Highlights from

ISTH 2020

The International Society of Thrombosis and Haemostasis

Virtual 12-14 July 2020

Finding the sweet spot of anticoagulation in AF patients with ACS

Patients with both atrial fibrillation (AF) and acute coronary syndrome (ACS) are constantly trapped between the Scylla of bleeding and Charybdis of ischaemic events. The large AUGUSTUS trial showed that dual therapy with a direct oral anticoagulant (DOAC) and a P2Y12 inhibitor is safer than triple therapy with aspirin or VKA use in this challenging patient population [1].

Prof. Renato D. Lopes (Duke University School of Medicine, USA) reviewed this challenging patient population and raised 2 important questions: "whether we should use triple or double therapy for patients with AF and ACS/percutaneous coronary intervention (PCI), and what drug combination we should prescribe" [2]. Patients with AF and coronary artery disease have overlapping indications for antithrombotic therapy. Coronary stenting in patients with AF and a high stroke risk is a problem because to prevent both stent thrombosis and stroke, a combination of dual antiplatelet therapy (DAPT) and oral anticoagulant is necessary, which comes with high bleeding risk.

The AUGUSTUS trial compared the safety of standard-dose apixaban with a vitamin K antagonist (VKA) in addition to low-dose aspirin or placebo, on a background of concomitant P2Y12 inhibitor therapy for 6 months in patients with AF and recent ACS or PCI (see Figure) [1]. The primary study endpoint was major or clinically relevant non-major bleeding. Secondary outcomes included death or hospitalisation and a composite of ischaemic events. The trial enrolled 4,614 patients with ACS or had undergone an elective PCI and were planning to take a P2Y12 inhibitor. They were randomly assigned to open-label apixaban or a VKA. Additionally, patients in both groups were either treated with a placebo or aspirin. Among the patients who underwent randomisation, 37.3% had ACS and underwent PCI, 23.9% had medically managed ACS, and 38.8% underwent an elective PCI [1].

Figure: The 2x2 factorial design of the AUGUSTUS trial. Adapted from [1]

Figure- The 2x2 factorial design

BID, twice daily; INR, international normalised ratio; VKA, vitamin K antgonist. † 2.5 mg dose for patients with 2 or more of the follwing criteria: age ≥80 yeras, weight ≤60 kg, or serum creatine ≥1.5 mg/dL.

Adding aspirin increases bleeding Results from the AUGUSTUS trial showed that 14.7% of patients treated with VKA had major or clinically relevant non-major bleeding compared with 10.5% of patients with apixaban, both a clinically relevant and statistically significant difference both for non-inferiority and superiority (HR 0.69; 95% CI 0.58-0.81; P<0.001). This effect was the same with and without aspirin. "This is the beauty of the 2 by 2 factorial design, the results are independent from each other, so you recognise the treatment effect that exists independent from aspirin," Prof. Lopes explained.

In addition, apixaban-treated patients had a lower incidence of death or hospitalisation in comparison with patients treated with VKA (23.5% vs 27.4%; HR 0.83; 95% CI 0.74-0.93; P=0.002). No significant differences were observed in ischaemic events between the apixaban and VKA groups; however, the trial was not powered for these outcomes. Death or hospitalisation and ischaemic events in the aspirin group were similar compared with the placebo group [1].

Regardless of the anticoagulation therapy, aspirin use was more deleterious than beneficial: a 11.4% absolute risk reduction in bleedings was found with the combination of apixaban and placebo compared with VKA and aspirin. "This means we have to treat only 9 patients with the dual therapy including apixaban to prevent a bad bleeding compared with the triple therapy," Prof. Lopes explained.

"The AUGUSTUS trial is the only trial that also included medically managed patients with ACS. Therefore, in the whole spectrum of coronary artery disease the data from apixaban being safer than vitamin K antagonists is very consistent," Prof. Lopes concluded.

Keywords: Atrial Fibrillation, Acute Coronary Syndrome, ACS, Percutaneous coronary intervention, PCI, AUGUSTUS, DOAC, Anticoagulation, VKA, P2Y12 inhibitor, Apixaban

  1. Lopes R, et al. N Engl J Med 2019;380:1509-1524.
  2. Lopes RD. SOA 05.03, ISTH 2020 Virtual Congress, 12-14 July.

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