Update: Deja vu in ATLAS ACS-2: rivaroxaban in the subset of patients with ST-segment elevation myocardial infarction

In an article posted on theheart.org last week highlighting the results of several late-breaking clinical trials revealed at the 2012 European Society of Cardiology (ESC) meeting, experts again debated the utility of adding low-dose rivaroxaban (2.5 mg twice daily) to dual antiplatelet therapy in patients with acute coronary syndromes (ACS). The discussion involved a pre-specified sub-analysis of ATLAS ACS 2 [1], a trial that randomized patients with ACS who were already receiving aspirin and clopidogrel to either rivaroxaban or placebo.  A sub-analysis of the patients with ST-segment elevation myocardial infarction (STEMI) found a small but marginally significant reduction in major adverse cardiovascular events (absolute risk reduction 1.9%, HR 0.81 (95% CI 0.65-1.00), p = 0.047) with rivaroxaban. However, as observed in the overall cohort of patients with ACS, this benefit was accompanied by a significant increase in several types of bleeding (details unavailable at this time).

As I describe in a previous entry on the results of ATLAS ACS 2, I am still not sure it is worth pursuing the addition of rivaroxaban in patients with ACS until we know its risk versus benefit profile in combination with aspirin and one of the newer P2Y12 inhibitors prasugrel or ticagrelor.  Although, given the results of another trial revealed at ESC 2012, perhaps we should be dropping aspirin from the "triple therapy" strategy anyway.

What is perhaps an even more challenging scenario, as the article goes on to discuss, is what to do when patients have multiple indications for anticoagulation or are already receiving rivaroxaban for a different indication and have an ACS event.  The appropriate dose of rivaroxaban depends on indication -- 10 mg once daily for prophylaxis of venous thromboembolism following major orthopedic surgery, 15 mg twice daily for the treatment of deep vein thrombosis or pulmonary embolism (assuming the agent will be approved for these indications based on the results of the two EINSTEIN investigations [2,3]), or 20 mg daily for atrial fibrillation (15 mg once daily if impaired renal function). If someone has an ACS event that requires dual antiplatelet therapy and is already taking rivaroxaban for one of these indications, do we reduce the dose to 2.5 mg twice daily given that higher doses are already known to increase the risk of bleeding in this population [4]?

I suppose nobody has any definitive answers to these and other challenging clinical scenarios that will soon be at our doorstep, but one thing I do know for sure -- what an exciting time to be practicing in the area of cardiology.

Note: the 2.5 mg twice daily dose of rivaroxaban was up for approval by the US Food & Drug Administration earlier this year, but failed to gain the indication for use in acute coronary syndromes.

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 2012; 366:9-19.
2. The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010; 363:2499-2510.
3. The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012; 366:1287-1297.
4. Mega JL, Braunwald E, Gibson CM, et al; for the ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009 Jul 4;374(9683):29-38.