Apixaban (3) – Eliquis®

• Clinical trials
  • The study was a randomised, double-blind, multicentre (358 centres) Phase III trial in which 2,691 patients were randomised to the apixaban arm and 2,704 patients to the comparator arm.
  • In the AMPLIFY trial, apixaban was administered in accordance with the German marketing authorisation (10 mg twice daily for 7 days, followed by 5 mg twice daily for up to 6 months) and, in the comparator arm, enoxaparin (1 mg/kg every 12 hours until INR ≥ 2) was administered over a period of ≥ 5 days, followed by warfarin (dosage adjusted to a target INR range of 2.0 to 3.0) for 6 months.
  • Data on apixaban for prolonged secondary prophylaxis (following completion of a 6-month course of treatment) are available from a placebo-controlled trial (AMPLIFY-Ext trial, CV185057).

a) Initial treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) and concomitant prophylaxis in adults (for treatment up to 6 months)

• For the initial treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) and concomitant prophylaxis in adults (for treatment lasting up to 6 months), there is an indication for a minor additional benefit for apixaban compared with warfarin and enoxaparin.
• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’.
• Overall, uncertainties remain regarding the validity of the study, despite its methodological quality. Consequently, with regard to the certainty of the evidence in the overall assessment of additional benefit, an indication of additional benefit is assumed.
• The G-BA classifies the extent of the additional benefit of apixaban as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• mortality
  • Overall mortality was recorded as a secondary efficacy endpoint in the AMPLIFY study.
  • No statistically significant difference was observed between the treatment arms for the endpoint of all-cause mortality. For this endpoint, the additional benefit of apixaban compared with enoxaparin/warfarin is not proven.
• Morbidity – Composite endpoint: symptomatic, recurrent VTE (non-fatal DVT or non-fatal PE) or all-cause mortality
  • This efficacy endpoint comprises the combination of symptomatic recurrent VTE (defined as non-fatal proximal DVT or non-fatal PE) or all-cause mortality (deaths from all causes).
  • Overall, there is no statistically significant difference between the treatment arms for this endpoint; therefore, an additional benefit of apixaban compared with enoxaparin / warfarin is not proven for this endpoint.
  • Furthermore, there is an effect modification by the characteristic ‘BMI category I’ (interaction test p = 0.072). This effect modification by the characteristic ‘BMI category I’ also applies to the endpoints ‘symptomatic non-fatal DVT’ and ‘symptomatic non-fatal PE’.
  • Consequently, in this benefit assessment, the effect modifications associated with the BMI variable are not taken into account any further when assessing the extent of the additional benefit.
• Morbidity – Symptomatic non-fatal DVT
  • For this endpoint, there is an effect modification by the BMI Category I variable (interaction test p = 0.164). For the reasons already discussed above, the effect modification for the BMI variable is not taken into account any further in the benefit assessment.
  • Overall, there is no statistically significant difference between the treatment arms for this endpoint. For symptomatic non-fatal DVT, the additional benefit of apixaban compared with enoxaparin/warfarin is not proven.
• Morbidity – Symptomatic non-fatal PE
  • For symptomatic non-fatal VTE, there is an effect modification by the BMI category I (interaction test p = 0.005) and also for BMI category II (interaction test p = 0.069). For the reasons already discussed above, the effect modification for the BMI variable is not taken into account further in the benefit assessment.
  • Overall, there is no statistically significant difference between the treatment arms for this endpoint. For symptomatic non-fatal LE, the additional benefit of apixaban compared with enoxaparin/warfarin is not proven.
• morbidity
  • Overall, no additional benefit for apixaban compared with the appropriate comparator therapy can be inferred for the benefit category ‘morbidity’.
• Health-related quality of life
  • Health-related quality of life is a patient-relevant endpoint and is included in the assessment.
  • Data on this endpoint were not collected in the included AMPLIFY trial. An additional benefit for apixaban is not proven for this endpoint.
• Side effects – severe bleeding
  • Severe bleeding was defined, in accordance with the definition of the ‘International Society on Thrombosis and Haemostasis’, as clinically acute bleeding characterised by one or more of the following criteria: a drop in haemoglobin of ≥ 2 g/dL, transfusion of two or more units of packed red blood cells, bleeding occurring in a critical organ system, or fatal bleeding.
  • For the endpoint of severe bleeding, a statistically significant result was observed showing a minor incidence of adverse events with apixaban compared with enoxaparin/warfarin. Severe bleeding occurred significantly less frequently in the apixaban arm than in the comparator group. (0.6% vs. 1.8%; ARR 1.2%; RR 0.31 [0.17; 0.55]).
  • Severe bleeding is classified as a serious side effect. However, the absolute risk reduction of 1.2% achieved by treatment with apixaban for this endpoint represents a non-relevant reduction in the incidence of serious side effects; consequently, no considerable additional benefit can be inferred from the extent of the effect for this endpoint.
  • An additional benefit of apixaban in preventing severe bleeding is identified, the extent of which is assessed as minor.
• Conclusion
  • For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE in adults, an overall assessment of the available results on mortality, morbidity, health-related quality of life and side effects, there is an additional benefit for apixaban compared with warfarin and enoxaparin.
  • Classifying the extent of this additional benefit as ‘considerable’ is not justified, as, in particular, there was no alleviation of serious symptoms, no moderate prolongation of survival, nor any relief from the condition perceptible to patients; these would be regarded as a significant improvement in treatment-related benefit over the appropriate comparator therapy that has not yet been achieved.

b) Long-term prophylaxis of recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE) in adults (following completion of a 6-month course of treatment for DVT or PE) for whom continued anticoagulation is indicated

• For the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) (following completion of a 6-month course of treatment for DVT or PE) in adults, the additional benefit of apixaban compared with the appropriate comparator therapy (vitamin K antagonists) is deemed not proven.
• As the necessary evidence has not been provided, the additional benefit in relation to the appropriate comparator therapy is deemed not proven.

Courtesy translation only, please refer to the German original.