Deja vu in ATLAS ACS 2: rivaroxaban in acute coronary syndromes

Another major trial that emerged out of the 2011 American Heart Association meeting last month was ATLAS ACS 2 [1], which evaluated the addition of rivaroxaban (Xarelto^®) to dual antiplatelet therapy in patients with acute coronary syndromes (ACS).  A reduction in major cardiovascular events was demonstrated in the group randomized to rivaroxaban therapy, but this benefit was accompanied by an increase in major nonfatal bleeding.

The rationale behind ATLAS ACS 2 is similar to WARIS II [2], a study conducted in 2002 which randomized patients to aspirin, warfarin, or both following an acute myocardial infarction (MI). The study demonstrated that warfarin given alone or in combination with aspirin reduced major cardiovascular events (largely driven by reductions in reinfarctions and thromboembolic strokes) but was associated with an increase in major nonfatal bleeding.  However, the practice never really caught on. First, the addition of warfarin seemed impractical and inconvenient for the majority of patients who presented following an MI.  Secondly, as the results of WARIS II were being finalized, the CURE trial was published [3], paving the way for dual antiplatelet therapy as the new standard of care in patients with ACS.  Given the follow-up and monitoring required for long-term warfarin therapy, the addition of clopidogrel to aspirin seemed like a more attractive strategy for reducing major cardiovascular events following ACS.  Since that time, no robust randomized prospective trials have specifically investigated the addition of warfarin to dual antiplatelet therapy for the purpose of improving outcomes in ACS, so the practice was largely abandoned before it ever began.

Given the complex thrombotic risk associated with ACS, the addition of rivaroxban was expected to provide a similar benefit as warfarin in WARIS II, but without the cumbersome monitoring and follow-up required (and perhaps a lower incidence of certain types of bleeding) -- but given the evolution of antiplatelet therapy, is ATLAS ACS 2 simply a case of deja vu?

In ATLAS ACS 2, rivaroxaban was added to dual antiplatelet therapy comprised of aspirin and clopidogrel (and in a few instances, ticlopidine). However, some would argue that we have entered an era where clopidogrel will be gradually phased out in favor of the newer antiplatelet agents prasugrel (Effient^®) and ticagrelor (Brillinta^®) (or, at the very least, its use will be primarily reserved for the minority of patients who are not candidates for other therapies).  While I anticipate this process will take years to occur, several recently published guidelines already reflect this shift in practice -- the 2011 European guidelines for non-ST elevation myocardial infarction (NSTEMI) recommend prasugrel and ticagrelor as first-line therapy in appropriate patients and the 2011 US guidelines for percutaneous coronary intervention (PCI) recommend these agents as reasonable alternatives to clopidogrel.

So, while the addition of low-dose rivaroxaban appeared to benefit patients in ATLAS ACS 2, is this simply the modification of a standard of care that is already on its way out?  Prasugrel is clearly associated with increased rates of bleeding versus clopidogrel. While ticagrelor is associated with a similar incidence of bleeding overall, it had higher rates of bleeding in certain key subgroups, including intracranial hemorrhage and non-CABG related major bleeding.  Therefore, given the incidence of bleeding already associated with newer antiplatelet therapies, the risks of adding rivaroxaban to these emerging standards of care may actually outweigh its benefits. Moreover, if a clinician's reasoning for avoiding prasugrel or ticagrelor in a specific patient is related to concerns for bleeding, the addition of long-term rivaroxaban seems even more unlikely.

With the patent for clopidogrel set to expire late in the second quarter of next year, it will likely remain a standard of care for many patients in the US for some time.  If patients who would otherwise be candidates for prasugrel or ticagrelor are placed on clopidogrel for financial considerations, I cannot imagine any financially justifiable advantages of adding rivaroxaban -- an agent that will probably only be available as a brand name product for the next decade or more.

Either way, it is still too early to tell how ATLAS ACS 2 will influence the management of patients with ACS. However, if history (i.e., WARIS II) has taught us anything, the addition of rivaxoban in patients with ACS may also be a practice that is abandoned before it ever begins...

References

1. Mega JL, Braunwald E, Gibson CM; for the ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med. 2011 Nov 13.
2. Hurlen M, Abdelnoor M, Arnesen H, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-74.
3. The CURE Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345: 494-502.