Comparison of the anticoagulant intensities of fondaparinux and enoxaparin in the organization to assess strategies in acute ischemic syndromes (OASIS)‐5 trial

Summary.  Background: In the OASIS‐5 trial, fondaparinux reduced major bleeding with similar short‐term efficacy as enoxaparin but lowered death and stroke during long‐term follow‐up. The mechanism of lower bleeding and improved efficacy with fondaparinux is uncertain. Methods and Results: We compared the anti‐Xa concentration (reflecting drug levels), Xa clot time (reflecting anticoagulant effect) and endogenous thrombin potential (ETP; a global test of hemostatic function) in plasma samples collected 6, 24 and 72 h after the first dose of the study drug in 48 patients randomly assigned fondaparinux 2.5 mg day−1 and 42 patients assigned enoxaparin 1 mg kg−1 twice daily in the OASIS‐5 trial. Patients assigned to fondaparinux compared with enoxaparin had a significantly lower mean anti‐Xa level [0.52 IU mL−1 (SD 0.22 IU mL−1) vs. 1.2 IU mL−1 (SD 0.45 IU mL−1), P < 0.0001] and Xa clot time [64.9 s (SD 17.7 s) vs. 111.8 s (SD 29.6 s), P < 0.0001], and significantly higher ETP area under the curve (AUC) [386.7 mA (SD 51.5 mA) vs. 206.4 mA (SD 90.6 mA), P < 0.001] at 6 h, and these differences remained evident at 24 and 72 h. There was significantly less variability of the results of anti‐Xa levels, Xa clot time and ETP AUC for fondaparinux compared with enoxaparin at 6 h (P < 0.001 for each comparison). Conclusion: Fondaparinux 2.5 mg day−1 compared with enoxaparin 1 mg kg−1 twice daily produces less variable anticoagulant effect and lower mean anticoagulant intensity. These results most likely explain the reduced risk of bleeding seen with fondaparinux compared with enoxaparin in the OASIS‐5 trial and suggest that a lower intensity of anticoagulation than used in the past may be sufficient to prevent recurrent ischemic events and death in patients with ACS who are concurrently treated with aspirin and clopidogrel.