1. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN - Purpose To assess efficacy of long-term treatment with the low molecular mass heparin dalteparin, in non-invasive treatment strategy for unstable coronary artery disease Reference FRISC II Investigators. Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:701–7.

2. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: TRIAL DESIGN - Design Randomized, multicenter, double-blind, placebo-controlled: non- invasive arm of trial also investigating invasive treatment Patient selection Hospitalized with ischemia symptoms for <48 h before start of heparin/dalteparin increasing or at rest (chest pain with ST depression, T inversion or raised biochemical markers) Pre-randomization therapy Aspirin 300–600 mg; blockade unless contraindicated; organic nitrates, Ca ++ antagonists as required; statins, ACE inhibitors, aggressive antidiabetic treatment according to guidelines Dalteparin 120 U/kg every 12 h or infusion of standard heparin

3. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: TRIAL DESIGN cont. - Randomization Up to 72h after start of open-label dalteparin, patients randomized to: early invasive or non-invasive treatment (in absence of contraindications for invasive treatment) or dalteparin or placebo for 90 days (all patients) All patients received open-label dalteparin 120 U/kg every 12h for at least 5 days until: non-invasive double-blind dalteparin/placebo treatment started or revascularization and double-blind dalteparin/placebo started

4. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: TRIAL DESIGN cont. - Patients 2267 (median age 67 years) entered long-term heparin vs. placebo arm Follow up and primary endpoint Primary endpoint death or MI at 30 days Treatment Dalteparin 5000 (women <80 kg, men <70 kg) or 7000 U SC twice daily or placebo for 90 days

5. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: RESULTS - For double-blind period: Decrease in death or MI significant at 30 days but not at 3 months For total treatment period: Significant decrease at 3 months in triple endpoint of MI, death or revascularization for total cohort but this benefit not carried over to end of 6 months Subgroups: Patients with raised troponin-T at entry showed 30% relative (2.7% absolute) decrease in MI or death at 3 months (P=0.07); this effect not seen in patients with normal troponin T

6. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: RESULTS cont. - 0 0 102040506070309080 0.08 0.06 0.04 0.02 0.10 0.12 0.14 Days after start of treatment Death or MI during double-blind and total treatment period FRISC II Investigators.Lancet 1999;354:701–7. Placebo Dalteparin Double-blind period Total treatment period Probability of death, MI or revascularization

7. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: RESULTS cont. - Days after start of open-label dalteparin 0 0 102030506070904080 0.10 0.20 0.30 0.40 Placebo Dalteparin Triple outcome: death, MI or revascularization FRISC II Investigators.Lancet 1999;354:701–7. Probability of death, MI or revascularization

8. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: RESULTS cont. -

9. FRISC II: Fragmin and fast Revascularization during InStability in Coronary artery disease - LONG-TERM HEPARIN: SUMMARY - Dalteparin lowers risk of death, MI and the need for revascularization during the first month Initial benefits not sustained during longer term follow up within non-invasive treatment strategy