Low-Dose Rivaroxaban Curbs Thrombotic Events in STEMI Patients

MUNICH, Germany—After ST-segment elevation myocardial infarction (STEMI), a twice-daily 2.5-mg dose of the novel anticoagulant rivaroxaban reduces thrombotic events. The late-breaking findings, from a new analysis of the ATLAS ACS 2-TIMI 51 trial, were released August 27 at the European Society of Cardiology (ESC) Congress 2012.

In the overall ATLAS ACS 2-TIMI 51 (Addition to standard therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51) trial, rivaroxaban (Xarelto; Johnson & Johnson, Bayer Healthcare) reduced the recurrence of cardiovascular events compared with placebo in more than 15,000 ACS patients. The main results were published in the New England Journal of Medicine in January 2012.

Better Safety, Efficacy

Jessica L. Mega, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), presented a prespecified subanalysis looking solely at the trial’s 7,817 STEMI patients, of whom approximately 71% underwent PCI. After being stabilized following their event, patients were randomized to placebo (n = 2,632), rivaroxaban 2.5 mg twice daily (n = 2,601), or rivaroxaban 5 mg twice daily (n = 2,584).

At 24 months, Kaplan-Meier analyses showed that rivaroxaban held an overall advantage compared with placebo for the primary efficacy endpoint (composite of CV death, MI, and stroke [ischemic, hemorrhagic, or uncertain), with the curves diverging by 30 days. While the 5 mg dose failed to reduce cardiovascular death, the 2.5 mg dose proved successful at reducing not only cardiovascular death but all-cause death (table 1).

Table 1. Efficacy Endpoints at 24 Months




HR (95% CI)

P Value

CV Death, MI, Stroke



0.81 (0.67-0.97)


5 mg Dose
CV Death, MI, Stroke
CV Death



0.81 (0.66-1.00)
0.92 (0.67-1.28)


2.5 mg Dose
CV Death, MI, Stroke
CV Death
All-Cause Death



0.60 (0.42-0.87)
0.63 (0.45-0.89)


Results were consistent even when considering only those patients on dual antiplatelet therapy.

The primary safety endpoint of TIMI non-CABG major bleeding at 24 months was lowest in the placebo group (0.6%) and rose progressively to 1.7% with the 2.5-mg dose of rivaroxaban (HR 3.63; 95% CI 1.73-7.61; P < 0.001 vs. placebo) and 2.7% with the 5-mg dose (HR 5.47; 95% CI 2.68-11.17; P < 0.001 vs. placebo).

Compared with the 5-mg rivaroxaban dose, the 2.5-mg dose reduced the composite of non-CABG TIMI major or minor bleeding (2.46% vs. 4.51%; P = 0.019) and fatal bleeding (0.04% vs. 0.40%; P = 0.18).

But How Will Rivaroxaban Fare in the Real World?

In short, “rivaroxaban 2.5 twice daily resulted in a survival benefit and less bleeding than 5 mg twice daily,” Dr. Mega concluded. “Treatment with very low dose rivaroxaban (2.5 mg twice daily) offers an effective strategy to reduce thrombotic events in patients following a STEMI.”

Dr. Mega explained the likely mechanism behind rivaroxaban’s benefit. “In the setting of acute coronary syndromes, there is evidence of thrombin generation [that] occurs not only during the index event but persists over time. It has come to be known that thrombin induces both thrombosis and hemostasis through a number of different [mechanisms],” such as platelet degradation and adhesion as well as inflammation. Rivaroxaban, an oral factor Xa inhibitor, reduces downstream thrombin generation, she added.

Andreas M. Zeiher, MD, of the University of Frankfurt (Frankfurt, Germany), praised the STEMI subanalysis for “addressing the challenge of balancing ischemic vs. bleeding risk in patients with acute coronary syndromes, in this case using rivaroxaban.”

Reassuringly, results from the STEMI subanalysis closely mirror those of ATLAS ACS 2-TIMI 51 as a whole for both rivaroxaban and placebo, Dr. Zeiher said. But he questioned what happened to the 30% of STEMI patients who did not undergo PCI, as well as whether PCI use correlated with outcome. Another outstanding concern is “the almost linear relationship between time and bleeding” in patients receiving rivaroxaban, which raises the possibility that bleeding rates may grow higher after long-term use.

Most importantly, Dr. Zeiher said, “prasugrel and ticagrelor were not allowed . . . because they have been shown to [carry] an increased bleeding risk,” so it is unknown what effect low-dose rivaroxaban would have on bleeding in patients taking those antiplatelet medications. Nor is it known what happens in patients who experience STEMI while taking higher rivaroxaban doses for other indications including nonvalvular atrial fibrillation and deep vein thrombosis/pulmonary embolism.

But low-dose rivaroxaban is already gaining notice, with the new ESC guidelines on STEMI management giving a IIa B recommendation for consideration in selected patients at low bleeding risk who receive aspirin and clopidogrel, he pointed out.


Mega J. ATLAS ACS 2-TIMI 51: Rivaroxaban in patients with ST-elevation myocardial infarction. Presented at: European Society of Cardiology Congress; August 27, 2012; Munich, Germany.



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  • ATLAS ACS 2-TIMI 51 was supported by research grants from Johnson &amp; Johnson and Bayer Healthcare.
  • Dr. Mega reports receiving research grants via the TIMI Study Group and Brigham and Women’s Hospital from Accumetrics, Bayer Healthcare, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson &amp; Johnson, Nanosphere, Sanofi-Aventis, and the National Institutes of Health. She also reports serving as a consultant for Janssen and Merck.
  • Dr. Zeiher reports having financial relationships with Baxter, BerlinChemie, Sanofi-Aventis, and t2cure.

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