Context: The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes(ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction(MI) at 30 days. Objective: To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up. Design, Setting, and Patients: Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year. Main Outcome Measures: Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all-cause death. Results: Six-month and 1-year follow-up data were available for 9957(99.8% ) and 9608(96.3% ) of 9978 patients, respectively; 541 patients(5.4% ) had died at 6 months and 739(7.4% ) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin(17.6% ) vs 884 receiving unfractionated heparin(17.8% )(hazard ratio[HR], 0.98; 95% confidence interval[CI], 0.89- 1.07; P=.65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization(n=6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days(HR, 0.85; 95% CI, 0.75- 0.95; P=.006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin(17.9% ) and 911 receiving unfractionated heparin(19.0% )(HR, 0.94; 95% CI, 0.85- 1.03; P=.17). One-year all-cause death rates were similar in the 2 treatment groups(380/4974[7.6% ] for enoxaparin vs 359/4948[7.3% ] for unfractionated heparin; HR, 1.06; 95% CI, 0.92- 1.22; P=.44). One-year death rates in patients receiving consistent therapy were also similar(251/3386[7.4% ] for enoxaparin vs 213/2720[7.8% ] for unfractionated heparin; HR, 0.95; 95% CI, 0.79- 1.14; P=.55). Conclusions: In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies. Context: The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days. Objective: To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up. Design, Setting, and Patients: Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year. Main Outcome Measures: Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all- 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65) consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; 006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17) The cause of death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P =. 55). Conclusions: Inthe SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies.