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Study Overview
Objective. To compare the benefit of apixaban with a vitamin K antagonist and compare aspirin with placebo in patients with atrial fibrillation who had acute coronary syndrome or underwent percutaneous coronary intervention (PCI) and were planning to take a P2Y12 inhibitor.
Design. Multicenter, international, open-label, prospective randomized controlled trial with a 2-by-2 factorial design.
Setting and participants. 4614 patients who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor.
Intervention. Patients were assigned by means of an interactive voice-response system to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.
Main outcome measures. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.
Main results. At 6 months, major or clinically relevant nonmajor bleeding had occurred in 10.5% of the patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.58-0.81, P < 0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (HR 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR 0.83; 95% CI, 0.74-0.93; P = 0.002) and similar incidence of ischemic events.
Conclusion. Among patients with atrial fibrillation and recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than the regimens that included a vitamin K antagonist, aspirin, or both.
Commentary
PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.
Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.1 Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).2 Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).3
In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.
The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.
The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.
Applications for Clinical Practice
In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, dual therapy with a P2Y12 inhibitor and DOAC should be favored over a regimen that includes a vitamin K antagonist and/or aspirin.
—Taishi Hirai, MD, University of Missouri Medical Center, and John Blair, MD, University of Chicago Medical Center
1. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115.
2. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434.
3. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377:1513-1524.
Study Overview
Objective. To compare the benefit of apixaban with a vitamin K antagonist and compare aspirin with placebo in patients with atrial fibrillation who had acute coronary syndrome or underwent percutaneous coronary intervention (PCI) and were planning to take a P2Y12 inhibitor.
Design. Multicenter, international, open-label, prospective randomized controlled trial with a 2-by-2 factorial design.
Setting and participants. 4614 patients who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor.
Intervention. Patients were assigned by means of an interactive voice-response system to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.
Main outcome measures. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.
Main results. At 6 months, major or clinically relevant nonmajor bleeding had occurred in 10.5% of the patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.58-0.81, P < 0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (HR 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR 0.83; 95% CI, 0.74-0.93; P = 0.002) and similar incidence of ischemic events.
Conclusion. Among patients with atrial fibrillation and recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than the regimens that included a vitamin K antagonist, aspirin, or both.
Commentary
PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.
Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.1 Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).2 Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).3
In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.
The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.
The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.
Applications for Clinical Practice
In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, dual therapy with a P2Y12 inhibitor and DOAC should be favored over a regimen that includes a vitamin K antagonist and/or aspirin.
—Taishi Hirai, MD, University of Missouri Medical Center, and John Blair, MD, University of Chicago Medical Center
Study Overview
Objective. To compare the benefit of apixaban with a vitamin K antagonist and compare aspirin with placebo in patients with atrial fibrillation who had acute coronary syndrome or underwent percutaneous coronary intervention (PCI) and were planning to take a P2Y12 inhibitor.
Design. Multicenter, international, open-label, prospective randomized controlled trial with a 2-by-2 factorial design.
Setting and participants. 4614 patients who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor.
Intervention. Patients were assigned by means of an interactive voice-response system to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months.
Main outcome measures. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.
Main results. At 6 months, major or clinically relevant nonmajor bleeding had occurred in 10.5% of the patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.58-0.81, P < 0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (HR 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR 0.83; 95% CI, 0.74-0.93; P = 0.002) and similar incidence of ischemic events.
Conclusion. Among patients with atrial fibrillation and recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than the regimens that included a vitamin K antagonist, aspirin, or both.
Commentary
PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.
Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.1 Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).2 Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).3
In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.
The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.
The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.
Applications for Clinical Practice
In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, dual therapy with a P2Y12 inhibitor and DOAC should be favored over a regimen that includes a vitamin K antagonist and/or aspirin.
—Taishi Hirai, MD, University of Missouri Medical Center, and John Blair, MD, University of Chicago Medical Center
1. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115.
2. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434.
3. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377:1513-1524.
1. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115.
2. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434.
3. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377:1513-1524.