Edoxaban (1) – Lixiana®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted the ENGAGE-AF-TIMI 48 study. This was a completed, randomised, controlled, multicentre, double-blind study with three treatment arms: two edoxaban arms, of which only the arm compliant with the marketing authorisation – with an edoxaban dose of 60 mg – is relevant for the benefit assessment (N = 7035), and one warfarin arm (N = 7,036) with individualised dosing to maintain an INR between 2.0 and 3.0.
  • To demonstrate the additional benefit of edoxaban in the treatment of DVT or PE and the prevention of recurrent DVT and PE in adults, the pharmaceutical manufacturer cites the results of the HOKUSAI-VTE study in the dossier. The study was a randomised, double-blind, multicentre Phase III trial in which 4,143 patients were randomised to the edoxaban arm (60 mg/day) and 4,149 patients to the comparator arm.

a) For the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) and one or more risk factors such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, a history of stroke or transient ischaemic attack (TIA).

• The G-BA assesses the extent of the additional benefit of edoxaban for the prevention of strokes and systemic embolisms in adult patients with non-valvular atrial fibrillation (NVAF) and one or more risk factors such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, a history of stroke or transient ischaemic attack (TIA), as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in the treatment of the condition.
• The certainty of the finding (probability of additional benefit) is classified in the ‘indication’ category.
• Mortality (overall survival)
  • For overall survival, there is no statistically significant difference between edoxaban and the appropriate comparator therapy, warfarin, in the overall population of the ENGAGE study. An additional benefit is not proven for this endpoint.
• morbidity
  • Overall, there are no advantages for edoxaban over warfarin in the endpoint categories of morbidity and mortality. An additional benefit is not proven for edoxaban in these endpoints.
  • Combined (primary) endpoint: stroke and SEE (systemic embolic event)
  • Irrespective of the assessment of the combined endpoint for the benefit assessment of edoxaban, an indication is made in this context of the comments made by the regulatory authority regarding the results for this endpoint depending on the extent of time spent in the therapeutic target INR range (TTR). It can be assumed that the superiority of edoxaban over warfarin in the stroke/SEE endpoint was significantly influenced by the extent of the TTR.
  • Stroke (ischaemic, haemorrhagic or of unknown cause)
  • For the endpoint of stroke (ischaemic, haemorrhagic or of unknown cause), there is no statistically significant difference between edoxaban and the appropriate comparator therapy, warfarin (HR 0.88 [CI 0.75; 1.03], 4.0% vs. 4.5%; annual event rate 1.5% vs. 1.7%).
  • For the endpoint of haemorrhagic stroke, there was a difference in favour of edoxaban compared with warfarin. In the ENGAGE trial, fewer haemorrhagic strokes occurred with edoxaban (0.7% vs. 1.3%; annual event rate 0.30% vs. 0.50%; HR: 0.54 [CI 0.38; 0.77], p<0.001).
  • Haemorrhagic strokes are generally not classified under the morbidity endpoint category in this indication but, in accordance with the EMA guideline on the clinical investigation of medicinal products for the prevention of stroke and SEE in patients with non-valvular atrial fibrillation” dated 26 June 2014, they should be recorded as adverse events and should not be taken into account for efficacy endpoints.
  • Further endpoints: systemic embolisms, myocardial infarction, TIA
  • There are no statistically significant differences for the respective endpoints of systemic embolisms, myocardial infarction and TIA.
• Health-related quality of life
  • The health-related quality of life endpoint was assessed in the ENGAGE study using the EQ-5D-3L and evaluated as a utility value. No information was available as to whether the utility value was determined using a patient-reported assessment of health status. Furthermore, a large proportion of patients were excluded from the analysis, meaning that no usable data are available for this endpoint.
  • An additional benefit is not proven for this endpoint.
• Mortality, morbidity and side effects
  • Stroke, SEE, severe bleeding or all-cause mortality
  • For the composite endpoint of stroke, SE, severe bleeding or all-cause mortality, a statistically significant difference was observed in favour of edoxaban (HR 0.89 [0.83; 0.96], p = 0.003). As the individual endpoints were analysed separately, the result has no bearing on the overall conclusion regarding additional benefit.
• Conclusion
  • Taken together, the results show that edoxaban does not demonstrate any improvement in treatment-related benefit compared with warfarin in terms of all-cause mortality and morbidity. There is no significant difference in the reduction of systemic embolisms and ischaemic strokes. Although there is a statistically significant difference in favour of edoxaban for the endpoint of haemorrhagic strokes (0.7% vs. 1.3%; annual event rate 0.3% vs. 0.5%), this advantage is not reflected in the overall stroke rate nor does it affect overall mortality. Furthermore, it should be borne in mind that haemorrhagic strokes should be considered primarily when assessing safety endpoints.
  • Both severe and clinically relevant non-severe bleeding events occurred significantly less frequently with edoxaban than with warfarin.
  • Taking into account their severity in comparison with the appropriate comparator therapy, the G-BA assesses the absolute and relative magnitudes of the effects as a moderate improvement in patient-relevant benefit and thus as a minor additional benefit.

b) Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prophylaxis of recurrent DVT and PE in adults.

• On the basis of the criteria set out in Section 5(7) of the AM-NutzenV, and taking into account the severity of the condition and the therapeutic objective in treating the condition, the additional benefit is therefore not proven.
• Mortality / Morbidity
  • In the endpoints of mortality (overall mortality) and VTE recurrence (symptomatic DVT, fatal or non-fatal pulmonary embolism) and their individual components (pulmonary embolism with or without symptomatic deep vein thrombosis, symptomatic deep vein thrombosis), no statistically significant difference was observed between the treatment arms.
• quality of life
  • Health-related quality of life is a patient-relevant endpoint and is included in the assessment. The quality of life endpoint was not assessed in the HOKUSAI-VTE study.
• Side effects
  • No statistically significant difference was observed between the treatment arms for the endpoints of adverse events, serious adverse events and therapy discontinuation due to adverse events.
  • Bleeding events
  • Combined endpoint: severe bleeding or clinically relevant non-severe bleeding
  • For the combined endpoint of severe bleeding or clinically relevant non-severe bleeding, a statistically significant difference was observed between the treatment arms in the HOKUSAI-VTE study (HR 0.87 [0.76; 0.99] p = 0.039; ARR 1.4% (9.8 vs. 11.2 %)). Most events within this endpoint consisted of events relating to the endpoint ‘clinically relevant non-severe bleeding’, meaning that the statistical significance is also based on this individual component of the combined endpoint.
  • The absolute risk reduction of 1.4% achieved by treatment with edoxaban is assessed as an insignificant reduction in the incidence of this endpoint; consequently, based on the extent of the effect for this composite endpoint, no additional benefit over warfarin can be inferred.
  • Severe bleeding,
  • For the endpoint of severe bleeding, the HOKUSAI-VTE trial showed no statistically significant difference between the treatment arms.
  • clinically relevant non-severe bleeding
  • Clinically relevant non-severe bleeding occurred significantly less frequently with edoxaban than with warfarin (8.4% vs. 9.7%; HR 0.85 [0.74; 0.98], p=0.026).
  • The absolute risk reduction of 1.3% in clinically relevant non-severe bleeding achieved with edoxaban is assessed as a non-clinically relevant reduction in other side effects; consequently, based on the extent of the effect for this endpoint, no additional benefit over warfarin can be inferred.
• Mortality, morbidity and side effects
  • Symptomatic VTE recurrence, severe bleeding, all-cause mortality
  • For the composite endpoint comprising VTE recurrence, severe bleeding and all-cause mortality, as well as the individual components of symptomatic VTE recurrence described above, there was no statistically significant difference between edoxaban and warfarin in the overall population of the HOKUSAI study- VTE study, no statistically significant difference was observed between edoxaban and warfarin.
• 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 review of the available results on mortality, morbidity, health-related quality of life and side effects, there is no additional benefit of edoxaban over warfarin.
  • When the results are considered as a whole, the only statistically significant effects in favour of edoxaban compared with warfarin are observed for the combined endpoint ‘severe bleeding or clinically relevant non-major bleeding’ and for the endpoint ‘clinically relevant non-major bleeding’. However, in terms of the extent of the effect size, the prevention of these side effects is not considered clinically relevant.

Courtesy translation only, please refer to the German original.