Low-Dose Rivaroxaban Reduces Thrombotic Events, Increases Bleeding After STEMI

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Key Points:
  • Subanalysis shows rivaroxaban 2.5 mg twice daily reduces thrombotic events including cardiovascular death in STEMI patients
  • 5-mg dose less effective at reducing mortality, causes more bleeding
  • Ideal duration, combination of antithrombotics yet to be determined

By Yael L. Maxwell
Tuesday, March 05, 2013

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After ST-segment elevation myocardial infarction (STEMI), a twice-daily 2.5-mg dose of the novel anticoagulant rivaroxaban reduces thrombotic events, according to a subanalysis of the ATLAS ACS 2-TIMI 51 trial. The study, published online March 5, 2013, ahead of print in the Journal of the American College of Cardiology, also found an increased risk of bleeding with the drug.

The findings were previously presented in August 2012 at the European Society of Cardiology Congress in Munich, Germany. In the overall ATLAS ACS 2-TIMI 51 (Addition to standard therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51) trial, published in the New England Journal of Medicine in January 2012, rivaroxaban (Xarelto, Johnson & Johnson, Bayer Healthcare) reduced the recurrence of cardiovascular events compared with placebo in more than 15,000 ACS patients.

In the prespecified subanalysis, Jessica L. Mega, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), and colleagues considered only the trial’s 7,817 STEMI patients, of whom approximately 71% underwent PCI. After being stabilized, patients were randomized to placebo (n = 2,632) or 1 of 2 twice-daily doses of rivaroxaban, 2.5 mg (n = 2,601) or 5 mg (n = 2,584).

Kaplan-Meier analyses showed that rivaroxaban was associated with a lower risk of the primary efficacy endpoint (composite of CV death, MI, and stroke [ischemic, hemorrhagic, or uncertain]), compared with placebo at 24 months. While the 5 mg dose failed to reduce cardiovascular death, the 2.5-mg dose lowered the likelihood of cardiovascular and 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



0.81 (0.65-1.00)
0.60 (0.42-0.87)
0.63 (0.45-0.89)


The results were maintained even after excluding patients not on dual antiplatelet therapy.

TIMI non-CABG major bleeding at 24 months, the primary safety endpoint, was lowest in the placebo group (0.6%), rising 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 placebo, rivaroxaban, regardless of dosing, also increased intracranial hemorrhage (0.6% vs. 0.1%; P = 0.015), without a significant increase in fatal bleeding (0.2% vs. 0.1%; P = 0.51).

Optimal Dose Still Unclear

Since the 2.5-mg twice daily dose of rivaroxaban “[exhibited] a better safety profile than the 5-mg twice daily dose . . . [the lower dose] may offer an effective strategy to reduce thrombotic events in patients following a STEMI,” the authors write. In aggregate, they say, this study and others “underscore the efficacy of greater degrees of antithrombotic therapy beyond aspirin and standard dose clopidogrel following a STEMI.”

Dr. Mega told TCTMD in an e-mail communication that the “issue of dosing antiplatelet and anticoagulants among patients with both ACS and atrial fibrillation warrants additional research.”

A Better Antiplatelet May Suffice

In an e-mail communication with TCTMD, Sunil V. Rao, MD, of Duke Clinical Research Institute (Durham, NC), said “the mortality reduction is surprising, but also exciting. Any new strategy that can reduce mortality in these high-risk patients is welcome.”

As for the benefits of the novel anticoagulant vs. the increased bleeding risk, he said, “It likely depends on the individual patient, but the analysis from the overall trial as well as this substudy support a net clinical benefit of rivaroxaban in ACS patients.”

Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), agreed that a net clinical benefit seems likely. He told TCTMD in a telephone interview, however, that rivaroxaban may not be the answer.

“[T]he problem is that the magnitude of risk reduction when you add rivaroxaban to aspirin and [clopidogrel] is about the same as what you’d get from substituting [clopidogrel] with a more powerful antiplatelet agent, either prasugrel or ticagrelor,” Dr. Brener pointed out, in particular citing ticagrelor in the PLATO trial.

The “main question is whether you do need an oral anticoagulant or just a better antiplatelet agent,” he said.


Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-elevation myocardial infarction: Results from the ATLAS ACS 2-TIMI 51 trial. J Am Coll Cardiol. 2013;Epub ahead of print.



  • Dr. Mega reports receiving research support from Accumetrics, Bayer Healthcare, Bristol-Myers Squibb/Sanofi-aventis, Daiichi Sankyo, Eli Lilly, Johnson and Johnson, and Nanosphere and honoraria from Merck.
  • Dr. Rao reports serving as a consultant to Janssen Pharmaceuticals.
  • Dr. Brener reports no relevant conflicts of interest.


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