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Oral Rivaroxaban Reduces Death/Stroke/Further Heart Attack For Patients After Heart Attack Or Unstable Angina

Update: Xarelto (rivaroxaban) Now FDA Approved - July 1, 2011

LONDON, June 16, 2009--Administration of the oral anticlotting drug rivaroxaban to patients after an acute coronary syndrome (ie, heart attack or unstable angina) reduces the incidence of stroke, further heart attack, and death in those patients. The findings of the ATLAS ACS-TIMI 46 study are reported in an Article Online First and in an upcoming edition of The Lancet, written by Dr Jessica L Mega, Brigham and Women's Hospital, Boston, MA, USA, and colleagues.

Rivaroxaban inhibits factor Xa, which is involved in the blood clotting mechanism. It has already been shown, in earlier studies, to be effective in the prevention of venous thromboembolism in patients following orthopaedic surgery. In this randomised, phase II study, the authors tested the safety and efficacy of rivaroxaban in subjects who had an acute coronary syndrome and aimed to find the most favourable dose and dosing regimen.

The trial studied 3491 patients from 297 sites in 27 countries, and participants were required to have symptoms suggestive of a coronary syndrome that lasted at least 10 minutes at rest. All of the patients were given standard background therapy of either aspirin (761 patients), or aspirin plus a thienopyridine (eg, clopidogrel) (2730 patients). Then, in each of these two groups, patients were randomised 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg daily) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding. The primary efficacy endpoint was death, heart attack, stroke, or severe recurrent ischaemia (inadequate blood flow) to the heart requiring intervention within 6 months.

The researchers found that the risk of clinically significant bleeding was increased by rixaroxaban in a dose-dependent manner. Compared with placebo, there was a 2.2 times increased risk with the 5 mg dose, which increased to 5 times for the 20 mg dose. Fewer patients given rivaroxaban reached the primary efficacy endpoint 5.6% vs 7.0% placebo), translating to a reduced risk of 21%. When examining just death, heart attack or stroke (the secondary endpoint), 3.9% of rivaroxaban patients experienced one of these events versus 5.5% with placebo-a reduced risk of 31% for patients given rivaroxaban. The most common adverse event was chest pain, experienced by around 10% of patients in both groups.

The authors conclude: "The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway."

In an accompanying Comment, Dr Kim Eagle and Dr Hitinder S Gurm, University of Michigan Cardiovascular Center, Ann Arbor, MI, USA, say: "In the ATLAS ACS-TIMI 46 study there was no suggestion of benefit in patients receiving dual antiplatelet therapy; robust clinical benefits without major increase in bleeding risk would need to be shown in the ongoing trials before this drug could be integrated into practice."

They add that, although estimation of the drug's benefit in secondary prevention on the basis of the results of a dose-finding study would be premature, rivaroxaban could potentially displace intravenous anticoagulants for early management of these syndromes. They say: "This indication has not yet been assessed, and we hope that the drug's sponsors will actively pursue this hypothesis."

Posted: June 2009