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AUGUSTUS Trial - A Summary

What is the risk/benefit ratio of the association of an oral anticoagulation (OAC) with a double antiplatelet therapy (DAPT)? AUGUSTUS (presented at the ACC Congress on March, 18, 2019) brings new data.



AUGUSTUS was a prospective, multicenter, two-by-two factorial, randomized clinical trial, supported by the pharmaceutic industry, including 4614 patients with atrial fibrillation who had a recent acute coronary syndrome (ACS) and/or underwent PCI with stent, all of them on a P2Y12 inhibitor (Clopidogrel in most of the cases) with a 6 months follow up. (1)

The primary “safety” outcome was major or clinically relevant non major (CNRM) bleeding on International Society on Thrombosis and Haemostasis (ISTH) criteria. 

Secondary outcomes included death or hospitalization and a composite of ischemic events.

The protocol allowed two independent hypothesis to be investigated:

  1. Apixaban (5 mg BID or 2.5 mg BID in selected patients) is non-inferior or superior to VKA (INR to be maintained 2 to 3) for ISTH major or CRNM bleeding.
  2. Aspirin is inferior to placebo for ISTH major or CRNM bleeding in patients on oral anticoagulation (OAC)

Results

Major hypothesis

  • In the anticoagulant-regimen comparison, a bleeding event was observed in 10.5% apixaban patients, as compared with 14.7% of those receiving a vitamin K antagonist, resulting in an event rate per 100 patient-years significantly lower among patients receiving apixaban (HR 0.69; 95% [CI], 0.58 to 0.81), which met the prespecified criteria for both non inferiority (P<0.001) and superiority (P<0.001). The number needed to treat (NNT) over 6 months to avoid one ISTH major or CRNM bleeding event with apixaban instead of a vitamin K antagonist was 24.
  • In the antiplatelet-regimen comparison, a bleeding event was observed in 16.1% patients receiving aspirin, as compared with 9.0% in those receiving placebo. (HR 1.89; 95% CI, 1.59 to 2.24; P<0.001). The NNT over 6 months to cause one ISTH major or CRNM bleeding event with aspirin instead of placebo was 14.

Death / hospitalisations

Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group: 23.5% vs. 27.4% (HR 0.83; 95% CI, 0.74 to 0.93; P = 0.002), essentially driven by less hospitalisations.  No difference in death or hospitalization at 6 months was noted between patients receiving aspirin and those receiving placebo.

Ischemic events

At 6 months, there was no difference with regards to death or ischemic events (myocardial infarction, definite or probable stent thrombosis, stroke, or urgent revascularization) in the different groups: 154 events versus 163 in the apixaban as compared with the vitamin K antagonist group; 149 events versus 168 in the aspirin as compared with the placebo group.

The event rate per 100 patient-years for stroke was lower among patients receiving apixaban than among those receiving a vitamin K antagonist (hazard ratio, 0.50; 95% CI, 0.26 to 0.97)

Although the trial was not adequately powered to assess differences in individual ischemic outcomes, a greater number of coronary ischemic events among patients who did not take aspirin than among those who did was observed (stent thrombosis: 21 vs 11, myocardial infarction 84 vs 68, urgent revascularization 47 vs 37).

Conclusions

  1. In case of association to mono or double antiplatelet therapy, Apixaban, prescribed at the usual doses, causes less serious bleeding events and must be preferred to VKA in non valvular AF patients presenting acute coronary syndrome or needing a stent.
  2. In these patients, adding Aspirin to the association of OAC and Clopidogrel highly increases the absolute risk of serious bleeding events, but this has to be weighed against a potential small decrease of the absolute risk of ischemic events.                  Therefore, AUGUSTUS does not toll the knell of Aspirin in this clinical setting: patients undergoing complex or high-risk PCI, or presenting high-risk ACS, should probably benefit of its upholding “for at least several weeks or longer, depending on bleeding risk".(2)
  3. Finally, the incorporation of AUGUSTUS data to recent meta-analysis (3) will probably help for a more robust and tailored prescription of Aspirin in this kind of patients.

References

  1. Renato D. Lopes (for the AUGUSTUS Investigators)
    Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation.
    NEJM March 17, 2019 DOI: 10.1056/NEJMoa1817083
  2. Shamir R. Mehta
    Refining Antithrombotic Therapy for Atrial Fibrillation and Acute Coronary Syndromes or PCI
    NEJM March 17, 2019 DOI: 10.1056/NEJMe1902214
  3. Harsh B. Golwala and al.
    Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials
    European Heart Journal (2018) 39, 1726–1735