AUGUSTUS: Apixaban Surpassed Warfarin Despite Prior Stroke or Thromboembolism

Mitchel L. Zoler

March 10, 2020

LOS ANGELES — The edge that the direct-acting oral anticoagulant apixaban (Eliquis, Bristol-Myers Squibb) has over warfarin for safely preventing ischemic events in patients with atrial fibrillation and either a recent acute coronary syndrome event or a recent percutaneous coronary intervention held up even in patients with a history of stroke, transient ischemic attack (TIA), or thromboembolic (TE) event, according to a prespecified secondary analysis of data collected in the AUGUSTUS trial.

M. Cecilia Bahit, MD

The treatment advantages of apixaban, compared with warfarin, seen in the overall AUGUSTUS results, first reported in March 2019, "were consistent" with the benefits seen in the subgroup of enrolled patients with a prior stroke, TIA, or TE, M. Cecilia Bahit, MD, said at the International Stroke Conference 2020 sponsored by the American Heart Association.

All patients in AUGUSTUS received a P2Y12 inhibitor antiplatelet drug, which was clopidogrel for more than 90% of patients. The two-by-two factorial design of AUGUSTUS also assessed the safety and efficacy of either adding or withholding aspirin from the two-drug regimen that all patients in the study received with a P2Y12 inhibitor plus an anticoagulant (apixaban or warfarin).

The most notable finding of the aspirin vs placebo analysis was that patients without a prior stroke, TIA, or TE event had a "more profound" increase in their rate of major or clinically relevant minor bleeds when also treated with aspirin, compared with patients who received aspirin and had a history of stroke, TIA, or TE event, reported Bahit, a chief of cardiology and director of clinical research at the INECO Foundation in Rosario, Argentina.

In general, the findings of the secondary analysis that took into account stroke, TIA, or TE history "confirmed" the main AUGUSTUS findings, Bahit said; an antithrombotic regimen of apixaban plus clopidogrel (or other P2Y12 inhibitor) without aspirin was superior for both efficacy and safety, compared with the alternative regimens that either substituted warfarin for apixaban or that added aspirin.

AUGUSTUS enrolled 4614 atrial fibrillation (AF) patients who either had a recent acute coronary syndrome (ACS) event or had recently undergone percutaneous coronary intervention (PCI) at any of 492 sites in 33 countries during 2015-2018. The study's primary endpoint was the incidence of major or clinically relevant minor bleeds after 6 months, which was significantly lower in the subgroups that received apixaban instead of warfarin and in patients who received placebo instead of aspirin.

The secondary endpoint of death or hospitalization after 6 months was also significantly lower in the apixaban-treated patients, compared with those on warfarin, while the aspirin and placebo subgroups showed no difference in the incidence of these events ( N Engl J Med. 2019;380[16]:1509-24).

Larry B. Goldstein, MD

The results reported by Bahit also highlighted both the high risk faced by patients with AF who also have had an ACS event or PCI, as well as a prior stroke, TIA, or TE event, noted Larry B. Goldstein, MD, professor and chairman of neurology at the University of Kentucky, Lexington.

"It's difficult, because these patients had an ACS event or PCI, and you don't want a coronary too close up, but do these patients really need a P2Y12 inhibitor plus an anticoagulant? Could these patients do as well on apixaban only? I would have liked to see that treatment arm in the study," Goldstein commented in an interview.

"These are challenging patients because they often require anticoagulation for the AFib as well as antiplatelet agents" for the recent PCI or ACS event, commented Mitchell S.V. Elkind, MD, professor of neurology at Columbia University, New York City.

"The question has always been: How many blood thinners should these patients be on? Potentially they could be on three different agents [an anticoagulant and two antiplatelet drugs], and we know that all of those drugs together pretty dramatically increase the risk of bleeding. About 15% of the patients in the overall AUGUSTUS trial had either cerebrovascular disease or systemic thromboembolism, so this was a small subgroup of the overall trial, but the overall trial was large so it's a significant number of patients who met this criteria.

"The results confirmed that even in a group of patients who may be considered at high risk because they have a prior history of cerebrovascular disease, use of apixaban instead of warfarin seemed safer, and that those patients did not need to be on aspirin as well as their other antiplatelet agent. Patients with a history of stroke, in fact, had a lower risk of bleeding than the other patients in this trial, so one could argue that they should be on an agent like apixaban as well as an antiplatelet agent like clopidogrel without addition of aspirin," Elkind said in a recorded statement.

In addition to implications for using prescription drugs like apixaban and clopidogrel, the findings also send a message about the need for very aggressive implementation of lifestyle measures that can reduce cardiovascular disease risk in these patients, added Goldstein. The AUGUSTUS outcome analyses that subdivided the study population into those with a prior stroke, TIA, or TE event — 633 patients or about 14% of the 4581 patients eligible for this analysis — and those who did not have this history showed the extremely high, incrementally elevated risk faced by patients with these prior events.

A history of stroke, TIA, or TE event linked with a jump in the 90-day rate of major or clinically relevant minor bleeds from 13% without this history to 17%, which is a 31% relative increase; it boosted the 90-day rate of death or hospitalization from 25% to 31%, a 24% relative increase; and it jacked up the rate of death or ischemic events from 6% to 9%, a 50% relative increase, Bahit reported.

These substantial increases "suggest we need to be very aggressive" in managing these high-risk patients who combine a background of AF, a prior stroke, TIA, or TE events, and a recent ACS event or PCI, Goldstein observed. In these patients, he suggested that clinicians make sure to address smoking cessation, obesity, exercise, diet, and statin use, and get each of these to an optimal level to further cut risk. If all five of these basic interventions were successfully administered to a patient, they could collectively cut the patient's event risk by about 80%, he added.

AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, the companies that jointly market apixaban. Bahit has received honoraria from Pfizer, CSL Behring, and Merck. Elkind and Goldstein have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2020: Abstract LB22. Presented February 21, 2020.

This article first appeared on MDedge.com.

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