ATLAS 2: New Role of Anticoagulant in Acute Coronary Syndrome?

This is my personal comments on the result of ATLAS ACS 2 TIMI 51 (Anti Xa Therapy to Lower cardiovascular events in addition to standard therapy in subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction 51) study which was published recently in NEJM. I was personally involved in this study as a Principal Investigator of UKM Medical Centre site.

A good study design and cautious study protocol had finally sown a prommising result in this study investigating the role of Rivaroxaban, an oral factor Xa inhibitor in patients with Acute Coronary Syndrome. Of interest, the positive result of this study came in the midst of the following background:
Relatively recent publications of the result of newer antiplatelets (thienopyridine or the like) in ACS which in general have shown superiority over existing drug clopidogrel.
Negative result (lack of benefits, higher bleeding risk) of other new oral anticoagulants namely apixaban, another oral Xa inhibitor (APPRAISE 2) and Vorapaxar (thrombin receptor antagonist or PAR1 blocker) also recently published in NEJM.
Positive result albeit to varying extent, of new oral anticoagulants versus warfarin in stroke prevention in atrial fibrillation trials – led by dabigatran(direct thrombin inhibitor) in RELY study; apixaban in ARISTOTLE study and Rivaroxaban itself in ROCKET AF study.

The study recruited over 15000 patients diagnosed with ACS – a broader group than that of TRACER since they included patients with STEMI as well. Patients were randomised to three different treatment groups receiving either placebo, 2.5mg Rivaroxaban or 5mg daily dose of Rivaroxaban (both given twice daily). The mean duration of study treatment was 13 months, and up to 31 months.

In contrast to a more liberal study protocol of TRACER ACS, this particular study differed in the following:
Patients were recruited following ‘stabilisation’ ie after undergoing their percutaneous revascularisation.
If they were to undergo PCI or CABG, the protocol strictly require cessation of study drug prior to these procedures.
Patients must not be on more than 100mg of Aspirin daily.
Doses of rivoraxaban used in the study ( 2.5mg or 5mg twice daily) was much lower than that used in the ROCKET AF study at 20mg daily. This perhaps contributed to a more favourable safety endpoint in this ACS group of patients treated with the drug.

The final analysis of the study indicated that rivaroxaban 2.5mg twice daily is superior to both 5mg rivaroxaban or placebo in terms of benefits and safety outcome. Combined results of both doses of rivaroxaban demonstrated superity over placebo in preventing primary end point events – death from CV causes, MI or stroke, however the 5mg was inferior since it did not reduce combined death from CV or any causes. Furthermore, the 2.5mg dose resulted in less bleeding events overall.

In conclusion, in patients with recent episode of acute coronary syndrome (including STEMI), rivaroxaban reduced the risk of composite end point of death from CV, MI or stroke – at the expense of increased in major bleed including intracranial bleed.

What are the implications of the results from this study? It certainly bears a promising future of closing the gap in reducing the risk in patients with recent ACS. The key thing here is ‘low dose’ anticoagulation with new anticoagulant that is anti-factor Xa inhibitor rivaroxaban (others have yet to show similar result).