Context: Despite many therapeutic advances, mortality in patients with acute S T-segment elevation myocardial infarction(STEMI) remains high. The role of addi tional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. Objective: To evaluate the effect of fondaparinux, a facto r Xa inhibitor, when initiated early and given for up to 8 days vs usual care(pl acebo in those in whom unfractionated heparin[UFH] is not indicated[stratum 1] o r unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. Design, Setting, and Participants: Randomiz ed double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12 092 patients with STEMI from 447 hospitals in 41 countries(Septe mber 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. Main O utcome Measures: Composite of death or reinfarction at 30 days(primary) with sec ondary assessments at 9 days and at final follow-up(3 or 6 months). Results: Death or reinfarction at 30 days was significantly reduced from 677(11.2%) of 6056 patients in the control group to 585(9.7%) of 6036 patients in the fondaparin ux group(hazard ratio[HR], 0.86; 95%confidence interval[CI], 0.77-0.96; P=.008 ); absolute risk reduction, 1.5%; 95%CI, 0.4%-2.6%). These benefits were ob served at 9 days(537[8.9%] placebo vs 444[7.4%] fondaparinux; HR, 0.83; 95%CI , 0.73-0.94; P=.003), and at study end(857[14.8%] placebo vs 756[13.4%] fonda parinux; HR, 0.88; 95%CI, 0.79-0.97; P=.008). Mortality was significantly redu ced throughout the study. There was no heterogeneity of the effects of fondapari nux in the 2 strata by planned heparin use. However, there was no benefit in tho se undergoing primary percutaneous coronary intervention. In other patients in s tratum 2, fondaparinux was superior to unfractionated heparin in preventing deat h or reinfarction at 30 days(HR, 0.82; 95%CI, 0.66-1.02; P=.08) and at study e nd(HR, 0.77; 95%CI, 0.64-0.93; P=.008). Significant benefits were observed in those receiving thrombolytic therapy(HR, 0.79; P=.003) and those not receiving a ny reperfusion therapy(HR, 0.80; P=.03). There was a tendency to fewer severe bleeds(79 for placebo vs 61 for fondaparinux; P=.13), with significantly fewer car diac tamponade(48 vs 28; P=.02) with fondaparinux at 9 days. Conclusion: In pati ents with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction wit hout increasing bleeding and strokes. Context: Despite many therapeutic advances, mortality in patients with acute S T-segment elevation myocardial infarction (STEMI) remains high. The role of addi tional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. Objective: To evaluate the effect of fondaparinux, a facto r Xa inhibitor, when initiated early and given for up to 8 days vs usual care (pl acebo in those in unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours past by placebo for up to 8 days [stratum 2]) in patients with STEMI. Design, Setting, and Participants: Randomiz ed double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12 092 patients with STEMI from 447 hospitals in 41 countries (Septeber 2003-January 2006). From day 3 through day 9, all patients receive either fondaparinux or placebo according to the original randomized assignment. Main Outcome Measures: Composite of death or reinfarction at 30 days (primary) with sec ondary assessments at 9 days and at final follow-up (3 or 6 months). Results: Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparin ux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5% 95% CI, 0.73-0.94; P = .003 (95% CI, 0.4% -2.6%). These benefits were ob served at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; ), and at study end (857 [14.8%] placebo vs 756 [13.4%] fonda parinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced ced throughout the study. was no heterogeneity of the effects of fondapari nux in the 2 strata by planned heparin use. However, there was no benefit in tho se undergoing primary percutaneous coronary intervention. In other patients in s tratum 2, fondaparinux was superior to unfractionated heparin in preventing deat hoSignificant benefits were (r = 0.82; 95% CI, 0.66-1.02; P = .08) and at study e nd (HR, 0.77; 95% CI, 0.64-0.93; observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving a ny reperfusion therapy (HR, 0.80; P = .03). There was a tendency to reduce severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13) with significantly fewer car diac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. Conclusion: In pati ents with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction wit hout increasing bleeding and strokes.