AUGUSTUS: Apixaban Plus P2Y12 Inhibitor the Best Combo in A-fib Patients With ACS or Undergoing PCI

Aspirin increased bleeding with no ischemic benefit, but a trend toward more stent thrombosis with placebo warrants further study, researcher says.

AUGUSTUS: Apixaban Plus P2Y12 Inhibitor the Best Combo in A-fib Patients With ACS or Undergoing PCI

NEW ORLEANS, LA (UPDATED)—New findings released today solidify the stance that in A-fib patients with ACS or undergoing PCI, aspirin increases bleeding risk without reducing ischemic events. Additionally, use of the non-vitamin K antagonist oral anticoagulant (NOAC) apixaban can reduce the risks of both bleeding and hospitalization compared with a vitamin K antagonist, the 4,614-patient AUGUSTUS randomized trial shows.

Yet even with the newer anticoagulant, the incidence of ischemic events held steady, Renato Lopes, MD, PhD (Duke Clinical Research Institute, Durham, NC), reported here today at the American College of Cardiology (ACC) 2019 Scientific Session.

Beyond its size, Lopes told TCTMD, the AUGUSTUS trial has several unique assets: it included ACS patients treated medically (without PCI) and had a 2x2 factorial design that looked independently at two questions. Aspirin as an component in triple therapy has been on the decline since the WOEST trial, he said, but that was much smaller, with 573 patients in two countries, used warfarin as the anticoagulant, and was open-label. “When you look at the totality of data now, I think in this clinical setting of atrial fibrillation and ACS or PCI, less might be more. I think that’s the key message,” Lopes emphasized.

“In other words,” he continued, “a NOAC such as apixaban that has a better safety profile with clopidogrel, [which was] the main P2Y12 inhibitor used, is probably enough for most patients, because it will be the safest regimen and you don’t pay a high cost for ischemic endpoints.”

Usman Baber, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who did not take part in AUGUSTUS, said that the trial “adds another piece of evidence and it’s largely consistent with the paradigm that’s evolving, namely that in the vast majority of patients who have a need for both dual antiplatelet therapy and anticoagulation, the default strategy should be the combination of a novel oral anticoagulant and clopidogrel.”

There are, however, some useful insights, Baber said. “To me, it was interesting to see that . . . the withdrawal of aspirin produced a larger reduction in absolute terms than did the comparison between apixaban and vitamin K antagonists. We did not know that before.”

In combination, dropping aspirin and adding a NOAC seems to have a synergistic effect in lowering bleeding, he observed, adding, “Now we can actually quantify where that benefit comes from.”

The AUGUSTUS findings were simultaneously published online in the New England Journal of Medicine.

Aspirin at a Disadvantage

AUGUSTUS enrolled 4,614 A-fib patients in 33 countries who had undergone PCI or experienced ACS and were treated with a P2Y12 inhibitor. The researchers randomized patients to receive apixaban (Eliquis; Bristol-Myers Squibb) or a vitamin K antagonist and, in a double-blind comparison, to take aspirin or a placebo for 6 months.

When you look at the totality of data now, I think in this clinical setting of atrial fibrillation and ACS or PCI, less might be more. I think that’s the key message. Renato Lopes

Major or clinically relevant nonmajor bleeding, the primary outcome, was less common with apixaban than with a vitamin K antagonist (10.5% vs 14.7%; HR 0.69; 95% CI 0.58-0.81). Aspirin use resulted in a higher bleeding rate compared with placebo (16.1% vs 9.0%; HR 1.89; 95% CI 1.59-2.24).

Compared with the patients assigned to a vitamin K antagonist, those in the apixaban group were less likely to die or be hospitalized (23.5% vs 27.4%; HR 0.83; 95% CI 0.74-0.93). There was no difference in ischemic events (a composite of stroke, MI, definite/probable stent thrombosis, or urgent revascularization) between these two study arms. Yet the stroke rate was significantly lower with apixaban (0.6% vs 1.1%), which Lopes described as “very reassuring, because we know that apixaban 5 mg is the approved dose for stroke prevention. Seeing the same direction [indicates] that we chose the right dose.”

For the aspirin/placebo comparison, the rate of death or rehospitalization and the rate of ischemic events were both similar between groups.

More Analyses Forthcoming

In an accompanying editorial, Shamir Mehta, MD (McMaster University and Hamilton Health Sciences, Canada), agrees with the message to move away from vitamin K antagonists. “Given the totality of data, a direct oral anticoagulant should now routinely be recommended for patients with atrial fibrillation who have an acute coronary syndrome or undergo PCI,” he says.

However, Mehta also stresses that the “findings from this trial do not necessarily provide reassuring evidence that early discontinuation of aspirin therapy . . . is warranted in all patients.”

He points to a trend in more coronary thrombotic events (MI, urgent revascularization, and stent thrombosis) with placebo versus aspirin. Definite or probable stent thrombosis in particular was doubled in the placebo group (0.5% vs 0.9%), though the difference was not significant.

Additionally, Mehta notes, “the highest-risk period for coronary ischemic events is in the days and weeks after the index event. Patients were not enrolled in this trial until a mean of 1 week (and up to 2 weeks) after the index event or PCI, a period during which patients were receiving aspirin. Thus, the effect of very early withdrawal of aspirin therapy still remains undertain, and caution is advised during this time period.”

Baber said that, seeing as how prior studies have also seen an uptick in ischemic risk without aspirin, “this should prompt some degree of caution from clinicians to think perhaps very precisely about balancing [risks and benefits].” Some patients, such as those with more complex PCI and low bleeding risk, may need triple therapy for a few weeks or months to mitigate the risk of early thrombotic events, he suggested, noting that this is consistent with what’s advised by a recent consensus document. Others might benefit from a more potent P2Y12 inhibitor instead of clopidogrel.

Speaking with TCTMD, Lopes agreed that it’s important to look further at whether there are patients who might need to go on aspirin for a short time. Due to the numerically higher rate of stent thrombosis in the placebo group, he said, the researchers are now investigating the timing of these events.

“If they are early on, then we’re going to start trying to assess how that was related to stopping aspirin and see if . . . patients who have the highest risk of stent thrombosis maybe could potentially benefit from a few more weeks of aspirin. We don’t know the answer yet, but this is one of our top priorities now,” Lopes said.

After Lopes’ presentation in the main arena, panelist Freek W.A. Verheugt, MD (Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands), asked if the AUGUSTUS investigators had examined whether, among ACS patients, there was any variation based upon whether they did or didn’t undergo PCI, especially in the aspirin comparison.

Lopes replied that their prespecified subgroup analyses had not revealed any differential treatment effect among ACS patients who got PCI, ACS patients managed medically, and elective-PCI patients. A paper with more details on this topic is forthcoming, he added.

A closer look at this issue will indeed be useful, Vergheut said, since “worldwide there are still very many patients with ACS who do not undergo an intervention.”

  • Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;Epub ahead of print.

  • Mehta SR. Refining antithrombotic therapy for atrial fibrillation and acute coronary syndromes or PCI. N Engl J Med. 2019;Epub ahead of print.

  • Baber reports receiving speaking fees and honoraria from AstraZeneca and Boston Scientific.

  • AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer.
  • Lopes reports grants and personal fees from Bristol-Myers Squibb and Pfizer during the conduct of the study as well as personal fees from Boehringer Ingelheim and Bayer AG and grants from Amgen, GlaxoSmithKline, Medtronic, and Sanofi Aventis outside the submitted work.
  • Mehta reports grants from AstraZeneca, Boston Scientific, and Boeringher Ingelheim outside the submitted work.