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Patients with acute coronary syndromes (ACS) who take low doses of rivaroxaban, rather than placebo, in addition to aspirin and clopidogrel after receiving stents develop fewer cases of stent thrombosis. At the lowest dose of 2.5 mg, rivaroxaban is also associated with a reduction in mortality, according to a new analysis from the ATLAS ACS 2-TIMI trial scheduled to be published online April 16, 2013, ahead of print in the Journal of the American College of Cardiology.
The overall ATLAS ACS 2-TIMI 51 (Addition to standard therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51) trial showed that rivaroxaban (Janssen Pharmaceuticals, Titusville, NJ) 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.
For the current analysis, C. Michael Gibson, MS, MD, of Beth Israel Deaconess Medical Center (Boston, MA), and colleagues focused on the 9,631 patients (63%) who were implanted with at least 1 stent prior to randomization or during their index event. Among them, two-thirds (n = 6,433) received rivaroxaban doses of either 2.5 or 5.0 mg twice daily and the rest received placebo (n = 3,198). Stent thrombosis cases were independently adjudicated and classified according to Academic Research Consortium (ARC) criteria.
Only 2.5-mg Dose Lowers Death Risk
At 2 years, Kaplan-Meier analyses estimated that the definite/probable stent thrombosis rate was 1.5% for those who received rivaroxaban regardless of the dose, as well as for the individual 2.5-mg and 5.0-mg groups. Among patients taking placebo, the rate was 1.9%.
The difference between rivaroxaban and placebo reached significance in the pooled cohort and in the 2.5-mg group but not in the 5.0-mg group (table 1). Definite stent thrombosis followed a similar pattern.
Table 1. ARC Definite/Probable Stent Thrombosis at 2 Years: Rivaroxaban vs. Placebo
HR (95% CI)
Rivaroxaban’s effect was consistent across numerous subgroups and of similar magnitude for patients receiving BMS (HR 0.69; P = 0.042) as those receiving DES (HR 0.68; P = 0.170). Importantly, rivaroxaban’s advantage over placebo emerged during the period of active treatment with dual antiplatelet therapy (HR 0.68; 95% CI 0.50-0.92).
In addition, the risk of mortality was substantially reduced by the 2.5-m rivaroxaban dose compared with placebo (HR 0.56; 95% CI 0.35-0.89; P = 0.014). The 5-mg dose offered no such benefit.
“Since thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis,” the researchers note. However, the underlying mechanism is not fully understood, they say, adding that it is unclear as to whether the reduction in stent thrombosis is mediated by a reduction in thrombin generation or by a reduction in the stimulation of platelet aggregation.
According to the paper, a similar—but not significant—effect on stent thrombosis has been reported for apixaban, another direct factor Xa inhibitor, but not for the thrombin-receptor antagonist vorapaxar.
Low Dose Deserves Credit
Study coauthor Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD in a telephone interview that the results are “believable and biologically plausible.”
What is important to remember, Dr. Bhatt stressed, is that rivaroxaban at 2.5 mg twice daily stands out as a “very low dose.” Rivaroxaban is approved by the US Food and Drug Administration (FDA) for the prevention of stroke in patients with nonvalvular A-fib at once daily doses of 15 and 20 mg, for example.
In ATLAS ACS 2-TIMI 51, “that sprinkling of anticoagulation on top of what is largely dual antiplatelet therapy . . . does seem to provide incremental benefit,” he said, cautioning that there is still some excess risk of bleeding. “But at least with this dose in this population, it appears that the benefit on mortality and reduction in stent thrombosis likely then would outweigh any increase in bleeding.”
The protective effect of rivaroxaban in the context of ACS and dual antiplatelet therapy probably stems from that balance, Dr. Bhatt commented. “With the 2.5 [twice daily dose] of rivaroxaban, we managed to—perhaps with good fortune—hit the sweet spot where adding a little bit of anticoagulation actually seems to be useful in reducing ischemic outcomes.”
Because bleeding is still a valid concern even at the 2.5-mg dose, he said, only patients at low risk for bleeding should be considered for triple therapy if the FDA approves rivaroxaban for this indication.
While it would be “legitimate to explore” whether other anticoagulants might have similar benefits at low doses, such questions can only be answered in the setting of a large clinical trial, Dr. Bhatt concluded.