Apixaban (1) – Eliquis®

a) Patients undergoing elective knee replacement surgery

• For patients undergoing elective knee replacement surgery, additional benefit is not proven with apixaban compared with the appropriate comparator therapy.
• On an overall assessment of the available data, the G-BA finds no proof of greater or less benefit, nor of greater harm, from apixaban compared with the appropriate comparator therapy.
• Morbidity – pulmonary embolism
  • For the patient-relevant endpoint ‘pulmonary embolism’, the results of the ADVANCE-2 study must be considered separately for the treatment phase and the overall period with regard to the final assessment.
  • In the study forming the basis for the benefit assessment, four cases of pulmonary embolism (0.26 per cent) were diagnosed during the treatment period with apixaban, and no cases of pulmonary embolism (0 per cent) were diagnosed with enoxaparin. However, the results for this time frame were not statistically significant (p=0.062).
  • When the overall period was considered, a statistically significant result was observed for this endpoint to the detriment of apixaban (p=0.039), with seven pulmonary embolisms (0.46 per cent) occurring in the apixaban group versus one pulmonary embolism (0.07 per cent) in the enoxaparin group.
  • Given the high number of patients in the ADVANCE-2 study who may have received anticoagulation due to phlebographically diagnosed asymptomatic deep vein thrombosis, and taking into account the differing incidence rates between the two treatment arms, the results for the overall observation period – and thus also for the endpoint ‘pulmonary embolisms’ – can only be interpreted with caution.
• Side effects – Serious adverse events – Bleeding
  • With regard to the endpoints relating to side effects, with the exception of the endpoint ‘Serious adverse events – bleeding’, only data for the treatment period were available for analysis, as aggregating the recorded side effects for the entire period could lead to possible double-counting of events.
  • However, none of the results regarding side effects were statistically significant and therefore did not provide evidence of any additional benefit or greater harm from apixaban compared with the appropriate comparator therapy.
• Overall assessment
  • In light of these considerations, the studydata for the entire observation period has only a limited impact on the overall assessment of the extent of the additional benefit in patients undergoing elective knee replacement surgery and does not lead to a conclusion that apixaban offers less benefit than the appropriate comparator therapy.

b) Patients undergoing elective hip replacement surgery

• For patients undergoing elective hip replacement surgery, there is an indication of a minor additional benefit of apixaban compared with the appropriate comparator therapy.
• The certainty of the finding (probability of additional benefit) is classified as an indication.
• The G-BA classifies the extent of the additional benefit of apixaban for the patient population ‘patients undergoing elective hip replacement surgery’ as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV.
• Morbidity – symptomatic deep vein thrombosis
  • Compared with the appropriate comparator therapy, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a previously unachieved moderate – and not merely minor – improvement in treatment-related benefit, as a moderate reduction in non-serious symptoms (endpoint ‘symptomatic deep vein thrombosis’) is achieved over the entire period.
• Side effects – Adverse events
  • For the patient-relevant endpoint ‘adverse events’, the additional benefit of apixaban cannot be conclusively assessed.
  • Simply by excluding these patients from the total number of events for ‘Adverse events – overall rate’, the result in favour of apixaban for this endpoint was no longer statistically significant.
  • Overall, therefore, there is no indication that apixaban causes minor harm compared to enoxaparin with regard to the overall rate of adverse events.
• Side effects – Serious adverse events – Bleeding
  • For the endpoint ‘serious adverse events – bleeding’, a statistically significant result was observed to the detriment of apixaban.
  • As the results for other bleeding endpoints did not point in the same direction, this finding was not supported by further results.
  • In contrast, for the patient population aged ≥ 75 years, a statistically significant difference in favour of apixaban was observed for clinically relevant non-major bleeding events under apixaban.
  • This result was also not supported by further findings on other bleeding endpoints.
  • Overall, the results for the composite of bleeding events were therefore contradictory and not conclusive enough to infer that apixaban caused greater or minor harm to the patient group of ‘patients undergoing elective hip replacement surgery’.
• Overall assessment
  • As asymptomatic venous thrombosis was detected in only approximately 2% of patients in the ADVANCE-3 trial (compared with around 20% of patients in the ADVANCE-2 trial) and these patients could consequently be treated with therapeutic anticoagulation, the potential bias in this study due to the effects of therapeutic anticoagulation during the follow-up period is considered to be minor for the results of the overall period.

Courtesy translation only, please refer to the German original.