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AUGUSTUS: Dual therapy with apixaban, P2Y12 inhibitor safe in Afib patients post-ACS or PCI
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NEW ORLEANS — New data from the AUGUSTUS trial provide insight on the appropriate antithrombotic regimen after ACS or PCI in patients with atrial fibrillation.
An antithrombotic regimen that includes a P2Y12 inhibitor and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), without aspirin, resulted in less bleeding and fewer hospitalizations, with no difference in ischemic events compared with other regimens that included a vitamin K antagonist, aspirin or both in this patient population.
The 2x2 factorial randomized controlled trial enrolled 4,614 patients with AF from 33 countries who had ACS or had undergone PCI. Patients were randomly assigned within 14 days of having an ACS or undergoing PCI to treatment with apixaban 5 mg twice daily or 2.5 mg twice daily based on dose-reduction criteria or warfarin, on top of planned P2Y12 inhibitor therapy, and then also low-dose aspirin 81 mg once daily or matching placebo for 6 months. Choice of P2Y12 inhibitor was left to the treating physician; clopidogrel was used in 92.6% of patients.
On the basis of the findings in this trial, “I think that routinely and for most patients a regimen that includes a P2Y12 inhibitor and a novel oral anticoagulant — in this case, apixaban — would be enough” to achieve the best net clinical benefit between bleeding and ischemic events for these high group of patients, Renato D. Lopes, MD, MHS, PhD, professor of medicine in the division of cardiology at Duke University Medical Center, said during a press conference.
Reduced bleeding
Patients who received apixaban had a 31% reduction in risk for major or clinically relevant nonmajor bleeding vs. those who received warfarin (10.5% vs. 14.7%; HR = 0.69; 95% CI, 0.58-0.81; P < .001 for both noninferiority and superiority). Bleeding risk was reduced by 47% among patients who received placebo vs. aspirin (HR = 1.89; 95% CI, 1.59-2.24; P < .001).
Putting the results together, Lopes said, the highest rate of bleeding occurred in patients who were treated with clopidogrel, warfarin and aspirin (18.5%) and the lowest rate was in those treated with clopidogrel, apixaban and placebo (7.3%).
Other findings
AUGUSTUS also looked at secondary outcomes including death or hospitalization and a composite of ischemic events, including MI, definite/probable stent thrombosis, stroke or urgent revascularization.
Use of apixaban reduced the rate of death or hospitalization by 17% (23.5% vs. 27.4%; HR = 0.83; 95% CI, 0.74-0.93; P = .002). This was primarily driven by a reduction in hospitalization, Lopes said. With aspirin vs. placebo, the researchers observed no significant difference in this outcome.
Again, putting the results together, the highest rate of death or hospitalization occurred in patients who were treated with clopidogrel, warfarin and aspirin (27.5%) and the lowest rate was in those treated with clopidogrel, apixaban and placebo (22%).
The treatment groups did not differ in ischemic events, except for a 50% lower risk for stroke with apixaban compared with warfarin.
The researchers noted, however, a greater number of coronary ischemic events in patients who did not receive aspirin. However, they cautioned in the NEJM study that “event rates were low and the trial was not adequately powered to assess differences in individual ischemic outcomes.
“Although this analysis should be considered exploratory, similar trials have shown a similar pattern of numerically more coronary ischemic events when aspirin was omitted. Thus, when clinicians consider aspirin as a component of antithrombotic therapy after PCI in patients with atrial fibrillation, a potential small absolute decrease in the risk of coronary ischemic events needs to be weighed against a larger absolute increase in the risk of clinically significant bleeding,” they wrote in NEJM.
In other results, the median age of AUGUSTUS participants was 71 years and 29% were women. Among those who underwent randomization, 37.3% had ACS and underwent PCI, 24% had medically managed ACS and nearly 39% underwent elective PCI. In the anticoagulation group, 12.7% of patients stopped apixaban and 13.8% stopped warfarin before the study concluded. In the antiplatelet group, 17% stopped aspirin and nearly 15% stopped placebo.
‘Less is more’
AUGUSTUS evaluated a high-risk population. It is estimated that 5% to 8% of patients undergoing PCI have AF, which complicates the choice of antithrombotic therapy after PCI, according to the researchers.
“For the majority of patients, if you look at the totality of data, one lesson learned that is now confirmed by AUGUSTUS is that less is more. ... If we use a P2Y12 inhibitor with one of the NOACS at the right dose for stroke prevention in atrial fibrillation — in this case, apixaban 5 mg twice daily — you have the safest strategy and you don’t seem to pay a high cost on ischemic events,” Lopes said during the press conference. – by Katie Kalvaitis, with additional reporting by Erik Swain
References:
Lopes RD. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
Lopes RD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1817083.
Disclosures: AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer. Lopes reports he received an institutional research grant from Bristol-Myers Squibb/Pfizer and received personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer.
Perspective
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Arnold Seto, MD, MPA
We know that 10% of patients who receive PCI also have AF, but have limited data on the safety of dual- and triple-therapy regimens. Too often physicians merely ‘add-on’ additional antithrombotic therapies — either DAPT or anticoagulation — without sufficient thought to the safety of multiple therapies, and yet we know that triple therapy with aspirin, a P2Y12 antagonist and oral anticoagulant is associated with a high 4% to 16% (average 5%) major bleeding rate.
Part of the AUGUSTUS trial results largely mirror the PIONEER-AF-PCI, RE-DUAL PCI and WOEST results which suggested that dropping the aspirin and leaving patients on an anticoagulant and P2Y12 inhibitor was associated with a reduced risk for bleeding. The other part of the trial, and what was most surprising, was the magnitude of the difference in bleeding between the vitamin K antagonist and apixaban groups.
None of these trials are powered for efficacy, however, so there will always be a question in this regard.
I think the AUGUSTUS results reinforce the conclusions of the AF guidelines, which favor a direct oral anticoagulant over a vitamin K antagonist for anticoagulation. Due to the drugs still being newer and more costly than warfarin, pharmacy and insurance restrictions have slowed the uptake of direct oral anticoagulants, but I think the additional data and guidelines will continue to force change for the benefit of patients.
For AF patients receiving a PCI, I think AUGUSTUS reaffirms that triple therapy is unnecessary for many patients, and de-escalation of therapy can occur possibly as early as 14 days following PCI.
With the newer P2Y12 antagonists ticagrelor (Brilinta, AstraZeneca) and prasugrel (Effient, Daiichi Sankyo/Eli Lilly) showing superiority to clopidogrel in ACS, future trials would ideally compare each P2Y12 antagonist in the setting of a direct oral anticoagulant, to see if the risk/benefit equation of efficacy/risk would still favor ticagrelor and prasugrel. I believe it would, however, the patient’s bleeding risk would need to be taken in to account.
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Roxana Mehran, MD
This was the largest trial in patients who require an oral anticoagulant and present with ACS or have a need for PCI. Because of the 2x2 factorial design, the trial was able to show that apixaban was superior in reduction in bleeding events compared with vitamin K antagonists and aspirin withdrawal in these patients with AF undergoing PCI who require another antiplatelet regimen plus an oral anticoagulant will reduce bleeding by 90%. That was an incredible finding.
The caveat is that I still believe one size does not fit all. The trial was not powered for the important rare ischemic events that may occur in this population. I don’t think we can say an oral anticoagulant plus a P2Y12 inhibitor without aspirin is the optimal therapy for 100% of these patients, but we can for a large majority of them, which is a giant leap forward.
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Dhanunjaya Lakkireddy, MD, FACC
This is a very nicely done study. My impression of this is this is perhaps the last nail in the coffin for aspirin and warfarin going forward. This, as a concept, was really not surprising at all because these results are pretty much expected and are very much in line with the PIONEER-AF and RE-DUAL PCI studies, which have clearly proven the advantages of a DOAC or NOAC, and this study is exactly in line with that.
It is very reassuring to see that the ischemic events were not significantly different and that you can do a PCI using a NOAC like apixaban along with a nonaspirin-type antiplatelet therapy and can get away without having to use the aspirin. This is fantastic. It again clearly shows the point that the shotgun approach of multiple targets for warfarin is really not going to be that helpful. I clearly see that as the cost of these drugs continues to come down, the adaptation and usage of NOACs is associated with a significant improvement in clinical outcomes.
Executive Medical Director
The Kansas City Heart Rhythm Insitute and Research Foundation
HCA Midwest Healthcare
Professor of Medicine, University of Missouri Columbia
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