the calculation derived from the IQWiG’s benefit assessment yields a Hedges’ g of 0.19 (95% CI [-0.06; 0.44]). The 95% confidence interval for Hedges’ g is therefore not entirely above the irrelevance threshold of 0.2. A clinically non-relevant effect cannot therefore be ruled out.
  • When considering the large number of analyses presented on multiple endpoints relating to visual acuity as a whole, isolated instances of statistical significance can indeed be identified; overall, however, there are no consistent effects across the various analyses of individual endpoints (effect sizes, sensitivity analyses) or across the different operationalisations of visual acuity. Taken as a whole, this means that, for the dimension of visual acuity, there is no clinically relevant advantage of aflibercept over ranibizumab. Consequently, no additional benefit of aflibercept over ranibizumab can be inferred from the data presented on visual acuity.
• quality of life
  • Data on quality of life were collected using the indication-specific NEI VFQ-25 (National Eye Institute 25-item Visual Function Questionnaire). In an indirect comparison, for which data were available from the VISTA, VIVID and RESTORE trials, no statistically significant difference was observed between aflibercept and ranibizumab with regard to the NEI VFQ-25.
  • In the quality of life endpoint category, therefore, an additional benefit of aflibercept compared with ranibizumab is not proven.
• Side effects
  • The desired effects of aflibercept are offset by adverse events (AEs). An indirect comparison between aflibercept and ranibizumab regarding the proportion of patients with at least one AE was not possible, as no corresponding data were available from the ranibizumab studies.
  • For the endpoint ‘serious adverse events (SAEs)’, data were available for the entire study pool (VISTA, VIVID, RESTORE, REVEAL). As there was an indication of significant heterogeneity in the aflibercept studies VISTA and VIVID for this endpoint (p = 0.134), the aflibercept studies were not included in the meta-analysis and were instead compared separately with the ranibizumab studies in an indirect comparison. None of the analyses conducted for the SAE endpoint revealed a statistically significant difference between aflibercept and ranibizumab.
  • Similarly, for the endpoints ‘discontinuation due to AE’, ‘ocular AE’, ‘ocular SAE’, ‘discontinuation due to ocular AEs’, for which data were available from the VISTA, VIVID and RESTORE trials, no statistically significant difference was observed between aflibercept and ranibizumab.
  • In the endpoint category of side effects, therefore, the additional benefit of aflibercept compared with ranibizumab is not proven.

Courtesy translation only, please refer to the German original.