Scientific Sessions 2011
ORLANDO, Fla. — Rivaroxaban added to standard treatment reduced the risk
for CV death, MI and stroke among patients with acute coronary syndrome, but
was associated with an increase in TIMI major bleeding, according to C.
Michael Gibson, MS, MD, who presented results of the ATLAS ACS 2-TIMI 51
Both “very low” and “low” doses of the drug (2.5 mg
and 5.0 mg twice daily) were superior to placebo. However, the twice-daily
2.5-mg dose may be the more effective option to reduce CV events in patient
with recent ACS.
“Rivaroxaban did reduce the risk for CV death, MI or stroke
across a full spectrum of ACS, [from] low risk to high risk,” Gibson, an
interventional cardiologist and chief of clinical research in the division of
cardiology at Beth Israel Deaconess Medical Center, Boston, said during a press
conference. “The risk for major bleeding was higher with the rivaroxaban
arm; however, there was no excess risk for fatal [intracranial hemorrhage] or
fatal bleeding, particularly in the 2.5-mg arm. One death would be prevented if
56 patients on current antiplatelet therapies were treated for 2 years with
‘very low’ dose rivaroxaban.”
The study, simultaneously published in the New England Journal of
Medicine, included 15,526 patients with recent ACS. All participants
were randomly assigned to 2.5 mg or 5 mg rivaroxaban (Xarelto, Johnson &
Johnson) twice daily or placebo for up to 31 months. The primary endpoint was a
composite of CV death, MI or stroke.
Two-year Kaplan Meier estimates demonstrated that, together, both doses
of rivaroxaban reduced the risk for CV death, MI and stroke as compared with
placebo (8.9% vs. 10.7%; HR=0.84; 95% CI, 0.74-0.96). Additionally, rivaroxaban
at both doses was associated with a reduced risk for stent thrombosis (2.3% vs.
2.9%; HR=0.69; 95% CI, 0.51-0.93).
Compared with placebo, the 5-mg dose was associated with an improvement
in the primary endpoint (10.7% vs. 8.8%; P=.03), as was the 2.5-mg dose
(10.7% vs. 9.1%; P=.02). The 2.5-mg dose was also associated with a
decrease in the rate of death from CV causes (2.7% vs. 4.1%; P=.002) and
from any cause (2.9% vs. 4.5%; P=.002). This was not seen, however, with
the 5-mg dose.
The risk for non-CABG major bleeding was increased in the rivaroxaban
group vs. placebo (2.1% vs. 0.6%; P<.001); this was significant for
both doses (P<.001). Compared with placebo, rates of TIMI minor
bleeding (0.5% vs. 1.3%; P=.003), TIMI bleeding requiring medical
attention (7.5% vs. 14.5%; P<.001) and intracranial hemorrhage (0.6%
vs. 0.2%; P=.009) were higher in the combined rivaroxaban group.
However, there was no significant increase in fatal bleeding with rivaroxaban
(0.3 vs. 0.2%; P=.66).
Compared with the 5-mg dose, the 2.5-mg dose was associated with fewer
fatal bleeding events (0.4% vs. 0.1%; P=.04).
“We believe that the results of this study are an important
development for relatively young and healthy patients with an ACS,”
Matthew T. Roe, MD, and E. Magnus Ohman, MB, FRCPI, wrote in an
accompanying editorial published in NEJM. “However, there is
much work still to be done, since a large proportion of patients with an ACS
who are treated in routine practice are elderly with multiple coexisting
According to Roe and Ohman, based on the balance between ischemic
benefit and bleeding risk, a better understanding of the role of rivaroxaban in higher-risk must be ascertained.
– by Stacey L. Fisher
For more information:
Disclosure: Brigham and Women’s Hospital received a research
grant from Bayer and Johnson & Johnson, which funded the ATLAS ACS 2 –
TIMI 51 trial. Dr. Gibson reports receiving honoraria and consulting fees from
both companies. Dr. Roe and Dr. Ohman report no relevant financial disclosures.
This is an interesting and important study. One take-home message is that not all of the pieces fit. We need to learn more about the seeming paradox where high-dose affected MI but not mortality; perhaps this relates to excess bleeding. The benefit with the lower 2.5mg dose of rivaroxaban on mortality is striking - almost too good to be true - particularly since there was no benefit for MI or stroke. However, the accompanying data on stent thrombosis confirm a meaningful antithrombotic effect.
The increasing mortality benefit over time is puzzling. Sudden death out of the hospital caused by thrombosis may be at work.
Notwithstanding this benefit, we need to be concerned about bleeding, especially intracranial hemorrhage, and associated stroke which is in excess in both the low- and high-doses. There is a caveat to this, which is that patients with prior stroke are at particular risk of ICH, and hence avoiding this treatment in those patients is key. We need to learn more about bleeding so this can be applied to patients who will benefit.
The bottom line is that this is the first time we have evidence of an anti-thrombotic agent benefiting ACS which is in contrast to a prior study with another anti Xa agent failed to be beneficial and caused excess bleeding using a higher relative dose. This study is the fourth in a quartet of phase-3 anti thrombotic trials over the last 3 months. Hence, there has been an active flurry of results published, yet we need to better understand the balance between dosing and risk-benefit ratio in both ACS and AF.
– Paul Armstrong, MD
Professor of Medicine, Division of Cardiology
University of Alberta, Canada
Disclosure: Dr. Armstrong reports receiving research grants from Boehringer Ingelheim, Hoffmann LaRoche & Sanofi Aventis Canada in conjunction with Leuven Coordinating Centre, Sanofi Aventis Canada, Eli Lily, Merck Sharp & Dohme Corp. in conjunction with Duke Clinical Research Institute, Scios Inc., Ortho-Biotech, Johnson & Johnson and Jansen Ortho Inc. in conjunction with Duke Clinical Research Institute, GlaxoSmithKline, AstraZeneca in conjunction with Uppsala Clinical Research Center. He also receives honoraria from GlaxoSmithKline, Merck & Company Inc., Merck and Astra Zeneca and Regado Biosciences. He receives significant honoraria from F. Hoffmann-La Roche Ltd.