OASIS-5 trial


The factor Xa inhibitor fondaparinux prevents death, MI, and refractory ischemia at 9 days as well as the low-molecular-weight heparin enoxaparin in patients with acute coronary syndromes (ACS), while reducing the incidence of bleeding.

As a result, fondaparinux should be considered the preferred anticoagulant in patients with ACS who are already receiving aspirin and clopidogrel, said Dr Yusuf, professor of medicine and director of the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Ontario, Canada.

Although improvements in antithrombotic therapies over the past 2 decades have substantially reduced the risk of myocardial infarction, they have also been associated with a significant increase in bleeding risk, he said. Therapies that maintain the benefits of currently used antithrombotic therapies but cause less bleeding are therefore of great clinical importance.

OASIS-5 included 20,078 patients with ACS without ST-segment elevation who were randomized to receive fondaparinux 2.5 mg/d or enoxaparin 1 mg/kg twice daily for 2 to 8 days. The study medications were administered in addition to standard medical care, including aspirin, clopidogrel, GP IIb/IIIa inhibitors, and revascularization procedures. The primary objective was to evaluate whether fondaparinux was at least as effective as enoxaparin in preventing death, MI, or refractory ischemia. Secondary objectives included evaluation of safety (bleeding events) up to Day 9, as well as to determine if the relative effect on the primary end point of fondaparinux versus enoxaparin was sustained up to 6 months.

At 9 days, the primary composite end point occurred in 5.9% of fondaparinux recipients and 5.8% of enoxaparin recipients, for a hazard ratio of 1.01, which met the criterion for noninferiority of fondaparinux. Furthermore, fondaparinux was associated with a 47% reduction in major bleeding versus enoxaparin (2.1% and 4.0%, respectively; P<.001).

Previous studies have demonstrated that major bleeding is associated with a much higher risk of death in the immediate weeks following an ACS. "We know that major bleeding increases the risk of mortality independently by 400%," said Dr Yusuf.

In addition, 1-month mortality was 2.9% in the fondaparinux group and 3.5% in the enoxaparin group, which corresponds to a 17% reduction (P=.0219) in favor of fondaparinux. The difference in mortality between the 2 treatment groups was maintained at 6 months (5.8% and 6.6% in the fondaparinux and enoxaparin groups, respectively; P=.0373).

The risk of major bleeding at 6 months was 28% lower in the fondaparinux group (P<.00001). The composite of death, MI, refractory ischemia, and bleeding at 6 months was 13% lower with fondaparinux compared with enoxaparin (P<.00001).

The benefit of fondaparinux was apparent in hospitals with or without catheterization labs and whether or not patients received unfractionated heparin. With heparin use, a substantial reduction in bleeding at 9 days still occurred with fondaparinux, but this favorable effect was blunted.

"Put in context, our results showed that if you took 1,000 people with ACS and treated them with fondaparinux instead of enoxaparin, you would prevent 10 deaths from MI, 4 from stroke, and 25 major bleeds," said Dr Yusuf. Eighty-five percent of the difference in mortality between the treatment groups at 6 months was due to the difference in the incidence of major bleeding, he said.

With a price that is about 30% lower than that of enoxaparin, fondaparinux produces a net clinical benefit without incurring additional cost, he noted.

Based on the results of OASIS-5, "any physician wanting to write a prescription for enoxaparin should think twice or thrice," said Shamir Mehta, MD, co-investigator of the study and associate professor of medicine, McMaster University, Ontario, Canada.

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