AUGUSTUS: PCI or No PCI, Aspirin Uncalled For in Afib

SAN FRANCISCO — The route atrial fibrillation (Afib) patients take to needing antithrombotic therapy did not make a difference in the advantage of using a direct-acting oral anticoagulant and safety of skipping aspirin.

So found a pre-specified substudy of the AUGUSTUS trial, Stephan Windecker, MD, of Bern University Hospital in Switzerland, reported at the Transcatheter Cardiovascular Therapeutics (TCT) conference and online in Circulation.

The advantages at 6 months of apixaban (Eliquis) over a vitamin K antagonist (VKA) were the same for the subgroup managed medically for acute coronary syndrome (ACS), for those stented for ACS, and for those receiving a stent electively for stable coronary artery disease, consistent with the main trial results:

• Less major or clinically-relevant non-major bleeding: P=0.052 for interaction
• Reduced death or hospitalization: P=0.345 for interaction
• No difference in total death and ischemic event rates: P=0.356 for interaction

Similarly, the three groups were in line with the main trial findings regarding aspirin versus placebo, given atop a P2Y12 inhibitor:

• Greater bleeding risk with aspirin: P=0.479 for interaction
• Similar rates of combined death or hospitalization between arms: P=0.787 for interaction
• Similar rates of total death and ischemic events between arms: P=0.710 for interaction

“An antithrombotic regimen consisting of apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with Afib who have ACS, whether managed medically or with PCI [percutaneous coronary intervention], or those undergoing elective PCI than regimens that include VKAs, aspirin, or both,” Windecker concluded.

Balancing Ischemic, Bleeding Risk

For the overall cohort, Windecker’s team had previously reported a 31% reduction in bleeding risk with apixaban compared with VKA and 89% more bleeding with aspirin versus placebo.

It’s a new finding that the subgroup of Afib patients with ACS treated medically may find “an appealing therapeutic option” in a strategy consisting of oral anticoagulation with apixaban and single antiplatelet therapy with a P2Y12 inhibitor without aspirin for 6 months, according to the presenter.

AUGUSTUS had a two-by-two factorial design that tested apixaban (5 mg twice daily, unless patients met certain criteria for a lower dose) against VKA and aspirin (81 mg once daily) against placebo in a randomized fashion.

Randomization occurred a median 6 days after the index ACS or PCI, before which most patients were still receiving aspirin. All 4,614 Afib patients stayed on background P2Y12 inhibitor therapy during the whole 6 months of the study (clopidogrel [Plavix] in 93% of cases).

What cannot be identified definitively is the optimal duration of short-term aspirin given that it is given to everyone starting on day 1, Windecker acknowledged at a TCT press conference.

Presentation status was ACS treated medically for 23.9%, ACS treated with PCI for 37.3%, and elective PCI recipients with stable coronary artery disease for 38.8%. It was up to each physician’s discretion how each patient was managed.

Median age was 71 years, and 29% of the cohort were women. The average CHA₂DS₂-VASc score was 3.9 and mean HAS-BLED score was 2.5.

There were numerically fewer cases of stent thrombosis and MI with aspirin compared to placebo among PCI patients. Thus, AUGUSTUS “cannot exclude with certainty” this potential benefit of aspirin, Windecker and colleagues cautioned.

“[H]owever, any increase in ischemic events is offset by a reduction in bleeding and does not translate into clinically meaningful differences in the composite of death or ischemic events,” they continued.

“The ACS Afib population is big, about 7-10% of all the ACS patients, so it’s a big population and what’s been disappointing is that none of the trials have been big enough to really uncouple the bleeding vs ischemic issues,” said Robert Harrington, MD, of Stanford University in California and president of the American Heart Association (AHA), at the press conference.

Noting that he was on the data safety monitoring board for AUGUSTUS, Harrington said he agreed with the idea of moving from triple therapy to anticoagulation and an ADP inhibitor — “but when you’d do that is still unknown.”

Impact on Hospitalization

His group performed a separate analysis looking specifically at hospitalization rates within the AUGUSTUS population.

People randomized to apixaban rather than a VKA had a lower risk of hospitalization within 6 months of their qualifying ACS or PCI, the authors reported in a Circulation research letter:

• Overall hospitalization (22.5% vs 26.3%, HR 0.83, 95% CI 0.74-0.93)
• Cardiovascular hospitalizations (15.4% vs 18.5%, HR 0.81, 95% CI 0.71-0.94)
• Bleeding-related hospitalization (3.6% vs 5.4%, HR 0.65, 95% CI 0.50-0.86)

There was no difference in overall hospitalization and cardiovascular hospitalization between aspirin and placebo groups. However, there were more bleeding-related hospitalizations with aspirin (6.1% vs 2.9%, HR 2.11, 95% CI 1.58-2.81).

“Our findings further support the use of apixaban over warfarin, and the avoidance of aspirin to reduce bleeding, on background P2Y12 inhibitor in this high-risk patient population,” Windecker’s team said.

Nevertheless, the reliance on site-reported causes of hospitalization was a major study limitation, they cautioned.

Overall, limitations of AUGUSTUS included lack of statistical power in the subgroup analysis and allowing for open-label treatment with apixaban versus VKA.

Windecker announced that the AUGUSTUS stent thrombosis substudy will be presented at the AHA meeting in November.