Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation - AUGUSTUS

Mar 29, 2020
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Presenter/Author:
John H. Alexander, MD, FACC; Renato D. Lopes, MD, PhD, FACC
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb and Pfizer
Date Presented:
03/29/2020
Date Published:
03/29/2020
Date Updated:
03/29/2020
Original Posted Date:
03/17/2019
References

Contribution To Literature:

Among patients with atrial fibrillation with recent ACS or PCI in the AUGUSTUS trial, adding apixaban to a P2Y12 inhibitor resulted in lower bleeding compared with VKA with a lower rate of death or rehospitalization. In both arms, addition of aspirin resulted in greater bleeding without any difference in efficacy.

Description:

The goal of the trial was to evaluate the role of dual therapy compared with triple therapy among patients with atrial fibrillation undergoing coronary revascularization.

Study Design

In a 2 x 2 factorial design, patients with atrial fibrillation undergoing coronary revascularization were randomized in a 1:1 fashion to either apixaban 5 mg BID (n = 2,306) or vitamin K antagonist (VKA) with an internationalized ratio (INR) goal of 2-3 (n = 2,308), or aspirin 81 mg daily (n = 2,307) or matching placebo (n = 2,307).

All patients received a P2Y12 inhibitor.

  • Total number of enrollees: 4,614
  • Duration of follow-up: 180 days
  • Mean patient age: 70.7 years
  • Percentage female: 29%
  • Percentage with diabetes: 36%

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

Other salient features/characteristics:

  • White race: 92%
  • Creatinine ≥1.5 mg/dl: 8%
  • CHA2DS2-VASc score: 4.0
  • Stroke, transient ischemic attack, or thromboembolic event: 14%
  • Clopidogrel use: 92%
  • ACS as qualifying event: 61%
  • Time in the therapeutic range for VKA: 59%

Principal Findings:

The primary safety outcome, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant nonmajor bleeding for apixaban vs. VKA, was 10.5% vs. 14.7%, p < 0.0001.

The primary safety outcome, ISTH major or clinically relevant nonmajor bleeding for aspirin vs. placebo, was 16.1% vs. 9.0%, p < 0.0001.

Secondary outcomes:

  • Death or hospitalization for apixaban vs. VKA: 23.5% vs. 27.4%, p = 0.002
  • Death or ischemic event for apixaban vs. VKA: 6.7% vs. 7.1%, p > 0.05
  • Death or hospitalization for aspirin vs. placebo: 26.2% vs. 24.7%, p > 0.05
  • Death or ischemic event for aspirin vs. placebo: 6.5% vs. 7.3%, p > 0.05
  • ICH for apixaban vs. VKA: 0.2% vs. 0.6%, p > 0.05
  • ICH for aspirin vs. placebo: 0.4% vs. 0.4%, p > 0.05

ACS vs. stable ischemic heart disease: Apixaban compared with VKA reduced ISTH major or clinically relevant nonmajor bleeding in patients with ACS treated medically (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.28-0.68), ACS treated with PCI (HR 0.68, 95% CI 0.52-0.89), and undergoing elective PCI (HR 0.82, 95% CI 0.64-1.04) (p for interaction = 0.052). Similarly, compared with placebo, aspirin had a higher rate of bleeding than placebo in patients with ACS treated medically (HR 1.49, 95% CI 0.98-2.26), ACS treated with PCI (HR 2.02, 95% CI 1.53-2.67), and elective PCI groups (HR 1.91, 95% CI 1.48-2.47) (p for interaction = 0.479).

Stent thrombosis: Overall, the risk of definite/probable/possible stent thrombosis was 1.6% within 6 months, with 80% occurring within 30 days. The number (proportion) of patients with definite or probable stent thrombosis at 6 months was 13 (0.74%) for apixaban and 17 (0.97%) for VKA (HR 0.76, 95% CI 0.37-1.56) and 11 (0.63%) for aspirin and 19 (1.08%) for placebo (HR 0.58, 95% CI 0.28-1.22). For apixaban plus aspirin, apixaban without aspirin, VKA plus aspirin, and VKA without aspirin, the numbers were 5 (0.57%), 8 (0.91%), 6 (0.69%), and 11 (1.26%).

Aspirin use – risk vs. benefit: The use of aspirin vs. placebo acutely and for up to approximately 30 days resulted in an equal increase in severe bleeding (2.1% vs. 1.1%) and reduction in severe ischemic events (1.7% vs. 2.6%). After 30 days, aspirin continued to increase bleeding (3.7% vs. 2.5%) without significantly reducing ischemic events (3.8% vs. 4.0%).

Interpretation:

Among patients with atrial fibrillation with recent ACS (treated medically or with PCI) or PCI, adding apixaban to a P2Y12 inhibitor resulted in lower bleeding compared with VKA with a lower rate of death or rehospitalization, driven by a lower rate of rehospitalization. In both arms, addition of aspirin resulted in greater bleeding without any difference in efficacy.

In summary, several lines of evidence now suggest that it is safe to treat atrial fibrillation patients who require antiplatelet therapy with anticoagulation (warfarin studied in the WOEST trial, rivaroxaban studied in the PIONEER AF-PCI trial, dabigatran studied in the RE-DUAL PCI trial, and now apixaban in the AUGUSTUS trial) and clopidogrel monotherapy. In this trial, rates of bleeding were lower with apixaban compared with warfarin.

References:

Alexander JH, Wojdyla D, Vora AN, et al. The Risk/Benefit Tradeoff of Antithrombotic Therapy in Patients With Atrial Fibrillation Early and Late After an Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From AUGUSTUS. Circulation 2020;Mar 29:[Epub ahead of print].

Presented by Dr. John H. Alexander at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 29, 2020.

Presented by Dr. Renato D. Lopes at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

Windecker S, Lopes RD, Massaro T, et al. Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or With Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial. Circulation 2019;140:1921-32.

Presented by Dr. Stephan Windecker at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2019), San Francisco, CA, September 26, 2019.

Lopes RD, Heizer G, Aronson R, et al., on behalf of the AUGUSTUS Investigators. Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med 2019;380:1509-24.

Editorial: Mehta SR. Refining Antithrombotic Therapy for Atrial Fibrillation and Acute Coronary Syndromes or PCI. N Engl J Med 2019;380:1580-1.

Presented by Dr. Renato D. Lopes at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 17, 2019.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Prevention, Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and ACS

Keywords: acc20, ACC Annual Scientific Session, AHA Annual Scientific Sessions, AHA19, ACC19, Acute Coronary Syndrome, Anticoagulants, Arrhythmias, Cardiac, Aspirin, Atrial Fibrillation, Fibrinolytic Agents, Hemorrhage, Myocardial Revascularization, Percutaneous Coronary Intervention, Secondary Prevention, Thrombosis, Vitamin K, Warfarin, Transcatheter Cardiovascular Therapeutics, TCT19


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