Apixaban is an oral anticoagulant, a direct Xa factor inhibitor approved since June 2011 for the prevention of venous thromboembolism (VTE) in elective hip or knee replacement surgery, and recently approved for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) with one or more risk factors.
AF is the most common chronic cardiac arrhythmia and it is associated with increased rates of mortality, occurrence of stroke and other thromboembolic events, heart failure and hospitalisations, a reduced quality of life and decreased exercise tolerance, and left ventricular dysfunction. Management of patients with AF aims at reducing symptoms and preventing severe AF related complications. Prevention of thromboembolic complications involves antithrombotic therapy with oral anticoagulants or antiplatelet agents. The decision of starting antithrombotic therapy, as well as the choice of the most appropriate pharmacological alternative, should be the result of an individual assessment of the thromboembolic and haemorrhagic risk of each patient (CHADS2 classification scheme). There is currently a widespread consensus regarding the recommendation to anticoagulate those patients with a CHADS2 score ≥2.
There are five agents with an indication for preventing stroke and systemic embolism in patients with nov-valvular AF: two vitamin K antagonists (VKA) - acenocumarol and warfarin, a direct thrombin inhibitor - dabigatran, and the direct factor Xa inhibitors - rivaroxaban and apixaban (assessed in this report).
For patients with non-valvular AF and an indication for anticoagulant therapy, the following recommendations should be considered:
- Initiate treatment with a VKA, except for cases of hypersensitivity or contraindication, history of intracranial haemorrhage and ischaemic stroke at high risk for intracranial haemorrhage, or inability or important difficulty to comply with INR monitoring.
- Maintain VKA treatment in patients with an adequate INR control, history of gastrointestinal haemorrhage or in the presence of digestive disorders which may increase the risk of gastrointestinal bleeding and severe renal impairment.
- Start or switch to the new oral anticoagulants (OAC) in patients with poor INR control not due to lack of adherence, with history of intracranial haemorrhage (regardless the degree of INR control), patients with ischaemic stroke at high risk for intracranial haemorrhage, patients with allergy or known hypersensitivity to coumarins, serious adverse events associated with VKA therapy, specific contraindications to VKA, or the presence of a significant drug interaction which is difficult to control despite the dosage adjustment based on INR (not previously described for new OACs).
A randomised clinical trial assessed the efficacy and safety of apixaban versus warfarin. There are no comparative studies available versus acenocoumarol, dabigratran or rivarosaban.
Apixaban has shown to be superior to warfarin for the primary efficacy end point, which was a composite of stroke and systemic embolism (1.27% per year with apixaban compared to 1.6% per year with warfarin 95%CI 0.79 (0.66 to 0.95).
Apixaban was found to be superior to warfarin with regards to the primary safety outcome: major bleeding (2.13% per year with apixaban compared to 3.09% per year with warfarin 95%CI 0.69 (0.60 to 0.80). Among secondary outcomes, the rates of death from any cause was inferior with apixaban than it was with warfarin (3.52% per year vs. 3.94% per year 95%CI, 0.89 (0.80 to 0.998). However, this superiority is not found in patients who are well controlled on warfarin. There was no significant difference between apixaban and warfarin in the rates of myocardial infarction.
Indirect comparisons to date show no substantial differences between apixaban and the new OACs, which is consistent with a similar consideration of use.
Alterations of liver function tests and serious liver-related adverse events were found in a similar proportion with both apixaban and warfarin. However, long-term data are required with regards to safety. The Risk Management Plan from the European Medicines Agency identifies, as significant risks, the risk of bleeding and the risk of transient elevated values of liver function tests, and the risk of liver injury as potential. Consistent with the recommendations for the indication of apixaban in VTE, liver function testing is recommended to be performed prior to administration of apixaban. With regards to the risk of bleeding, the filling out of a questionnaire is proposed, gathering information on severe bleeding events and measures carried out to control the bleeding. There is no antidote to apixaban in case of excessive anticoagulation.
Apixaban is less likely to interact with food and other drugs and, like dabigatran and rivaroxaban, it does not require monitoring and periodic dosage adjustment. However, as it occurs with other chronic treatments, the lack of monitoring could reduce adherence besides hindering the identification of non-compliant patients.
The cost of apixaban is superior to that of acenocumarol or warfarin and it is similar to that of rivaroxaban and of dabigatran. The economic impact of the replacement of VKAs for apixaban could reach €44.5 millions in a year in Andalucia.
In the light of the available evidence, it may be concluded that apixaban, just like rivaroxaban and dabigatran, may offer an added value in specific situations, as an alternative to VKAs in the same cases as the new OACs, considering each case on an individual basis. These specific situations may refer to patients presenting: hypersensibility to VKAs, history of non acute intracranial haemorrhage, high risk for intracranial haemorrhage, patients on VKAs suffering severe thromboembolic events despite their good INR control, and those patients on VKAs unable to comply with monitoring despite good adherence to treatment.