Findings hammer a nail in the coffin for warfarin plus aspirin
When patients with atrial fibrillation have an acute coronary syndrome event or undergo percutaneous coronary intervention, their window of opportunity for benefiting from a triple antithrombotic regimen was, at best, about 30 days, according to a post hoc analysis of AUGUSTUS, a multicenter, randomized trial with more than 4,600 patients.
Dr. John H. Alexander
Beyond 30 days out to 180 days, the incremental benefit from reduced ischemic events fell to essentially zero, giving it a clear back seat to the ongoing, increased bleeding risk from adding a third antithrombotic drug.
Patients randomized to receive aspirin in addition to an anticoagulant, either apixaban or a vitamin K antagonist such as warfarin, and a P2Y12 inhibitor such as clopidogrel “for up to approximately 30 days” had a roughly similar decrease in severe ischemic events and increase in severe bleeding events, suggesting that even acutely the overall impact of adding aspirin on top of the other two antithrombotics was a wash, John H. Alexander, MD, said in a presentation of research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
Using aspirin as a third antithrombotic in patients with atrial fibrillation (AFib) who have also recently had either an acute coronary syndrome event (ACS) or underwent percutaneous coronary intervention (PCI), “may be reasonable,” for selected patients, but is a decision that requires careful individualization, cautioned Dr. Alexander, professor of medicine and director of Cardiovascular Research at the Duke Clinical Research Institute of Duke University, Durham, N.C.
“This is a superb secondary analysis looking at the time course of potential benefit and harm with aspirin, and they found that aspirin was beneficial only in the first 30 days. After 30 days, it’s startling and remarkable that the ischemic event curves were completely on top of each other,” commented Julia H. Indik, MD, a cardiac electrophysiologist at Banner–University Medical Center Tuscon and designated discussant for the report. “This substudy will be essential for updating the guidelines,” she predicted. “When a treatment’s benefit equals its risks,” which happened when aspirin was part of the regimen during the first 30 days, “then it’s not even a class IIb recommendation; it’s class III,” the classification used by the ACC and collaborating groups to identify treatments where net benefit and net risk are similar and hence the treatment is considered not recommended.
A key element in the analysis Dr. Alexander presented was to define a spectrum of clinical events as representing broad, intermediate, or severe ischemic or bleeding events. The severe category for bleeding events included fatal, intracranial, and any bleed rated as major by the International Society on Thrombosis and Haemostasis (ISTH) criteria, while the broad bleeding definition included all of these plus bleeds that directly resulted in hospitalization and clinically relevant nonmajor bleeds. For ischemic events, the severe group consisted of cardiovascular death, MI, stent thrombosis, and ischemic stroke, while the broad category also tallied urgent revascularizations and cardiovascular hospitalizations.
“I believe the severe bleeds and severe ischemic events we identified are roughly equal in severity,” Dr. Alexander noted. “Where I think we need more analysis is which patients have more bleeding risk and which have more ischemia risk. We need a more tailored approach to identify patient subgroups, perhaps based on angiographic characteristics, or something else,” that modifies the trade-off that, on a population level, seems very evenly balanced.
Applying this approach to scoring the severity of adverse outcomes, Dr. Alexander reported that, during the first 30 days on treatment, patients on aspirin had a net absolute gain of 1.0% in severe bleeding events, compared with placebo, and a 3.4% gain in broad bleeds, while showing a 0.9% drop in severe ischemic events but no between-group difference in the rate of broadly defined ischemic events. During days 31-180, the addition of aspirin resulted in virtually no reductions in ischemic events regardless of whether they were severe, intermediate, or broad, but adding aspirin continued to produce an excess of bleeding episodes in all three categories. The results also appeared in an article published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046534).
“We did not see a time window when the ischemia risk was greater than the bleeding risk,” Dr. Alexander noted, and he also highlighted that the one option the analysis could not explore is never giving these patients any aspirin. “Patients received aspirin for some number of days before randomization,” a median of 6 days from the time of their ACS or PCI event until randomization, “so we don’t have great insight into whether no aspirin” is an reasonable option.
The AUGUSTUS trial randomized 4,614 patients with AFib and a recent ACS or PCI event at any of 492 sites in 33 countries during 2015-2018. The study’s primary endpoint was the rate of major or clinically relevant nonmajor bleeding by the ISTH criteria during 6 months on treatment, while composites of death or hospitalization, and death plus ischemic events served as secondary outcomes. All patients received an antiplatelet P2Y12 inhibitor, with 93% of patients receiving clopidogrel, and were randomized in a 2 x 2 factorial design to one of four regimens: either apixaban or a vitamin K antagonist (such as warfarin), and to aspirin or placebo. The study’s primary findings showed that using apixaban instead of a vitamin K antagonist significantly reduced bleeding events as well as the rate of death or hospitalization, but the rate of death and ischemic events was similar in the two arms. The primary AUGUSTUS finding for the aspirin versus placebo randomization was that overall throughout the study ischemic events were balanced in the these two treatment arms while aspirin boosted bleeding (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
AUGUSTUS was sponsored by Bristol-Myers Squibb and Pfizer, the companies that market apixaban. Dr. Alexander has been a consultant to and received research funding from Bristol-Myers Squibb and Pfizer; has been a consultant to AbbVie, Bayer, CryoLife, CSL Behring, Novo Nordisk, Portola, Quantum Genomics, XaTek, and Zafgen; and has received research funding from Boehringer Ingelheim, CryoLife, CSL Behring, GlaxoSmithKline, and XaTek. Dr. Indik had no disclosures.
SOURCE: Alexander JH et al. ACC 2020, Abstract 409-08.