NEW ORLEANS — For atrial fibrillation (Afib) patients who also need antiplatelet therapy due to a recent cardiac event, using apixaban (Eliquis) without aspirin may be the sweet spot for balancing thrombotic and bleeding risk, the two-by-two factorial AUGUSTUS trial showed.
In the arm comparing apixaban and vitamin K antagonist (VKA), the direct-acting oral anticoagulant (DOAC) cut clinically-relevant nonmajor or major bleeding by a relative 31% (10.5% vs 14.7%, P<0.001 for both non-inferiority and superiority), Renato Lopes, MD, PhD, of Duke University School of Medicine in Durham, North Carolina, and colleagues found.
In the aspirin versus placebo comparison, that bleeding risk was a relative 89% higher with the antiplatelet (16.1% vs 9.0%, P<0.001).
Ischemic events were similar between groups in both comparison, the researchers reported here at the American College of Cardiology (ACC) annual meeting and simultaneously in the New England Journal of Medicine.
“This is perhaps the last nail in the coffin for aspirin and warfarin,” said ACC press conference panel discussant Dhanunjaya Lakkireddy, MD, of the Kansas City Heart Rhythm Institute in Overland Park, Kansas.
Patients in the apixaban group also had a lower incidence of death or hospitalization compared with patients in the vitamin K antagonist group (23.5% vs 27.4%, HR 0.83, 95% CI 0.74-0.93, P=0.002).
“Prior studies, including WOEST, PIONEER AF-PCI, and RE-DUAL PCI were designed to identify strategies to reduce the bleeding associated with triple antithrombotic therapy. However, there are limited data with apixaban in patients with AFib requiring dual antiplatelet therapy, and data on the independent effects of aspirin on this population are limited,” Lopes said.
In patients at high risk for bleeding, ischemic events, and stroke, these results “give physicians a good sense and reliable data to decide what regimen they are going to use…basically, we show that if we use apixaban and clopidogrel [Plavix] without aspirin for the majority of patients, it will be the safer regimen without compromise in efficacy endpoint so far,” Lopes told MedPage Today.
While it is fair to extrapolate the aspirin findings across the the direct-acting oral anticoagulants (DOACs), Lopes cautioned against extrapolating the warfarin comparison across the class.
“Fortunately, we do have trials with other DOACs,” Lakkireddy said at an ACC press conference. He noted that the AUGUSTUS findings fall into line with existing literature. “This as a concept was really not very surprising at all, because this is also pretty much expected.”
The AUGUSTUS researchers evaluated 4,614 patients (median age 70.7; 29% women) across 33 countries, including Mexico, Canada, the U.K., and the U.S.
Patients had to have recent PCI with planned use of a P2Y12 inhibitor for at least 6 months, or a recent ACS, along with paroxysmal, persistent, permanent, or previous AFib and planned long-term use of an oral anticoagulant.
“We are the only trial that actually included, in this field, patients with acute coronary syndrome who were medically managed; in other words, who did not get a PCI. The other two studies, PIONEER and RE-DUAL, only included patients who underwent PCI…this is another differentiation of the [AUGUSTUS] trial,” Lopes told MedPage Today.
A history of intracranial hemorrhage, planned or recent coronary artery bypass graft surgery, severe renal insufficiency, ongoing bleeding or coagulopathy, contraindication to apixaban, aspirin, all P2Y12 inhibitors, and vitamin K antagonist, as well as patients taking anticoagulation for other reasons, such as venous thromboembolism, mitral stenosis, and prosthetic valves made up the exclusion criteria.
At baseline, the cohort had a mean CHA2DS2-VASc score of 3.9 and a mean HAS-BLED score of 2.9. Patients in the open-label aspect of the study were randomized to a vitamin K antagonist group or an apixaban group. Patients in the double-blind study component were then further randomized to a placebo group or an aspirin group.
Secondary safety and efficacy outcomes for the apixaban versus vitamin K antagonist randomization were:
- Death/ischemic events at 6 months: 6.7% vs 7.1%
- Stroke: 0.6% vs 1.1%
- Death: 3.3% vs 3.2%
- MI :3.1% vs 3.5%
- Death from cardiovascular (CV) causes: 2.5% vs 2.3%
- Hospitalization: 22.5% vs 26.3%
- Academic Research Consortium (ARC) definite or probable stent thrombosis: 0.6% vs 0.8%
- Urgent revascularization: 1.7% vs 1.9%
Secondary safety and efficacy outcomes for the aspirin versus placebo randomization were:
- Death/ischemic events at 6 months: 6.5% vs 7.3%
- Stroke: 0.9% vs 0.8%
- Death: 3.1% vs 3.4%
- Hospitalization: 25.4% vs 23.4%
- MI: 2.9% vs 3.6%
- Death from CV causes: 2.3% vs 2.5%
- ARC definite or probable stent thrombosis: 0.5% vs 0.9%
- Urgent revascularization: 1.6% vs 2.0%
Referring to the secondary findings, ACC panel discussant Kristen Patton, MD, of the University of Washington in Seattle, stated that she was “struck by the mortality data, which I understand the trial was not powered for, but it did stand out that numerically the mortality was lower in both the aspirin and VKA groups [77 patients on apixaban, 72 on aspirin, 74 on VKA, 77 placebo]. In addition, in the aspirin groups that the MI, thrombosis, revascularization, was lower,” she said.
Lopes acknowledged that a study limitations was the challenge in assessing efficacy endpoints in a high-risk patient population with high CHA2DS2-VASc and HAS-BLED scores. “So that’s a limitation that is intrinsic of all these trials is that they are not powered enough to assess efficacy endpoints,” he emphasized.
Also, the time in therapeutic range was about 59% for patients who were assigned to a vitamin K antagonist, “This is a little bit lower than other studies…our follow-up is only 6 months, and for the other studies it’s 1 year,” Lopes added.
In an accompanying editorial, Shamir Mehta, MD, of McMaster University and Hamilton Health Sciences in Hamilton, Canada) noted that “Given the totality of data, a direct oral anticoagulant should now routinely be recommended for patients with atrial fibrillation who have an acute coronary syndrome or undergo PCI.”
But he cautioned that “findings from this trial do not necessarily provide reassuring evidence that early discontinuation of aspirin therapy after an acute coronary syndrome or PCI is warranted in all patients,” adding that “although the AUGUSTUS trial was a large trial evaluating this question, it was still substantially underpowered for coronary ischemic events.”
Mehta emphasized that “clinical decision making should continue to be based on a balanced assessment of three competing risks: cardioembolic stroke, coronary ischemic events, and bleeding.”
He concluded that guideline committees will now have to determine how to incorporate AUGUSTUS results into recommendations, but “it is clear that a one-size-fits-all policy is unlikely to apply in these patients.”
The study was funded by Bristol-Myers Squibb (BMS) and Pfizer. Some co-authors are BMS employees.
Lopes disclosed relevant relationships with Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Co-authors disclosed multiple relevant relationships with industry.
Patton disclosed no relevant relationships with industry.
Mehta disclosed support from AstraZeneca, Boston Scientific, and Boehringer Ingelheim.