OASIS 5: Fondaparinux reduced major, minor bleeds

Head-to-head trial found that agent reduced risk of MI, stroke and death due to lower rate of bleeding.

STOCKHOLM — Bleeding proved to be a major determinant of death in the OASIS 5 trial results presented here. Investigator Salim Yusuf, MBBS, DPhil, reported that use of fondaparinux significantly reduced the risk of bleeding in patients with acute coronary syndrome and non-ST segment elevation and, as a result, meant a lower risk of death.

“Bleeding is a very important event and increases the risk of death substantially,” Yusuf said at the European Society of Cardiology Congress 2005. The OASIS 5 trial, a direct comparison of the synthetic factor Xa inhibitor fondaparinux (Arixtra, GlaxoSmithKline) vs. enoxaparin (Lovenox, Aventis), found a lower rate of bleeding and death with fondaparinux in all subgroups of the 20,000-patient trial.

Use of fondaparinux instead of enoxaparin in 1,000 patients would prevent 10 deaths from MI, four from stroke, and 25 major bleeds, Yusuf said. Yusuf is a professor of medicine at McMaster University in Hamilton, Ontario. He said that the trial results indicate that fondaparinux should be the preferred anticoagulant.

Bleeding has clinical significance, Yusuf said. Minor bleeds can increase the risk of death threefold; major bleeds, 6.5-fold.

Study design

The phase-3 trial randomized 10,057 patients to 2.5 mg of fondaparinux once daily and 10,021 patients to 1 mg/kg enoxaparin twice daily. Other medications were given at the discretion of the physician and included aspirin, clopidogrel (Plavix Sanofi-Synthelabo/Bristol Myers Squibb) and GP IIb/IIIa inhibitors. The trial was conducted at 576 centers in 41 countries.

At nine days, the rate of the primary endpoint of death, MI or refractory ischemia was 5.9% in the fondaparinux group and 5.8% in the enoxaparin group; major bleeds at the same time point were 2.1% in the fondaparinux group vs. 4.0% in the enoxaparin group, a significant difference.

At 30 days, the data “favored fondaparinux even more,” Yusuf said. There was no difference between treatment groups in the composite of death, MI or refractory ischemia; however, mortality was significantly lower in the fondaparinux group. The mortality rate was 2.9% in the fondaparinux arm vs. 3.5% in the enoxaparin group (P=0.022). The lower rate of mortality was also observed at six months.

Total bleeds were 3.2% in the fondaparinux arms vs. 7.0% in the enoxaparin arm, a highly significant difference. Significantly more patients in the enoxaparin arm had bleeds that required surgery and transfusions.

Fondaparinux was more beneficial in patients older than 65, Yusuf said. The benefits were independent of the patient going to the cath lab or prior use of heparin. Event rates increased with both enoxaparin and fondaparinux when heparin was used, but there were fewer bleeding events in the fondaparinux arm.

Dosing too high?

Discussant Robert Califf, MD, director of the Duke Clinical Research Institute, noted the dose of enoxaparin, suggesting that it may have been too high, particularly because of the high rate of bleeding events in the older patients who may have had impaired renal function. He questioned whether the difference in bleeding was intrinsic to the drug or to the dosing regimen.

He said that the treatment protocol called for use of unfractionated heparin with enoxaparin, perhaps raising the potential role of dual antithrombin therapy and excess bleeding, an effect observed in the SYNERGY trial.

Fondaparinux is not approved for treatment of acute coronary syndrome; it is approved for prevention of venous thromboembolism in patients undergoing certain types of surgery and for treatment of acute DVT and acute PE when administered in conjunction with warfarin sodium in the hospital. – by Kathy Holliman

For more information:

• Yusuf S, Mehta SR. Efficacy and safety of fondaparinux compared to enoxaparin in 20,000 high risk patients with ACS without ST elevation: the OASIS 5 Michelangelo programme. Presented at a Hot Line session of the European Society of Cardiology Congress 2005. Sept. 3-7, 2005. Stockholm.