Review of the OASIS-5 trial

Fondaparinux vs enoxaparin in patients with unstable angina or myocardial infarction without ST-segment elevation

N Engl J Med 2006; 354:1464-1476

Background: Prior studies showed that combined antiplatelets and anticoagulants reduce ischemic events in patients with acute coronary syndrome but increases the risk of bleeding. We saw this in the FRISC trial where low-molecular-weight heparin plus aspirin reduced the primary endpoint of death or nonfatal myocardial infarction compared to placebo at 6 days but also increased minor bleeding events (8.2% vs 0.3%).

Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa and has a long half-life (17 – 21 hours). In contrast, low-molecular-weight heparin is biologic and has a half-life of 3 - 6 hours.

Pilot studies showed that fondaparinux may be as effective as enoxaparin in patients with acute coronary syndrome. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial sought to test the hypothesis that in patients with unstable angina or NSTEMI, fondaparinux would be noninferior to enoxaparin in reducing ischemic events but would be associated with less bleeding.

Patients: Patients were enrolled if they had at least two of the following criteria: at least 60 years of age, elevated cardiac biomarkers (troponin or creatine kinase MB) or ischemic EKG changes but not ST elevation. Patients were excluded if they had contraindication to low-molecular-weight heparin, recent hemorrhagic stroke or serum creatine of 3 mg/dl or more.

Baseline characteristics: The trial enrolled 20,078 patients. The average age of patients was 67 years with 62% being men. About 45% had unstable angina and the rest had NSTEMI. Prior myocardial infarction was present in 26% of the patients, stroke in 6%, heart failure in 14%, hypertension in 67% and diabetes in 25%. About half the patients were active or former smokers.

After randomization, about 98% of the patients were on aspirin, 67% were on clopidogrel or ticlopidine, 75% were on ACEi or ARB and 87% were on beta-blockers.

During first hospital stay, coronary angiography was performed in 63% of the patients but percutaneous coronary intervention was performed in only 34% and this was similar between both treatment groups. Coronary artery bypass graft (CABG) was performed in 9% in the enoxaparin group and 9.6% in the fondaparinux group.

Procedures: The trial was a double-blind, double-dummy trial. Patients were randomly assigned within 24 hours of onset of symptoms to receive fondaparinux at a dose of 2.5 mg once daily plus placebo twice daily or enoxaparin at a dose of 1 mg/ kg twice daily plus placebo once daily. All medications and placebo were administered using subcutaneous injection. Fondaparinux was given until hospital discharge or up to 8 days (whichever occurred first).  Enoxaparin was given for 2 – 8 days. Coronary angiogram was permitted at any time.

Endpoints: The primary efficacy endpoint was a composite endpoint that included death, myocardial infarction or refractory ischemia at 9 days. The primary safety endpoint was major bleeding. Secondary endpoint included the primary endpoint and its individual components at 30 days and end of the study (up to 180 days).

Based on an expected incidence of 8% at 9 days for the primary endpoint and a noninferiority margin of 1.185 for a one-sided alpha level of 2.5%, the estimated sample size was 16,000. However, a blinded review after the first 4,000 patients were enrolled showed a lower than expected event rate. Therefore, the sample size was increased to 20,000 patients.

Results: The study randomized 10,057 patients to receive fondaparinux and 10,021 to receive enoxaparin. At 9 days, the primary composite end point occurred in 5.8% patients assigned to fondaparinux and 5.7% patients assigned to enoxaparin (HR: 1.01, 95% CI: 0.90 - 1.13; p= 0.007 for non-inferiority). All components of the primary endpoint were also similar between both treatment arms at 9 days.

At 30 and 180 days, there was no significant difference in the composite primary endpoint between both treatment arms. However, death (secondary endpoint) was significantly lower with fondaparinux at 30 days (2.9% vs 3.5%; p= 0.02) and the difference persistent at 180 days (5.8% vs 6.5%; p= 0.05).

Major bleeding at 9 days was significantly lower with fondaparinux (2.2% vs. 4.1%; HR: 0.52,  95% CI: 0.44 - 0.61; p<0.001).

There were no significant differences in subgroups for the primary efficacy endpoint at 9 days. Similarly, bleeding was lower with fondaparinux across different subgroups.

For patients who underwent coronary angiography, catheter-related thrombus was significantly more common with fondaparinux (0.9% vs 0.3%, p= 0.001).

Conclusion: In patients admitted with unstable angina or NSTEMI, the use of fondaparinux as compared to enoxaparin resulted in similar risk of death, myocardial infarction or refractory ischemia at 9 days, but a significantly lower risk of bleeding. The NNT to prevent major bleeding with fondaparinux was 52. Fondaparinux increased the risk of catheter-related thrombus. The double-blind, double-dummy design enhanced the internal validity of the trial and reduced performance bias.

Whether the results of this study apply to the contemporary practice is unclear due to the high rate of coronary angiography and the frequent use of radial access in the current era. However, based on our interpretation of OASIS-5 we feel that Fondaparinux should be considered at least an equal alternative to low-molecular-weight heparin in patients admitted with ACS without ST segment elevation.