AUGUSTUS: DOAC plus P2Y12 inhibitor minus aspirin in high-risk AF
An antithrombotic regimen consisting of the direct-acting oral anticoagulant (DOAC) apixaban and omitting aspirin reduces bleeding and hospitalizations without compromising protection against ischaemic events in atrial fibrillation (AF) patients with a recent acute coronary syndrome (ACS) or percutaneous coronary (PCI) and treated with a P2Y12 inhibitor, as compared with regimens including a vitamin K antagonist (VKA), aspirin or both, according to the results of the AUGUSTUS trial.
In a two-by-two factorial design, AUGUSTUS randomized 4,614 AF patients (median age, 70.7 years; 29.0 percent female) who had ACS or had undergone PCI and were initiating treatment with P2Y12 inhibitor (mostly clopidogrel) to receive apixaban or a VKA and to receive aspirin or matching placebo for 6 months.
“There were no significant interactions between the two randomization factors on the primary [outcome of a major or clinically relevant nonmajor bleeding] or secondary outcomes [of death or hospitalization and a composite of ischaemic events],” the investigators said.
Compared with VKA, apixaban demonstrated both noninferiority and superiority for the primary outcome (10.5 percent vs 14.7 percent). The DOAC produced a 31-percent decrease in the risk of bleeding (hazard ratio [HR], 0.69, 95 percent CI, 0.58–0.81; p<0.001 for both noninferiority and superiority). [N Engl J Med 2019;380:1509-1524]
Furthermore, apixaban cut the risk of death or hospitalization by 17 percent relative to VKA (23.5 percent vs 27.4 percent; HR, 0.83, 0.74–0.93; p=0.002), which was primarily driven by a reduction in all-cause hospitalization. There was no significant between-group difference in the risk of ischaemic events.
Meanwhile, aspirin was associated with a significantly elevated risk of bleeding compared with placebo (16.1 percent vs 9.0 percent; HR, 1.89, 1.59–2.24; p<0.001). Results for the secondary outcomes were similar between the two groups.
“Our trial…confirms the safety and efficacy of apixaban, as compared with a VKA, at a dose recommended for patients with AF and shows that the effect of avoiding aspirin on the incidence of bleeding events seems to be even greater than the benefit of using apixaban instead of a VKA,” the investigators said.
Also, the present data are said to extend the results of the WOEST* trial in a high-risk population of AF patients by showing fewer bleeding events among patients treated without vs with aspirin, although the incidence of ischaemic events did not significantly differ. [Lancet 2013;381:1107-1115]
“Thus, when clinicians consider aspirin as a component of antithrombotic therapy after PCI in patients with AF, a potential small absolute decrease in the risk of coronary ischaemic events needs to be weighed against a larger absolute increase in the risk of clinically significant bleeding,” they added.
Antithrombotic therapy not a one-size-fits-all approach
While AUGUSTUS sheds light on the issue of whether bleeding risk may be reduced through the use of a DOAC or through the early discontinuation of aspirin, the evidence is not strong enough to support that early discontinuation of aspirin therapy after an ACS or PCI is warranted in all patients, as pointed out in a linked commentary piece by Dr Shamir Mehta from the McMaster University and Hamilton Health Sciences in Canada. [N Engl J Med 2019;380:1580-1581]
What is certain is that “a DOAC should now routinely be recommended for patients with AF who have an ACS or undergo PCI,” Mehta said. “Clinical decision making [regarding antithrombotic therapy] should continue to be based on a balanced assessment of three competing risks: cardioembolic stroke, coronary ischaemic events and bleeding.”
Assessment should be comprehensive, including demographic and clinical variables related to the risks as well as the clinical setting and angiographic complexity of PCI and risks associated with the procedure, he added.
“In patients with a low risk of thrombotic events (eg, those undergoing elective PCI who do not have high-risk clinical or angiographic features) or a high risk of bleeding, early omission of aspirin therapy and treatment with a DOAC plus clopidogrel is entirely warranted,” he said.
“However, in patients undergoing complex, multivessel, or high-risk PCI or in those presenting with high-ACS, aspirin should probably not be routinely omitted for at least several weeks or longer, depending on bleeding risk.”