Antithrombotic regime with NOAC but no aspirin most favorable for patients with AF and ACS/PCI

ACC 2019 The AUGUSTUS trial showed less bleeding and fewer hospitalizations without differences in ischemic events with apixaban and no aspirin, as compared with regimens with VKA, aspirin or both.

An Open-label, 2 x 2 Factorial, Randomized Trial to Evaluate the Safety of Apixaban versus Vitamin K Antagonist and Aspirin versus Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention: Primary Results of the AUGUSTUS Trial

Presented at ACC.19 by Renato Lopes (Durham, NC)

Finding the right treatment for patients with atrial fibrillation (AF) and a recent acute coronary syndrome (ACS) and/or who underwent percutaneous coronary intervention (PCI) is complex. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been shown to reduce heart attacks and stent thrombosis in patients with ACS, but not stroke associated with AF. Moreover, combining an anticoagulant to prevent stroke with DAPT increases the risk of potentially life-threatening bleeding.

Most AF treatment trials have excluded patients with ACS, while most ACS treatment trials have excluded patients with AF.

The AUGUSTUS trial aimed to fill this gap in the evidence, by evaluating whether apixaban is more effective than warfarin for reducing episodes of bleeding in this group of patients and whether these patients fare better if they take aspirin plus a P2Y12 inhibitor, in addition to an anticoagulant.

The AUGUSTUS trial was set up as a 2x2 trial that randomized 4600 patients with AF and an indication for oral anticoagulation (OAC) and a recent ACS or PCI and planned P2Y12 inhibitor treatment for at least 6 months. In a first randomization step, patients were allocated (open-label) to either apixaban 5 mg BID (or 2.5 mg BID in selected patients) or vitamin K antagonists (VKA, INR: 2-3), and in a second randomization step to aspirin or placebo (double blind). The primary outcome was ISTH major/CRNM bleeding, and secondary outcomes were death/hospitalization and death/ischemic events.

Main results

• Major/CRNM bleeding was observed less often in patients randomized to apixaban as compared with VKA (10.5% vs. 14.7%, HR: 0.69, 95%CI: 0.58-0.81, P<0.001 for non-inferiority and superiority, absolute risk reduction [ARR]: 4.2%, NNT: 24). A higher bleeding rate was seen with aspirin as compared with placebo (HR: 1.89, 95%CI: 1.59-2.24, P<0.001, ARI=7.1%, NNH=14).
• Taken together, the highest rate of bleeding was seen in those on VKA + aspirin (18.7%) and the lowest rate in those on apixaban + placebo (7.3%). Comparison of these groups yielded an ARR of 11.4% and an NNT of 9.
• Death/hospitalization was observed less often in patients on apixaban vs. VKA (23.5% vs. 27.4%, HR: 0.83, 95%CI: 0.74-0.93, P=0.002, ARR: 3.9%, NNT: 26). Aspirin and placebo did not significantly differ (HR: 1.08, 95%CI: 0.96-1.21, P=0.20).
• The highest rate of death/hospitalization was seen in those on VKA + aspirin (27.5%) and the lowest in those on apixaban + placebo (22.0%). Comparison of these groups yielded an ARR of 5.5% and an NNT of 18.
• Regarding ischemic outcomes, stroke was halved upon treatment with apixaban vs. VKA (0.6 vs. 1.1%, HR: 0.50, 95%CI: 0.26-0.97). Hospitalization was also lower with apixaban (HR: 0.83, 95%CI: 0.74-0.93). Other ischemic outcomes did not differ significantly between treatment arms.

Conclusion

Dr. Lopes concluded that in patients with AF and a recent ACS or PCI, who are treated with a P2Y12 inhibitor, an antithrombotic regimen that includes apixaban, without aspirin, results in less bleeding and fewer hospitalizations without significant differences in ischemic events than regimens based on VKA, aspirin, or both.

Discussion

Discussant Dhanunjaya Lakkireddy (Columbia, MO, USA) called these results ‘perhaps the last nail in the coffin for aspirin and warfarin’. These results were to be expected, as they are in line with PIONEER and RE-DUAL. It is very reassuring that the ischemic events did not differ significantly between treatments.

Because guidelines will not be update very soon, Sana Al-Khatib, who chaired the press conference, asked whether the presenter had any guidance for the clinic at this point in time. He answered that, for the majority of patients, a lesson is learnt that has now been confirmed by the AUGUSTUS results: less is more. For most patients, a NOAC plus a P2Y12 inhibitor is enough. The panel agreed though that these results on use of apixaban probably cannot just be extrapolated to other NOAC’s. On the other hand, the aspirin results seem fair to extrapolate to the combination of other anticoagulation regimes.

It should be noted, that there was no true no-aspirin condition, as patients got aspirin at the time of PCI. It remains to be established whether some patients should still receive aspirin. A numerically higher rate of ischemic events was seen; it should be looked into when these events of stent thrombosis occur, and when the bleeding occurs. Are these early or late events? For the moment, it may be wise to tailor treatment based on ischemic vs. bleeding risk.

A question was asked about the low time in therapeutic range (TTR: in the low 50% range), whether the results would have been less favorable for apixaban if the TTR had been better? The presenter answered that most patients did not receive OAC therapy and this TTR is often seen in those starting on OAC. Time out of therapeutic range often means underdosing. That means that if TTR was better, more bleeding would be expected in the VKA arm.

- Our coverage of ACC.19 is based on the information provided during the congress –

The AUGUSTUS results were published simultaneously in NEJM