Aspirin Okay for Up to 30 Days in A-fib Patients After ACS or PCI: AUGUSTUS
Bleeding risk and possible ischemic benefit seem to be balanced in the first 30 days, though bleeding risk dominates after that.
Among patients with A-fib who are treated for ACS or undergo elective PCI, it’s possible that some will benefit from up to 30 days of aspirin on top of a P2Y12 inhibitor and oral anticoagulant, post hoc analysis of the AUGUSTUS trial suggests.
In that first month, it appeared that the magnitude of the increase in severe bleeding with aspirin versus placebo was counterbalanced by the size of the decrease in severe ischemic events, John Alexander, MD (Duke Clinical Research Institute, Durham, NC), reported during the virtual American College of Cardiology (ACC) 2020 Scientific Session.
Between 30 days and 6 months, however, the increase in severe bleeding with aspirin was not accompanied by any hint of ischemic benefit.
“So using aspirin up to 30 days might be reasonable, and these results should inform patient-centric, shared decision-making regarding the ideal duration of aspirin after an ACS or PCI in patients with atrial fibrillation receiving oral anticoagulation,” Alexander said.
The findings were published simultaneously online in Circulation, and the paper included a similar analysis examining the risk-benefit balance with apixaban (Eliquis; Bristol-Myers Squibb) versus warfarin. The analysis showed that “apixaban caused fewer ischemic and bleeding events than warfarin in the first 30 days after ACS and/or PCI and similar or fewer ischemic and bleeding events from 30 days to 6 months,” leading the authors to conclude that apixaban is preferred over warfarin in this setting.
Finding the Right Balance
Recent trials exploring antithrombotic therapy in patients with A-fib undergoing PCI have together shown that a dual approach using a direct oral anticoagulant (DOAC) and a P2Y12 inhibitor provides a better balance between bleeding risks and ischemic benefits compared with triple therapy that also includes aspirin. All of the trials, however, have shown that certain ischemic events, such as stent thrombosis, occur at numerically higher rates when aspirin is left off, suggesting that at least some patients might benefit from keeping aspirin on board for a little longer before switching to DOAC-based dual therapy.
The 4,614-patient AUGUSTUS trial included patients with A-fib who either had ACS that was treated medically or with PCI or were undergoing an elective PCI procedure and who were slated for 6 months of P2Y12 inhibitor therapy. They were randomized in the 2 x 2 factorial trial to apixaban or warfarin and to aspirin or placebo. The median time between ACS or PCI and randomization was 6 days, and during that time all patients received aspirin.
The main results of the trial showed that ISTH major bleeding or clinically relevant nonmajor bleeding (primary outcome) was reduced with apixaban versus warfarin and increased with aspirin versus placebo. A composite endpoint of ischemic events did not significantly differ between the aspirin and placebo arms, although aspirin was associated numerically lower rates of probable/definite stent thrombosis (0.5% vs 0.9%), MI (2.9% vs 3.6%), and urgent revascularization (1.6% vs 2.0%). A secondary analysis of the trial showed that most of the stent thrombosis occurred in the first 30 days.
Alexander pointed out that the trade-off between bleeding and ischemic risks in the context of potent antithrombotic therapy may change over time due to the front-loaded risk of ischemic events and the constant risk of bleeding.
The investigators explored that idea in the AUGUSTUS trial, in which 39% of patients underwent elective PCI, 37% underwent PCI for ACS, and 24% were treated medically for ACS. For the purposes of this post hoc analysis, the researchers came up with new composite endpoints for both bleeding and ischemic events to better match the severity of the outcomes.
The severe category included fatal, intracranial and ISTH major bleeds and—on the ischemic side—CV death, stent thrombosis, MI, and stroke. The intermediate category added bleeding hospitalizations and urgent revascularization to those respective endpoints, and the broad category additionally included clinically relevant nonmajor bleeding on one side and CV hospitalization on the other.
“I, at least, feel like what we call severe bleeding in this analysis and severe ischemic events, both of which have a range of severity within those categories, are roughly equal in severity,” Alexander said.
Within the first 30 days, severe bleeding was more frequent with aspirin versus placebo (7.5% vs 4.0%), whereas severe ischemic events were less common with aspirin (1.7% vs 2.6%). The absolute increase in bleeding (0.97%) was roughly equal in magnitude to the absolute decrease in ischemic events (0.91%).
From 30 days to 6 months, however, the balance shifted. Aspirin continued to carry a greater risk of severe bleeding, with an absolute difference of 1.25%, but it was not associated with a significant reduction in severe ischemic events (3.8% vs 4.0%).
Senior author Renato Lopes, MD, PhD (Duke Clinical Research Institute), told TCTMD that these can help refine the message regarding use of aspirin in these types of patients. “Which is, you can stop aspirin for most patients at the time of discharge, but in some patients, if you want to keep aspirin, it might reasonable to keep aspirin for 30 days,” he said.
More Research Needed on Patient Subgroups
Serving as a discussant following Alexander’s presentation, Julia Indik, MD, PhD (University of Arizona College of Medicine, Tucson), noted that because the absolute increase in bleeding and reduction in ischemic risk with aspirin versus placebo in the first 30 days are roughly equal, so are the numbers needed to harm and to treat (about 100 for each).
“Just as Dr. Alexander pointed out, it is a trade-off. It’s an equal amount of potential benefit as harm in those first 30 days,” Indik said, adding that AUGUSTUS and this analysis will be essential to consider when guidelines are ultimately updated.
“A future guideline committee’s going to think about how this data might inform a recommendation, but keep in mind that if a treatment benefit equals its risk, that’s not a class IIa or even a class IIb recommendation. That’s a class III recommendation [ie, not recommended],” she said.
On that backdrop, she asked Alexander whether there might be a patient population or time period in which the risk-benefit balance might favor aspirin use.
Alexander reiterated that all patients in AUGUSTUS received aspirin for at least some period of time before being randomized, so “we don’t have a great insight [into] whether no aspirin is acceptable from the data that we have from AUGUSTUS.”
More data, he said, is needed regarding whether there are specific patient populations that might benefit more from the addition of aspirin. “I do think there’s more work to be done in identifying particular subgroups of patients, maybe based on angiographic characteristics or other variables, where there’s a differential risk-benefit trade-off and more-tailored therapy can be used.”
Alexander JH, Wojdyla D, Vora AN, et al. The risk/benefit tradeoff of antithrombotic therapy in patients with atrial fibrillation early and late after an acute coronary syndrome or percutaneous coronary intervention: insights from AUGUSTUS. Circulation. 2020;Epub ahead of print.
- AUGUSTUS and this analysis were funded by Bristol-Myers Squibb and Pfizer.
- Alexander reports research grants from Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, the US Food and Drug Administration, the National Institutes of Health, Sanofi, and VoluMetrix; and consulting fees from Pfizer, Bristol-Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, and Zafgen.