Major Bleeding in AF Patients Treated With Apixaban or Warfarin
Aim In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban.
Methods and results Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3–161.8) as was stroke or MI with HR 21.95 (95% CI 9.88–48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI.
Conclusion Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients.
Clinical perspective Major bleedings in patients with atrial fibrillation treated on anti-coagulation therapy was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following intracranial haemorrhage. This risk was similarly elevated regardless of treatment with apixaban or warfarin. The results underscore the importance of preventing bleeding in anti-coagulated patients.
Atrial fibrillation (AF) is an important risk factor for stroke. Anti-coagulation is highly effective for reducing thrombo-embolic complications. Bleeding complications during anti-coagulation are, however, common and associated with increased risk of subsequent death and thrombotic events. Warfarin is known to be associated with bleeding and medication related emergent hospitalizations that relate to a narrow therapeutic window and difficulties in adjusting the dose due to a variable dose response. The direct acting oral anti-coagulants that have emerged in recent years as alternatives to warfarin are proven to reduce these events (similar to or more than warfarin) with a similar or lower risk of bleeding complications. In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin significantly reduced the risk of stroke, major bleeding, and death in patients with AF. Bleeding among patients on anti-coagulant therapy often leads to cessation of anti-coagulant treatment, which may increase the risk of subsequent thrombotic events. Termination of warfarin after a gastrointestinal (GI) bleed was shown in one study to increase the risk of death and thrombotic events. In a real-world registry, patients who experienced serious bleeding had a three-fold increase in the risk of thrombotic events even though the majority of patients did not permanently stop oral anti-coagulation. We have in a recent report presented data on the location and characteristics of bleeding, and the 30-day mortality associated with the first major bleed in the ARISTOTLE trial. In the present study, we evaluate the clinical consequences of major bleeds, including risk of death, ischaemic stroke, and myocardial infarction (MI) in the 30 days preceded by a major bleed. We also report the consequences of a major bleed in terms of management, such as therapeutic actions to stop the bleeding and to decrease subsequent bleeding risk, change in anti-thrombotic therapy, or study drug discontinuation and also treatment effects of apixaban vs. warfarin on clinical outcomes.
Abstract and Introduction
Abstract
Aim In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban.
Methods and results Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3–161.8) as was stroke or MI with HR 21.95 (95% CI 9.88–48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI.
Conclusion Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients.
Clinical perspective Major bleedings in patients with atrial fibrillation treated on anti-coagulation therapy was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following intracranial haemorrhage. This risk was similarly elevated regardless of treatment with apixaban or warfarin. The results underscore the importance of preventing bleeding in anti-coagulated patients.
Introduction
Atrial fibrillation (AF) is an important risk factor for stroke. Anti-coagulation is highly effective for reducing thrombo-embolic complications. Bleeding complications during anti-coagulation are, however, common and associated with increased risk of subsequent death and thrombotic events. Warfarin is known to be associated with bleeding and medication related emergent hospitalizations that relate to a narrow therapeutic window and difficulties in adjusting the dose due to a variable dose response. The direct acting oral anti-coagulants that have emerged in recent years as alternatives to warfarin are proven to reduce these events (similar to or more than warfarin) with a similar or lower risk of bleeding complications. In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin significantly reduced the risk of stroke, major bleeding, and death in patients with AF. Bleeding among patients on anti-coagulant therapy often leads to cessation of anti-coagulant treatment, which may increase the risk of subsequent thrombotic events. Termination of warfarin after a gastrointestinal (GI) bleed was shown in one study to increase the risk of death and thrombotic events. In a real-world registry, patients who experienced serious bleeding had a three-fold increase in the risk of thrombotic events even though the majority of patients did not permanently stop oral anti-coagulation. We have in a recent report presented data on the location and characteristics of bleeding, and the 30-day mortality associated with the first major bleed in the ARISTOTLE trial. In the present study, we evaluate the clinical consequences of major bleeds, including risk of death, ischaemic stroke, and myocardial infarction (MI) in the 30 days preceded by a major bleed. We also report the consequences of a major bleed in terms of management, such as therapeutic actions to stop the bleeding and to decrease subsequent bleeding risk, change in anti-thrombotic therapy, or study drug discontinuation and also treatment effects of apixaban vs. warfarin on clinical outcomes.
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