AUGUSTUS

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Lopes RD, et al. "Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation". The New England Journal of Medicine. 2019. epub doi 10.1056/NEJMoa1817083:.
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Clinical Question

In patients with atrial fibrillation (AF) presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI), is oral anticoagulation with apixaban superior to warfarin with regard to thrombotic events and bleeding? Is the addition of aspirin to oral anticoagulation and P2Y12 inhibitor therapy superior to placebo with regard to thrombotic events and bleeding?

Bottom Line

Among patients with AF presenting with ACS or undergoing PCI, apixaban is associated with a 4.2% absolute reduction in major or clinically relevant nonmajor bleeding when compared to warfarin at 180 days. Apixaban was also associated with a 3.9% absolute reduction in death or hospitalization when compared to warfarin (driven primarily by reduced hospitalization). Aspirin use in addition to oral anticoagulation and P2Y12 inhibitor therapy was associated with a 7.1% absolute increase in major or clinically relevant nonmajor bleeding. Overall thrombotic events were similar across individuals randomized to anticoagulation with apixaban versus warfarin, and those randomized to aspirin versus placebo.

Major Points

The optimal anticoagulation/antiplatelet strategy following acute coronary syndromes (ACS) and/or percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) is unclear and has been the subject of intense study. Oral anticoagulation (OAC) has been established as standard of care for stroke prevention in patients with AF. Similarly, P2Y12 inhibitors are used uniformly after ACS with or without PCI to prevent recurrent thrombosis (particularly stent thrombosis in the case of PCI). Whether anticoagulation with direct-acting oral factor Xa inhibitors (DOAC) is superior to warfarin in the post-PCI setting, and whether the addition of aspirin to OAC and P2Y12 inhibition provides superior thrombotic protection, are unclear.

The 2013 WOEST trial suggested that the addition of aspirin to warfarin and P2Y12 inhibitors in the post-PCI setting is associated with increased bleeding without a significant difference in thrombotic events. The 2016 PIONEER AF-PCI trial suggested that use of the DOAC rivaroxaban with P2Y12 inhibitor in AF patients post-PCI is associated with decreased bleeding when compared to triple therapy with ASA, P2Y12 inhibitor, and warfarin without a significant difference in thrombosis. The 2017 RE-DUAL PCI trial showed similar findings using the DOAC dabigatran. A limitation of both of latter DOAC trials is the comparison of dual therapy using DOAC and P2Y12 inhibitor versus triple therapy using ASA, P2Y12 inhibitor, and warfarin. Specifically, it becomes unclear whether the reduced bleeding observed on the dual therapy regimens is a product of DOAC use (as compared to warfarin), versus the withholding of aspirin. Therefore, a 2x2 factorial randomization study was needed to better assess the relative outcomes of DOAC (as compared to warfarin) and ASA (as compared to placebo in patients receiving anticoagulation and P2Y12 inhibitor).

The 2019 Open-label, 2x2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention (AUGUSTUS) trial randomized 4614 patients with known AF presenting with ACS and/or undergoing PCI in a 2x2 factorial design to a) apixaban versus warfarin, and b) aspirin versus placebo. At 6 months, apixaban was associated with a 4.2% absolute reduction in major or clinically relevant nonmajor bleeding when compared to warfarin. Apixaban was also associated with a 3.9% absolute reduction in death or hospitalization when compared to warfarin (driven primarily by reduction in hospitalization). Aspirin use in addition to oral anticoagulation was associated with a 7.1% absolute increase in major or clinically relevant nonmajor bleeding. Thrombotic events were similar across individuals randomized to anticoagulation with apixaban versus warfarin, and those randomized to aspirin versus placebo. Notably, however, there was a nonsignificant 0.4% absolute numerical increase in definite/probable stent thrombosis in patients not receiving aspirin.

In summary, the AUGUSTUS trial provides further evidence that DOAC use in the post-PCI setting is associated with decreased bleeding risk as compared to warfarin. Importantly, it provides more direct evidence that 'triple therapy' (ASA + P2Y12 inhibitor + either DOAC or warfarin) is associated with substantial increases in bleeding without clearly improved thrombotic protection when compared to therapy with P2Y12 inhibitor and oral anticoagulation alone. As with previous trials, however, there remains a very small numerical increase in stent thrombosis rates in regimens not containing aspirin. Although it remains prudent to individualize antiplatelet/anticoagulation decisions based on thrombosis and bleeding risk, blanket use of triple therapy, particularly in patients with elevated bleeding risk, is likely to decrease as a result of these findings.

Guidelines

As of April 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, open-label trial
  • N=4614
    • Randomization 1: apixaban (N=2306) versus warfarin (N=2308)
    • Randomization 2: aspirin (N=2307) versus placebo (N=2307)
  • Setting: 492 sites in 33 countries
  • Enrollment: September 2015 - April 2018
  • Duration of follow-up: 180 days
  • Analysis: Intention-to-treat
  • Primary Outcome: ISTH major or clinically relevant nonmajor bleeding

Population

Inclusion Criteria

  • Age ≥18 years
  • Recent acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) with planned use of P2Y12 inhibitor for at least 6 months
  • Previous atrial fibrillation and planned long-term use of oral anticoagulation

Exclusion Criteria

  • Bioprosthetic or mechanical heart valve
  • Anticoagulation for other indications (venous thromboembolism, mitral stenosis)
  • History of intracranial hemorrhage (ICH)
  • Severe renal insufficiency
  • Recent or planned coronary artery bypass grafting
  • Coagulopathy or ongoing bleeding
  • Contraindication to study medications

Baseline Characteristics

From the apixaban group.

  • Demographics: age 70.4 years, male 29.1%, white 91.9%
  • Comorbidities: creatinine > 1.5 7.6%, CHADS-VASc score 3.9, HAS-BLED score 2.9, HTN 88.6%, heart failure 42.3%, DM 36.5%, stroke/TIA/systemic embolism 14.2%
  • P2Y12 inhibitor: clopidogrel 93.4%, prasugrel 1.2%, ticagrelor 5.4%
  • Index event: ACS and PCI 38.0%, ACS medical therapy 23.8%, elective PCI 38.2%, days from index event to randomization 6.7

Interventions

  • Patients underwent 2x2 factorial randomization
    • Randomization 1: Apixaban versus warfarin
    • Randomization 2: Aspirin versus placebo
  • Patients underwent randomization within 14 days after having an acute coronary syndrome or undergoing PCI
  • Choice of P2Y12 inhibitor was left to the discretion of the treating physician
  • The treatment regimen comparing apixaban with a vitamin K antagonist was open-label; however, the regimen comparing aspirin with matching placebo was double-blind
  • Randomization was stratified according to indication (acute coronary syndrome or PCI) at enrollment
  • Patients receiving apixaban were directed to take 5 mg twice daily or to take 2.5 mg twice daily if they met two or more of the following dose-reduction criteria: were at least 80 years of age, had a weight of no more than 60 kg, or had a creatinine level of at least 1.5 mg per deciliter (133 μmol per liter)
  • Patients receiving warfarin had the dose adjusted to reach a target international normalized ratio (INR) within a range of 2.0 to 3.0
  • After 6 months, patients were transitioned from their two trial interventions to receive antiplatelet and anticoagulant therapy according to the local standard of care
  • All patients undergoing randomization were followed through 6 months, with an additional visit at month 7 to record transitions in antithrombotic therapy and associated outcomes
  • All bleeding and ischemic events (except for urgent revascularization) were independently adjudicated by the clinical-events classification committee, whose members were unaware of the trial-group assignments

Outcomes

RANDOMIZATION 1: Comparisons are apixaban versus warfarin

Primary Outcomes

ISTH major bleeding or clinically relevant nonmajor bleeding
241 (10.5%) vs. 332 (14.7%); HR 0.69 (95% CI 0.58-0.81); p < 0.001

Secondary Outcomes

Death or hospitalization
541 (23.5%) vs. 632 (27.4%); HR 0.83 (95% CI 0.74-0.93); p = 0.002
Death or ischemic event
154 (6.7%) vs. 163 (7.1%); HR 0.93 (95% CI 0.75-1.16); p = NS
Death
77 (3.3%) vs. 74 (3.2%); HR 1.03 (95% CI 0.75-1.42)
Hospitalization
518 (22.5%) vs. 607 (26.3%); HR 0.83 (95% CI 0.74-0.93)
Stroke
13 (0.6%) vs. 26 (1.1%); HR 0.50 (95% CI 0.26-0.97)
ARC definite or probable stent thrombosis
14 (0.6%) vs. 18 (0.8%); HR 0.77 (95% CI 0.38-1.56)

RANDOMIZATION 2: Comparisons are aspirin versus placebo

Primary Outcomes

ISTH major bleeding or clinically relevant nonmajor bleeding
367 (16.1%) vs. 204 (9.0%); HR 1.89 (95% CI 1.59-2.24); p < 0.001

Secondary Outcomes

Death or hospitalization
604 (26.2%) vs. 569 (24.7%); HR 1.08 (95% CI 0.96-1.21); p = NS
Death or ischemic event
149 (6.5%) vs. 168 (7.3%); HR 0.89 (95% CI 0.71-1.11); p = NS
Death
72 (3.1%) vs. 79 (3.4%); HR 0.91 (95% CI 0.66-1.26)
Hospitalization
585 (25.4%) vs. 540 (23.4%); HR 1.10 (95% CI 0.98-1.24)
Stroke
20 (0.9%) vs. 19 (0.8%); HR 1.06 (95% CI 0.56-1.98)
ARC definite or probable stent thrombosis
11 (0.5%) vs. 21 (0.9%); HR 0.52 (95% CI 0.25-1.08)

Subgroup Analyses

  • No significant interaction was observed between the two randomization factors and the primary outcome (p=0.64), death or hospitalization (p=0.21), or death or ischemic events (p=0.28)
  • The effects of apixaban as compared with a vitamin K antagonist and of aspirin as compared with placebo were generally consistent across prespecified subgroups with regard to bleeding events, death or hospitalization, and death or ischemic events

Criticisms

  • Use of apixaban versus warfarin was open-label which leads to observation bias. This is mitigated somewhat by blinded outcomes adjudication (for all outcomes other than urgent revascularization)
  • Time in therapeutic range among patients randomized to warfarin was 59%, modestly lower than that achieved in other large randomized trials, potentially biasing results toward lower thrombotic rates with DOAC than would be observed in the setting of more effective warfarin use
  • Over 90% of patients received clopidogrel as their P2Y12 inhibitor. Whether these findings can be extrapolated to individuals receiving other agents (e.g., prasugrel, ticagrelor) is unclear

Funding

  • Trial sponsored by Bristol-Myers Squibb and Pfizer
  • Sponsors assisted with data management

Further Reading