From Pages to Practice

By James Yeh, MD, MPH

Published May 8, 2019


I recently saw a patient for follow-up who had a history of atrial fibrillation and was taking apixaban for cardioembolic risk reduction. The patient was treated in the emergency department for acute coronary syndrome (ACS) one week earlier and was medically managed and discharged with aspirin and clopidogrel. What is the best way to manage the combination of antiplatelet therapy and anticoagulation to balance and minimize the risks of cardioembolism, coronary ischemia, and bleeding?

Atrial fibrillation and coronary artery disease are common conditions. An estimated one third of patients with atrial fibrillation have coronary artery disease and up to 20% of these patients have undergone a percutaneous coronary intervention (PCI) or coronary artery bypass graft.

Thromboembolism is a major complication of atrial fibrillation and can be significantly reduced with the use of oral anticoagulation. Dual antiplatelet therapy (aspirin and P2Y12 inhibitors) in patients with ACS or PCIreducesthe risk of death, myocardial infarction, and stent thrombosis. However, the combination of dual antiplatelet therapy plus oral anticoagulation (the so-called triple antithrombotic therapy) increases bleeding risk in patients with atrial fibrillation who underwent  ACS or PCI.

In a randomized, placebo-controlled trial with two-by-two factorial design published in NEJM, Lopes et al. examined the effect of apixaban or vitamin K antagonist with aspirin or placebo in patients with atrial fibrillation and a recent ACS or PCI treated with a P2Y12 inhibitor. The results indicate that the use of dual pathway agents (apixaban and a P2Y12 inhibitor) without aspirin reduces the risk of bleeding without significantly increases adverse events.

The following NEJM Journal Watch summary explains the study and results:


Three-Drug vs. Two-Drug Antithrombotic Therapy for Atrial Fibrillation plus Coronary Indications

The best outcomes were noted with apixaban plus clopidogrel — omitting aspirin.

When patients with atrial fibrillation develop acute coronary syndrome (ACS) or require percutaneous coronary intervention (PCI), they theoretically become candidates for triple antithrombotic therapy — an anticoagulant for atrial fibrillation, plus dual antiplatelet therapy for the coronary event. However, such regimens are associated with high rates of bleeding. In this industry-sponsored international study, researchers examined the efficacy and safety of two-drug alternatives in 4600 patients with atrial fibrillation who had either ACS (with or without PCI) or elective PCI.

All patients received a P2Y12 inhibitor (nearly always clopidogrel) and additionally were randomized twice — to apixaban or a vitamin K antagonist (VKA) and to aspirin or no aspirin. This randomization resulted in four treatment groups:

  • Aspirin, clopidogrel, apixaban [Eliquis]

  • Aspirin, clopidogrel, VKA

  • Clopidogrel, apixaban

  • Clopidogrel, VKA

At 6 months, major or clinically relevant nonmajor bleeding occurred more commonly with triple therapy than with two-drug therapy (16% vs. 9%) and more commonly with VKA-containing regimens than with apixaban-containing regimens (15% vs. 11%). Rates of myocardial infarction, stroke, and death were similar in the two-drug and three-drug groups. Hence, the best overall outcome (less bleeding, without sacrificing protection against ischemic events or death) was with the two-drug regimen of clopidogrel plus apixaban.

COMMENT: These results make a strong case for avoiding three antithrombotic agents in anticoagulated patients with atrial fibrillation who develop coronary events that are typically treated with dual antiplatelet therapy. The combination of clopidogrel plus apixaban — omitting aspirin — offered the most favorable balance of benefit and harm in this trial. However, an editorialist argues that the study might have been underpowered to show some protection against ischemic events with aspirin, and he argues that selected high-risk patients might still benefit from at least a few weeks of triple therapy.

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James Yeh, MD MPH, Physician at NEJM Group
James Yeh, MD MPH is an internist and assistant in medicine at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015-2016.