Reduced Risk Of Stroke, Further Heart Attack And Death For Patients After A Heart Attack Or Unstable Angina With Oral Rivaroxaban

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Main Category: Cardiovascular / Cardiology
Also Included In: Heart Disease
Article Date: 17 Jun 2009 - 10:00 PDT

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The findings of the ATLAS ACS-TIMI 46 study are reported in an article Online First and in a future edition of The Lancet, and written by Dr Jessica L Mega, Brigham and Women's Hospital, Boston, MA, USA, and collaborators. They suggest that the intake of the oral anti-clotting drug rivaroxaban in patients after an acute coronary syndrome (such as a heart attack or an unstable angina) reduces the risk of stroke, another heart attack, and death.

Rivaroxaban works by reducing factor Xa, which is involved in the blood clotting mechanism. Earlier studies have proven the drug´s effectiveness in preventing venous thromboembolism in patients following orthopaedic surgery. The safety and efficacy of rivaroxaban are put to the test in this randomized, phase II study. This assessment is relevant for subjects who had an acute coronary syndrome and is designed to find the most favorable dose and dosing regimen.

The study consisted of a trial including 3,491 patients from 297 sites in 27 countries. The requisite for the participants was to have symptoms suggestive of a coronary syndrome that lasted at least ten minutes at rest. All of the patients were given standard background therapy of either aspirin (first group of 761 patients), or aspirin plus a thienopyridine (for example, clopidogrel) (second group of 2,730 patients). Then, in each of these two groups, patients were randomized 1:1:1 to receive either placebo or rivaroxaban (in doses of 5-20 mg daily), with the same total daily dose given once or twice a day. The primary safety endpoint was clinically significant bleeding. The principal efficacy endpoint was death, heart attack, stroke, or severe recurrent inadequate blood flow (ischaemia) to the heart requiring intervention within six months.

The findings indicate that rixaroxaban increases the risk of clinically significant bleeding in a dose-dependent manner. There was a 2.2 times increased the risk with the 5 mg dose, which increased to five times for the 20 mg dose, compared with a placebo. Researchers found 5.6 percent of the patients given rivaroxaban reached the primary efficacy endpoint, compared to 7.0 percent in the placebo group. This translates to a reduced risk of 21 percent. When examining just death, heart attack or stroke (the secondary endpoint), 3.9 percent of rivaroxaban patients experienced one of these events versus 5.5 percent with placebo. This translates to a reduced risk of 31% for patients given rivaroxaban. In both group, about ten percent of the patients experienced chest pain as the most common adverse event.

The authors write in conclusion: "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 supplementary note, Dr Kim Eagle and Dr Hitinder S Gurm, of the University of Michigan Cardiovascular Center, Ann Arbor, MI, USA, write: "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 remark that it is too early to estimate the drug´s benefit in secondary prevention on the basis of the results of a dose-finding study. But, rivaroxaban could potentially displace intravenous anticoagulants for early management of these syndromes. They add: "This indication has not yet been assessed, and we hope that the drug's sponsors will actively pursue this hypothesis."

"Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial"
J L Mega, E Braunwald, S Mohanavelu, P Burton, R Poulter, F Misselwitz, V Hricak, E S Barnathan, P Bordes, A Witkowski, V Markov, L Oppenheimer, C M Gibson, on behalf of the ATLAS ACS-TIMI 46 study group
DOI: 10.1016/S0140-6736(09)60738-8

"Rivaroxaban in acute coronary syndromes: too soon to know?"
Hitinder S Gurm, Kim Eagle
DOI: 10.1016/S0140-6736(09)60952-1
thelancet

Written by Stephanie Brunner (B.A.)
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