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Journal of the American College of Cardiology

Clinical Articles, Lead Article

ARISTOTLE: new analysis shows less bleeding and strokes with apixaban

The novel oral anticoagulant apixaban is associated with fewer intracranial haemorrhages compared with warfarin, as well as less adverse consequences following extracranial haemorrhage, according to a study published recently in the Journal of the American College of Cardiology.1 The study also showed a 50% reduction in fatal consequences at 30 days in cases of major haemorrhage with apixaban.

All ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) patients who received at least one dose of a study drug were included in the analysis. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis, and factors associated with major haemorrhage were identified using a multivariable Cox model.

The on-treatment, safety population included 18,140 patients. The rate of major haemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (p<0.001). Compared with warfarin, apixaban was associated with less major extracranial haemorrhage, leading less often led to hospitalisation, a medical or surgical intervention, transfusion, or change in antithrombotic therapy.

Professor Claes Held (Uppsala Clinical Research Centre, Sweden)

Professor Claes Held (Uppsala Clinical Research Centre, Sweden)

Major haemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients compared with warfarin (p<0.001). Older age, prior haemorrhage, prior stroke or transient ischaemic attack, diabetes, lower creatinine clearance, decreased haematocrit, aspirin, and non-steroidal anti-inflammatory drugs were independently associated with an increased risk.

Warfarin not redundant

Despite the increasingly positive data regarding novel anticoagulants, however, warfarin should not be abandoned nor overly ostracised for its negative points, said Professor Michael Kim (Brown University Cardiovascular Institute, Rhode Island, USA) in an accompanying editorial.2

Warfarin, he says, “should be viewed as one of multiple choices in the tool box of anticoagulants that may be utilised for the shared risk assessment in determining the choice of anticoagulant therapy or no therapy in low risk or contraindicated patients”.

Speaking to BJC Arrhythmia Watch, co-author Professor Claes Held (Uppsala Clinical Research Centre, Sweden) said: “the take-home message is that apixaban as compared with warfarin was associated with significantly fewer bleeding complications and especially serious complications such intracranial haemorrhage. In addition, in case a patient suffers a serious bleed, the consequences were found to be less adverse with lower risk of hospitalisation, need for transfusion, less need for procedures to stop the bleeding and less need for change in antithrombotic therapy. Lastly, and very important, the risk of dying within 30 days after a serious bleed was halved on apixaban compared to if you were treated with warfarin.”

Needs for new bleeding risk score

“We recommend that all patients undergo an assessment of both the risk of thromboembolic complications and the bleeding risk. The challenge in clinical practice is that the risk factors for bleeding are most often the same as risk factors for stroke. We are trying to design a risk tool based on the data from ARISTOTLE trial, which also includes various biomarkers, that will be presented later. This might be a more efficient and accurate risk model than the HASBLED score,” Professor Held added.

Stroke reduction benefit also shown

Apixaban reduces the risk of stroke or systemic embolism, with fewer major bleeding events and reduced risk of all-cause mortality, compared to warfarin, according to an ARISTOTLE subanalysis published recently in the European Heart Journal.3

Apixaban was found to be more effective than warfarin in reducing the risk of stroke or systemic embolism, was associated with less major bleeding, less total bleeding and less intracranial haemorrhage, regardless of age and in reducing all-cause mortality across age groups. The p-value for interaction across age groups was non-significant (p>0.11 for all) for the major outcomes of stroke or systemic embolism, major bleeding, and all-cause mortality, meaning that the results of this subanalysis were consistent with the overall results of the ARISTOTLE trial.


1. Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin in the ARISTOTLE trial: predictors, characteristics, and clinical outcomes. J Am Coll Cardiol 2014.

2. Kim M. Shared risk factors for anticoagulation in non-valvular atrial fibrillation: a dilemma in clinical decision making. J Am Coll Cardiol 2014.

3. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. European Heart Journal 2014.

Published on: March 28, 2014

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