AUGUSTUS Update: Best Benefit With Apixaban, P2Y12 Inhibitor Dual Therapy

Roxanne Nelson, RN, BSN

September 28, 2019

SAN FRANCISCO — An antithrombotic regimen that includes apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and a P2Y12 inhibitor is effective and may be a safer option in patients with atrial fibrillation (AF) with acute coronary syndrome (ACS), a new analysis from the AUGUSTUS trial suggests.

Compared with regimens that include a vitamin K antagonist (VKA), aspirin, or both, the apixaban/P2Y12 inhibitor regimen provided superior safety and similar efficacy for patients managed medically or with percutaneous coronary intervention (PCI), or who underwent elective PCI for stable coronary disease. Adding aspirin to the regimen increased major bleeding episodes but did not significantly affect ischemic outcomes.

"The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups," said study author Stephan Windecker, MD, director and chief physician, Department of Cardiology, Swiss Cardiovascular Center, Bern, Switzerland.

"Accordingly, anticoagulation with apixaban, at the dose approved for stroke prevention in patients with AF, combined with a P2Y12 inhibitor without aspirin should be preferred in patients with atrial fibrillation and ACS irrespective of management with medical therapy or PCI, and those undergoing elective PCI than regimens that include VKAs, aspirin, or both," he said.

Windecker presented the results in a late-breaking clinical science session here at the Transcatheter Cardiovascular Therapeutics (TCT) 2019 Conference. The study was also published online September 26 in Circulation. The optimal antithrombotic strategy for this patient population continues to be unclear, Windecker noted. "The safety and efficacy of antithrombotic regimens may differ between patients with atrial fib who have ACS treated medically or with PCI, and those undergoing elective PCI," he said.

Double antithrombotic therapy has been proposed as an alternative to triple therapy, and previous research has shown that these regimens may reduce the risk of bleeding. Earlier results  from AUGUSTUS showed that there was a lower risk of bleeding and hospitalization but a similar risk of ischemic events with an antithrombotic regimen consisting of apixaban and a P2Y12 inhibitor without aspirin compared with regimens that included VKAs, aspirin, or both.

Apixaban Dual Therapy Superior

In the current study, Windecker and colleagues investigated the safety and efficacy of the regimens studied in AUGUSTUS in three mutually exclusive, prespecified patient subgroups: those with AF and ACS treated medically, those with AF and ACS undergoing PCI, and those with AF and stable coronary artery disease (CAD) undergoing elective PCI. 

Within the cohort of 4614 patients, 1097 (23.9%) had ACS treated medically, 1714 (37.3%) had ACS treated with PCI, and 1784 (38.8%) had elective PCI. Up to 14 days after ACS or PCI, patients were randomly assigned in a 2 × 2 factorial design to apixaban or VKA and to aspirin or aspirin placebo. All participants received a P2Y12 inhibitor for the 6-month duration of treatment.

The primary outcome was the first occurrence of ISTH (International Society on Thrombosis and Hemostasis) major or clinically relevant nonmajor (CRNM) bleeding, and secondary endpoints included the composite of death or hospitalization and the composite of death and ischemic events (composite of stroke, myocardial infarction, stent thrombosis, and urgent revascularization).

Among patients treated with apixaban or VKA, ISTH major or CRNM bleeding occurred in 8.4% of patients with ACS who were medically managed, 12.8% in the ACS PCI group, and 15.0% in the elective PCI cohort at 6 months.

The lower bleeding risk with apixaban vs VKA was observed in all three groups: ACS medically managed (hazard ratio [HR], 0.44; 95% CI, 0.28 - 0.68), ACS PCI (HR, 0.68; 95% CI, 0.52 - 0.89), and elective PCI (HR, 0.82; 95% CI, 0.64 - 1.04; P for interaction = .052).

Treatment with apixaban compared with VKA reduced ISTH-defined major or CRNM bleeding in patients with ACS who were treated medically (HR, 0.44; 95% CI, 0.28 - 0.68), as well as those treated with PCI (HR, 0.68; 95% CI, 0.52 - 0.89) and those who underwent elective PCI (HR, 0.82; 95% CI, 0.64 - 1.04; P for interaction = .052).

Compared with VKA, apixaban also reduced death or hospitalization in the ACS treated medically (HR, 0.71; 95% CI, 0.54 - 0.92), ACS treated with PCI (HR, 0.88; 95% CI, 0.74 - 1.06), and elective PCI (HR, 0.87; 95% CI, 0.72 - 1.04; P for interaction = .345) groups and had a similar effect on death and ischemic events in the three groups.

Patients treated with aspirin had a higher rate of bleeding compared with placebo in the ACS treated medically group (HR, 1.49; 95% CI, 0.98 - 2.26), ACS treated with PCI group (HR, 2.02; 95% CI, 1.53 - 2.67), and elective PCI group (HR, 1.91; 95% CI, 1.48 - 2.47; P for interaction = .479).

Questions Remain

Windecker pointed out that while extended aspirin therapy out to 6 months can be detrimental, a limitation of the study is that it doesn't address the optimal short-term duration of aspirin treatment after PCI before initiation of dual antithrombotic therapy.

Ori Ben-Yehuda, MD, from the University of California, San Diego, and moderator of a press briefing held before the presentation, noted that the 2 × 2 factorial design is a real strength and that "this adds very important information that aspirin in triple therapy is not the way to go."

Panelist Vijay Kunadian, MD, MBBS, senior lecturer, Newcastle University, Newcastle upon Tyne, United Kingdom, and consultant interventional cardiologist, asked Windecker what the primary reason was for treating the patients with medical therapy. "There is a tendency to treat these patients with pharmacotherapy for a number of reasons, and you elegantly showed that the same effect was seen in all categories," she said.

Windecker reported that detailed information on that is unavailable because treatment was up to the physician's discretion. "What was somewhat surprising to me is that I would have anticipated that it would be more the elderly and those with comorbidities who would be treated medically," he said. "What we saw were more female patients and younger patients, but I think it reflects what we see in clinical practice."

Robert Harrington, MD, an interventional cardiologist and the Arthur L. Bloomfield Professor of Medicine and chairman of the Department of Medicine at Stanford University, California, pointed out that the ACS population with AF is large, making up about 7% to 10% of these patients. "What's been disappointing is that none of the trials have been big enough to really uncouple the bleeding vs ischemic issue," he said.

There have been concerns about the balance of bleeding and ischemic risks, said Harrington, who is also a member of the data and safety monitoring board for AUGUSTUS.

"I think you're spot on, which is we don't the know the answer for how long do you need the triple therapy vs when you can switch to the double therapy," Harrington said.

Windecker agreed. "We know triple therapy is not the way to go, but we need to fine-tune and probably individualize which patients may benefit from a certain duration of aspirin."

The AUGUSTUS study was funded by Bristol-Myers Squibb and Pfizer Inc. Windecker disclosed research grants to the institution from Abbott, Amgen, Bayer, Bristol Myers-Squibb, Boston Scientific, Biotronik, CLS Behring, Edwards Lifesciences, Medtronic, Polares, and Sinomed.

Transcatheter Cardiovascular Therapeutics (TCT) 2019 Conference. LBA Augustus Trial. Presented September 26, 2019.

Circulation. Published online September 26, 2019. Abstract

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