AUGUSTUS Backs Apixaban 'Double Therapy' in Most AF Post-ACS, PCI

UPDATED MARCH 18, 2019 // NEW ORLEANS — The risk-vs-benefit quandary of antithrombotic therapy in patients with both atrial fibrillation (AF) and an indication for dual-antiplatelet therapy (DAPT) may become a little less daunting given results from the randomized AUGUSTUS trial.

In the study, which entered people with both AF and recent acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), all of whom went on a P2Y12 inhibitor, such as clopidogrel, the risks of major bleeding and of death or hospitalization were both lower on the novel oral anticoagulant (NOAC) apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) than on a vitamin K antagonist (VKA), such as warfarin.

In another finding based on a separate randomization in the trial, which had a 2 × 2 factorial design, DAPT seemed unnecessary and even riskier for major bleeding compared to a P2Y12 inhibitor alone in most patients with AF and recent ACS or PCI.

Putting the two independent findings together, treatment with apixaban on top of a P2Y12 inhibitor seemed to pose the lowest risk for bleeding and clinical events, while neither comparison showed an effect, either way, on risk for ischemic events, observed AUGUSTUS principal investigator Renato D. Lopes, MD, MHS, PhD, from Duke Clinical Research Institute (DCRI), Durham, North Carolina, in an interview.

But the trial doesn't say such "double therapy" is necessarily the best option for all patients with AF and recent ACS or PCI, he cautioned; the trial's design wasn't set up to make such a conclusion.

Also, the findings didn't necessarily rule out a role for triple therapy, he pointed out for theheart.org | Medscape Cardiology. With a P2Y12 inhibitor on board, there were substantially less major bleeding and fewer clinical events with apixaban plus aspirin than with VKA plus aspirin.

"That's another important message from the trial," Lopes said. "If you want to use triple therapy because you feel aspirin is important — say, because your patient is very high risk for stent thrombosis, or for ischemic events — the study shows that you're better off using aspirin with apixaban than aspirin with VKA."

Lopes presented the AUGUSTUS trial here at the American College of Cardiology 68th Annual Scientific Session 2019 (ACC.19) at about the time of its online publication in the New England Journal of Medicine.

Triple vs Double Therapy

At a media briefing following his presentation, Lopes further clarified what the study showed about selective use of triple therapy. Overall in the study, for example, the stent thrombosis rate was less than 1%. But numerically, he noted, its prevalence was lower when aspirin compared with placebo was on board — although the trial was not powered to show that conclusively.

Still, some clinicians may still feel aspirin is warranted with a NOAC and clopidogrel for protection against stent thrombosis.

But based on numbers from AUGUSTUS, Lopes said, "If you want to prevent 1 stent thrombosis, that would mean causing 15 bleeds that are major or clinically relevant nonmajor. I think in some situations you might want to pay that price. But I think routinely, and for most patients, a regimen that includes a P2Y12 inhibitor and a NOAC, in this case apixaban, would be enough."

The AUGUSTUS findings are "perhaps the last nail in the coffin for aspirin-warfarin," said Dhanunjaya R. Lakkireddy, MD, University of Kansas, Kansas City, Kansas, at the press conference.

They are very much in line with those from the NOAC trials PIONEER-AF PCI, which tested triple therapy with rivaroxaban (Xarelto, Bayer/Janssen), and RE-DUAL PCI, which looked at double therapy including dabigatran (Pradaxa, Boehringer Ingelheim), in the setting of AF and PCI, he said.

The AUGUSTUS trial is "reassuring" in suggesting that "you can actually get away with doing PCI using a NOAC like apixaban, along with a non–aspirin-type antiplatelet therapy," without aspirin," said Lakkireddy, who was not involved in AUGUSTUS.

Still, "it is clear that a one-size-fits-all policy is unlikely to apply in these patients," writes Shamir R. Mehta, MD, McMaster University, Hamilton, Ontario, Canada, in an accompanying editorial.

"Given these data, clinical decision making should continue to be based on a balanced assessment of three competing risks: cardioembolic stroke, coronary ischemic events, and bleeding" for each individual patient, he says.

For example, in patients at low thrombotic risk or with a high risk of bleeding, "early omission of aspirin therapy and treatment with a direct oral anticoagulant plus clopidogrel is entirely warranted."

But for those undergoing complex or high-risk PCI or presenting with high-risk ACS, "aspirin should probably not be routinely omitted for at least several weeks or longer, depending on bleeding risk," Mehta writes.

During the discussion period after the Lopes presentation of the trial at ACC.19, panelist Freek W.A. Verheugt, MD, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands, asked whether outcomes differed by the prespecified antiplatelet-indication subgroups, that is, in patients with AF who have PCI-treated ACS, ACS treated with meds only, or elective PCI in stable disease.

Lopes said a detailed subgroup analysis is yet to come, but "we did not find any differential treatment effect among these three groups," whether the treatment was an anticoagulant or antiplatelet.As for VKAs, such as warfarin, they are "pretty clearly now associated with worse outcomes. That was seen in PIONEER-AF PCI and RE-DUAL PCI as well," said AUGUSTUS senior author John H. Alexander, MD, MHS, from DCRI, at the media briefing.

"I think AUGUSTUS has certainly convinced me that there's no role for VKA in patients who need antiplatelet therapy and have Afib."

2 × 2 Randomization

AUGUSTUS entered 4614 patients at centers in North America, Europe, Asia, and South America who had AF as an indication for chronic oral anticoagulation and recent ACS or stent-based PCI. More than 90% were started on clopidogrel and the remainder, on other P2Y12 inhibitors.

Patients were randomly assigned to go on either open-label apixaban (at the established dosage for nonvalvular AF) or a VKA (2306 and 2308 patients, respectively), and in a separate and double-blind randomization, to receive aspirin at 81 mg/day or its placebo (2307 and 2307 patients, respectively). They were followed for 6 months.

In the apixaban vs VKA comparison, the adjusted hazard ratio (HR) for the primary endpoint, major or clinically relevant nonmajor bleeding, was 0.69 (95% CI, 0.58 - 0.81; P < .001 for both noninferiority and superiority), Lopes and colleagues report.

For aspirin vs placebo, the HR for the same endpoint was 1.89 (95% CI, 1.59 - 2.24; P < .001).

The primary endpoint event rate per 100 patient-years was highest with VKA and aspirin (49.1) followed by apixaban and aspirin (33.6), VKA and placebo (26.7), and apixaban and placebo (16.8).

For the secondary endpoint of death or hospitalization, the HR for apixaban vs VKA was 0.83 (95% CI, 0.74 - 0.93; P = .002); for aspirin vs placebo, it was nonsignificant at 1.08 (95% CI, 0.96 - 1.21).

And for the secondary endpoint of death or ischemic events (stroke, myocardial infarction, definite or probable stent thrombosis, or urgent revascularization), the HR was nonsignificantly reduced for apixaban vs VKA at 0.93 (95% CI, 0.75 - 1.16) and for aspirin vs placebo at 0.89 (95% CI, 0.71 - 1.11).

Bleeding in the primary endpoint was prospectively defined according to International Society on Thrombosis and Haemostasis (ISTH) criteria. But Lopes said bleeding outcomes across the trial were "consistent and robust" whether they were defined by ISTH or the alternative GUSTO or TIMI criteria.

Given that at least three NOACs have bested VKA for bleeding in the setting of AF and PCI, clinicians may be temped to apply the AUGUSTUS results using apixaban to other factor Xa inhibitors or dabigatran.

However, "I think it would be a mistake to extrapolate the results of AUGUSTUS with apixaban to other NOACs," Alexander said.

"I certainly wouldn't do that," agreed Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, at the media briefing.

"Clearly, if you look at the randomized clinical trials of these different agents, you'll see that the profiles of these medications were quite different in terms of not just the patient characteristics but also the outcomes of these patients in terms of bleeding and other endpoints," said Al-Khatib, who isn't associated with AUGUSTUS.

On the other hand, Alexander added, "I think it is fair to take the aspirin comparison and extrapolate it to other settings with other anticoagulants."

For example, in patients like those in the current trial, "If you were using rivaroxaban and you dropped aspirin from the regimen, I would expect a similar reduction in bleeding as we saw in AUGUSTUS."

AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer, from which Lopes discloses receiving grants and personal fees during the conduct of the trial. Lopes also discloses receiving personal fees from Boehringer Ingelheim and Bayer AG and grants from Amgen, GlaxoSmithKline, Medtronic, and Sanofi Aventis. Disclosures for the other authors are available at the journal website. Mehta discloses receiving grants from AstraZeneca, Boston Scientific, and Boehringer Ingelheim.

American College of Cardiology 68th Annual Scientific Session 2019 (ACC.19). Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials 405-08. Presented March 17, 2018.

N Engl J Med. Published online March 17, 2019. Full text, Editorial

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