History of bleeding and outcomes with apixaban versus warfarin in patients with atrial fibrillation in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial

De Caterina R, Andersson U, Alexander JH, et al.
Am Heart J 2016;175:175-83

Background

In patients with AF, the use of predictive algorithms for bleeding are recommended to guide clinical decision making regarding anticoagulation therapy [1,2]. The following scores are used for this purpose:

• HEMORR2HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke) [3]
• HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol) [4]
• ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) [5]

In these algorithms, history of bleeding is important for the estimation of future bleeding risk. Prior bleedings lead to limitations in the use of anticoagulants, which, in turn may lead to worse outcomes [6,7]. In this study, the association between efficacy and safety outcomes and a history of bleeding was evaluated in 18,140 participants of the ARISTOTLE study [8], in which apixaban versus warfarin was tested in AF patients at increased risk for stroke. Moreover, it was assessed whether the apixaban benefit over warfarin is related to a history of bleeding.

Main results

A history of clinically relevant or spontaneous bleeding was associated with:

• a 35% increase in risk for major bleeding (adjusted HR: 1.35; 95% CI: 1.14-1.61; P = 0.0008)
• a 48% increase in risk for major bleeding/clinically relevant non-major bleeding (adjusted HR: 1.48; 95% CI: 1.31-1.68; P = 0.001)
• increased risk of GUSTO mild bleeding: 7.7% vs 14.2 %; HR: 1.60; 95% CI: 1.46-1.77; P<0.001
• increased risk of ISTH minor bleeding: 5.2% vs 9.3%; HR: 1.58; 95% CI: 1.41-1.78; P<0.001
• similar risk of hemorrhagic stroke: 0.4% vs 0.3%; HR: 0.88; 95% CI: 0.52-1.49; P = 0.6215
• similar risk of intracranial bleeding: 0.6% vs 0.5%; HR: 0.90; 95% CI: 0.59-1.36; P = 0.6027
• similar risk of stroke or systemic embolism: 1.4% vs 1.5%; HR 0.97; 95% CI: 0.75-1.24; P = 0.7791 

A history of major bleeding (n=270) was not associated with a significantly higher risk of any type of future bleeding. However, a history of major bleeding had HR estimates for future major bleeding and major/clinically relevant bleeding that were similar to the history of clinically relevant or spontaneous bleeding HRs (HR: 1.28 vs 1.35 for future major bleeds; HR: 1.36 vs 1.48 for major or CR bleed).

A history of GI bleeding was associated with an increased risk of bleeding during the trial:

• major bleeding adjusted HR: 1.97; 95% CI: 1.28-3.02
• major or clinically relevant non-major bleeding adjusted HR: 1.79; 95% CI: 1.29-2.50

Prior GI bleedings were not associated with the use of aspirin at randomisation.

Despite a history of any clinically relevant or spontaneous bleeding being associated with more major bleeding occurring consistently throughout the trial, apixaban was consistently associated with lower rates of major bleeding compared with warfarin in both patient groups with and without a history of bleeding.

Conclusion

In AF patients at increased risk for stroke, a history of bleeding was associated with a higher risk of major bleeding, with the exception of intracranial haemorrhage. The beneficial effects of apixaban over warfarin remained consistent regardless of history of bleeding. A history of bleeding was not associated with the risk of subsequent ischemic events.

Editorial comment [9]

In his editorial article, Goodman points out that the De Caterina et al analysis supports the concept in which the stroke reduction benefit of oral anticoagulation (OAC) outweighs the bleeding risk, even in patients with a history of bleeding. Moreover, he outlines physicians’ and patients’ perspectives on this topic: ‘Physicians tend to underestimate the risk of stroke and overestimate the risk of bleeding: we will only see the bleeds we “cause” and never the strokes we “prevented”, however, ‘patients generally place more value on the avoidance of stroke and less value on the avoidance of bleeding and have different thresholds for initiating OAC from their physicians’.In addition, although up to 70% of ischemic strokes in patients with AF result in death or major disability,most patients with a major bleed associated with OAC will survive.’ And he concludes: ‘In summary, the identification of higher bleeding risk by way of a history of prior bleeding should not be focused upon reasons to not consider OAC but rather on potential modification of future bleeding risk by addressing “correctable” bleeding risk factors.’

Find this article online at American Heart Journal

References

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