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AUGUSTUS: Benefit of dual therapy with apixaban, P2Y12 inhibitor consistent across subgroups
SAN FRANCISCO — New data from the AUGUSTUS trial provide insight on the appropriate antithrombotic regimen after ACS or PCI in patients with atrial fibrillation, irrespective of treatment with medical therapy or elective PCI.
The 2x2 factorial trial compared apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) with a vitamin K antagonist (VKA) and aspirin with placebo in 4,614 patients with AF who had ACS or had undergone PCI and were taking a P2Y12 inhibitor.
At TCT 2019, the AUGUSTUS investigators presented data from three prespecified subgroups: patients with ACS who received medical therapy (23.9% of overall population), patients with ACS who underwent PCI (37.3%) and patients who underwent elective PCI (38.8%). The subgroup analyses build on data from the overall AUGUSTUS trial. As previously reported by Healio at the American College of Cardiology Scientific Session in March, data from the main AUGUSTUS trial demonstrated that dual therapy with apixaban and a P2Y12 inhibitor resulted in less bleeding and fewer hospitalizations, with no difference in ischemic events compared with other regimens that included a VKA, aspirin, or both in this patient population.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Stephan Windecker, MD, professor and chairman of the department of cardiology at Bern University Hospital, University of Bern, said during a press conference at TCT 2019.
“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 AF 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.
The new data were simultaneously published in Circulation.
Apixaban vs. VKA
The primary safety outcome, ISTH-defined major or clinically relevant nonmajor bleeding, occurred in 8.4% of the ACS-medical management group, 12.8% of the ACS-PCI group and 15% of the elective PCI group at 6 months. Treatment with apixaban, compared with VKA, reduced major or clinically relevant nonmajor bleeding in all three subgroups: ACS-medical management (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).
Apixaban also reduced death or hospitalization compared with VKA across all subgroups: ACS-medical management (HR = 0.71; 95% CI, 0.54-0.92), ACS-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).
The effect on death and ischemic events with apixaban and VKA was similar across the subgroups (P for interaction = .356).
Aspirin vs. placebo
In the aspirin-placebo comparisons, ISTH major or clinically relevant nonmajor bleeding occurred in 8.4% of the ACS-medical management group, 12.8% of the ACS-PCI group and 14.8% of the elective PCI group at 6 months. Bleeding risk was increased with aspirin, compared with placebo, and this finding was consistent across the subgroups: ACS-medical management (HR = 1.49; 95% CI, 0.98-2.26), ACS-PCI (HR = 2.02; 95% CI, 1.53-2.67) and elective PCI (HR = 1.91; 95% CI, 1.48-2.47; P for interaction = .479).
The researchers observed no difference between aspirin and placebo for the composite of death and hospitalization (P for interaction = .787) or death and ischemic events (P for interaction = .71).
Medical therapy choices
The highest bleeding risk was observed in the elective PCI group, followed by the patients with ACS who underwent PCI, driven largely in clinically relevant nonmajor bleeding, according to the investigators.
AUGUSTUS enrolled patients at 492 sites in 33 countries. Randomization occurred within 14 days of ACS or undergoing PCI, with a median time from index event to randomization of 6 days. The median age at baseline was 71 years and 29% were women.
The apixaban dose was 5 mg twice daily, or 2.5 mg twice daily based on dose-reduction criteria, on top of planned P2Y12 inhibitor therapy, and then also low-dose aspirin 81 mg once daily or matching placebo for 6 months. The reduced apixaban dose was used in 10.1% of the ACS-medical management group, 9.3% of the ACS-PCI group and 10.7% of the elective PCI group. Choice of P2Y12 inhibitor was left to the treating physician; clopidogrel was used in 92.6% of patients.
Of note, AUGUSTUS “is the only trial in the field that included patients with ACS managed medically,” Windecker said during the press conference. Inclusion of this population “is important as up to one-third of patients with ACS do not undergo PCI,” the investigators wrote in the study.
Moreover, these data provide crucial insights for the growing number of patients with AF who undergo elective PCI, which the investigators attribute in part to an aging population and concomitant cardiac comorbidities.
References:
Windecker S. Late-Breaking Science 1. Presented at: TCT Scientific Symposium; Sept. 25-29, 2019; San Francisco.
Windecker S, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.043308.
Disclosures: AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer. Windecker reports he received institutional research and educational grants from Abbott, Amgen, Bayer, Bristol-Myers Squibb, CSL Behring, Biotronik, Boston Scientific, Edwards Lifesciences, Medtronic, Polares and Sinomed.
Perspective
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The big take-home message from the AUGUSTUS trial presented at TCT 2019 is that it’s an expansion of the indications for de-escalation in patients who have had stenting or medical therapy. These results provide further evidence that there’s now a broader group that should be treated with dual therapy, rather than triple therapy, post-ACS or, in this case, PCI. So, it’s further evidence that dual therapy is the way to go in patients who require anticoagulation. Apixaban is a very good agent that can be used with a P2Y12 inhibitor, alone without aspirin, and it can be safely done with less bleeding, but without the expense of more ischemic and serious events like MI and death. That’s a huge win. The addition, or the elaboration, of what we saw with AUGUSTUS with the presentation at ACC 2019 is that [this finding] was also in the medically treated group and in the elective PCI group. Those two categories are something that hadn’t been explored before. There are various numbers out there, but in our ACS population, or even our PCI population, there might be as many as 20% to 30% of patients who are in need of anticoagulation. This is a big group that is going to be treated more safely now.