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OASIS 5 - OASIS 5
Description:
The goal of the trial was to evaluate treatment with fondaparinux, a new anticoagulant, compared with enoxaparin among patients with non-ST elevation acute coronary syndromes.
Study Design
Study Design:
Patients Enrolled: 20,078
Mean Follow Up: Six months
Female: 38
Patient Populations:
Non-ST elevation acute coronary syndrome with two of the following three risk factors: age >60, ST deviation, and/or positive cardiac markers
Primary Endpoints:
Efficacy: Death, MI, or refractory ischemia at nine days, assessed for noninferiority (upper bound of CI 1.185)
Safety: Major bleed at nine days
Secondary Endpoints:
Individual components of the primary composite at nine days, 30 days, and 180 days
Drug/Procedures Used:
Patients were randomized to fondaparinux (2.5 mg/day, n=10,057) or enoxaparin (1.0 mg/kg twice daily, n=10,021). Other medications including aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors were at the investigator's discretion. Patients who underwent percutaneous coronary intervention (PCI) in the enoxaparin group were to receive unfractioned heparin if the last dose of study medication was received >6 hours prior to PCI. The primary analysis was a test for noninferiority between the treatment groups.
Principal Findings:
Baseline characteristics were well balanced between the treatment groups, with 25% diabetics, 70% with a positive cardiac marker, and 80% with ST deviation. Concomitant medications included aspirin (97.5%), clopidogrel/ticlopidine (67%), and glycoprotein IIb/IIIa inhibitors (18%). Duration of therapy was 5.2 days in the enoxaparin group and 5.4 days in the fondaparinux group. PCI was performed in 34% of patients.
The primary endpoint of death, MI, or refractory ischemia at day 9 occurred in 5.7% of the enoxaparin group and 5.8% of the fondaparinux group, meeting the prespecified criteria for noninferiority of fondaparinux compared with enoxaparin (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.90-1.13, p=0.007 for noninferiority). Major bleed by day 9 was lower in the fondaparinux group (2.1% vs. 4.1%, HR 0.52, p<0.001), as was minor bleed (1.1% vs. 3.2%, p<0.001) and any bleed (3.3% vs. 7.3%, HR 0.41, p<0.001).
At 30 days, there was no difference in the composite of death, MI, or refractory ischemia (8.0% for fondaparinux vs. 8.6% for enoxaparin, p=NS), but mortality was significantly lower in the fondaparinux group (2.9% vs. 3.5%, p=0.02), a reduction maintained at six months (5.8% vs. 6.5%, HR 0.89, p=0.05). Stroke was also lower at six months in the fondaparinux group (1.3% vs. 1.7%, p=0.04), but there was no difference in MI (6.3% vs. 6.6%, p=NS). The composite endpoint that combined efficacy and safety (death, MI, refractory ischemia, or major bleeding) at 180 days was lower in the fondaparinux group (HR 0.86, p<0.001).
Results were similar across most subgroups. However, in patients age <65 years, no benefit of fondaparinux was observed (composite of death, MI, refractory ischemia, or major bleeding 7.4% for fondaparinux vs. 7.5% for enoxaparin, HR 0.99, p=NS), but benefit was observed in the age >65 years subgroup (12.1% vs. 15.4%, HR 0.77, p<0.001). In patients who underwent PCI, there was no difference in death or MI (6.2% for fondaparinux vs. 5.8% for enoxaparin, p=NS), but bleeding was lower in the fondaparinux group (2.3% vs. 5.1%, p<0.001), although it should be noted that 54% of patients in the enoxaparin group also received unfractionated heparin per protocol. Occurrence of thrombus formation on the catheter during PCI occurred more frequently in the fondaparinux group (n=29 vs n=8, HR 2.99, p=0.08).
Interpretation:
Among patients with non-ST elevation acute coronary syndromes, treatment with fondaparinux was noninferior for the primary composite endpoint of death, MI, or refractory ischemia at day 9 compared with treatment with enoxaparin. Additionally, there was a significant reduction in the safety endpoint of major bleeding at nine days and the secondary endpoint of mortality at six months.
Fondaparinux is a synthetic drug that acts early during the clotting cascade. Fondaparinux has been previously studied in the setting of deep vein thrombosis, but the present study is the first large-scale randomized trial to evaluate fondaparinux in the setting of acute coronary syndromes.
Mortality was significantly reduced among the fondaparinux group, although the reduction did not appear to be driven by a reduction in fatal coronary events, but rather by a reduction in fatal bleeds. Given this finding along with the age subgroup analysis, which showed no benefit in younger patients but an increased hazard with enoxaparin in those age >65 years, the discussant raised the question of whether there was benefit with fondaparinux or whether the dose of enoxaparin is too high, resulting in excess bleeding events among elderly patients with potentially impaired renal function.
It should also be noted that more than half of the patients who underwent PCI in the enoxaparin group also received unfractionated heparin per protocol, raising the question of the role of dual antithrombin therapy and excess bleeding, as was observed in SYNERGY. Additionally, the increase in catheter thrombus formation in the PCI cohort was of concern. The OASIS 6 trial evaluated fondaparinux therapy in the setting of ST elevation MI.
References:
OASIS-5 Investigators. Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes. N Engl J Med 2006;354:epub before print.
Presented by Dr. Salim Yusuf at the European Society of Cardiology Hot Line Session, September 2005.
Keywords: Polysaccharides, Stroke, Acute Coronary Syndrome, Coronary Disease, Ticlopidine, Risk Factors, Percutaneous Coronary Intervention, Enoxaparin, Research Personnel, Venous Thrombosis, Confidence Intervals, Diabetes Mellitus
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