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Apixaban – another new oral anticoagulant on the horizon for atrial fibrillation
Anticoagulation of patients with atrial fibrillation is crucial to prevent thromboembolic events. However, the currently used vitamin K antagonists (VKAs) have severe disadvantages, such as an increased risk of intracerebral bleeding or the necessity of laboratory monitoring. Recently, new oral anticoagulants directly inhibiting factor Xa or thrombin have been tested which may overcome these drawbacks. In 2011 the ARISTOTLE study testing the oral direct factor Xa inhibitor apixaban was published in the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1107039).
Apixaban was compared with a VKA in a low-risk population (mean CHADS2 score 2.1) of more than 18 000 patients with non-valvular atrial fibrillation in a randomized double-blind design. Apixaban was given at a dose of 5 mg twice daily. In selected patients with a high risk of bleeding the dose was reduced to 2.5 mg. The control of VKA therapy in control patients was rather good, with time in the therapeutic range of 66%. Of note, study discontinuation was lower in patients receiving apixaban, indicating good tolerance of the drug. An intention-to-treat analysis was used for statistical analysis of the outcome.
The rate of the combined primary efficacy endpoint stroke and systemic embolism was significantly reduced, by 21%, with apixaban. Haemorrhagic stroke was reduced by 49%. In addition, mortality was significantly reduced by 11%. However, the rate of ischaemic stroke was not significantly different between the two treatment arms. The effect of apixaban was independent of important comorbidities.
Apixaban reduced the primary safety endpoint major bleeding by 30%. Intracranial bleeding was reduced by 58%. With regard to potential interactions with important comorbidities no improved safety for apixaban was observed in patients with diabetes. On the other hand, apixaban showed a particularly favourable safety profile in patients with decreased renal function (clearance < 50 ml/min). There was no evidence of increased liver toxicity in the apixaban arm.
Evidence after studying new oral anticoagulants in 50 000 patients with atrial fibrillation
Since 2009, three studies testing new oral anticoagulants with more than 50 000 patients have been published (ARISTOTLE, RE-LY, ROCKET AF). All tested drugs (apixaban, dabigatran, rivaroxaban) were at least non-inferior to a VKA with regard to efficacy. Moreover, all three drugs showed an impressive reduction in intracerebral haemorrhages. Another major advantage is the lack of required laboratory controls. There is evidence that there are also differences between the new oral anticoagulants. Therefore, one should carefully select the appropriate anticoagulant for the individual patient. However, one has to be very careful to compare the new oral anticoagulants directly as there are no head-to-head comparisons of these three drugs. Rivaroxaban was the only drug administered once daily. Dabigatran (with the higher tested dose of 2 × 150 mg daily) was the only new oral anticoagulant that significantly reduced ischaemic strokes compared with VKAs. Apixaban was the only new oral anticoagulant which significantly improved the primary efficacy and safety endpoint at the same dose. The appropriate selection of a new oral anticoagulant may be further determined by comorbidities, such as diabetes, for apixaban that influence the safety profile of new oral anticoagulants. Another on-going study testing the direct factor Xa antagonist edoxaban for atrial fibrillation will further increase our knowledge of the new oral anticoagulants.
Professor of Cardiology
Vienna Medical School