1. FRagmin® and Fast Revascularization during InStablity in Coronary artery disease FRISC II

2. Trial Design Assessment of the efficacy of long-term treatment with Fragmin® vs. placebo in patients managed with a non- invasive treatment strategy –Enrolled 2276 patients with unstable coronary artery disease –Patients recruited from June, 1996 - August 1998 –58 Scandinavian Centers –Randomized –Double Blind –Placebo Controlled –Intention to Treat Analysis Lancet 1999; 354: 701-07

3. FRISC II Study Design for Primary Objective Fragmin vs. Placebo in Non-Invasive Arms * Randomized to Invasive or Non-Invasive Strategy within 72 hours of enrollment † Randomized to receive placebo or Fragmin® for 3 months 1  Endpoint Death or MI at 3 Months: Both Fragmin® arms compared to Both Placebo Arms UCAD Patients w/ symptoms < 48 hours eligible for revascularization, but randomized to a Non-Invasive Strategy arm* All Patients receive Fragmin® for 5 to 7 days in the open acute phase after enrollment UCAD Patients w/ symptoms < 48 hours contraindicated to revascularization Fragmin® s.c. twice daily for 3 months (n=1049) Placebo s.c. twice daily for 3 months (n=1056) † † Lancet 1999; 354: 701-07

4. FRISC II Primary Objectives In patients treated with a non-invasive strategy (randomized to non-invasive or contraindicated to an early invasive strategy): –Compare the prolonged treatment (after open Fragmin  s.c. 120 IU/kg/12h - maximal dose 10,000 IU/12h - during the acute phase) for three months using either Fragmin® or placebo s.c. twice daily concerning the: incidence of death or MI –(1  Endpoint of D/MI at 3 months) need for revascularization bleeding Fragmin vs. Placebo in Non-Invasive Arms Lancet 1999; 354: 701-07

5. FRISC II Randomization for Primary Objective Open acute treatment phase –Open Fragmin® 120 IU/kg twice daily for 5 to 7 days (median duration of open-label Fragmin ® treatment was 6 days) Patients should be randomized within 72 hours of this treatment Day 1 is the start of the double blind prolonged Fragmin® or placebo phase Fragmin vs. Placebo in Non-Invasive Arms Lancet 1999; 354: 701-07

6. FRISC II Randomization for Primary Objective (cont.) Placebo controlled double-blind phase – All patients randomized to Fragmin® or Placebo – Fragmin® or Placebo given s.c. twice daily for 90 days. Median treatment duration was similar for Fragmin ® and placebo (87 and 88 days respectively) Gender and Weight Dose Stratification Men > 70 kg 7500 IU, < 70 kg 5000 IU Women > 80 kg 7500 IU, < 80 kg 5000 IU Fragmin vs. Placebo in Non-Invasive Arms Lancet 1999; 354: 701-07

7. FRISC II Inclusion Criteria Men > 40 years or women postmenopausal > 12 months Last episode of pain < 48 hours before open Fragmin® Signs of myocardial ischemia or developing non-Q-MI –ST-depression or T-wave inversion –Available biochemical marker above normal range Lancet 1999; 354: 701-07

8. FRISC II Baseline Characteristics VariableFragminPlacebo (n=1049)(n=1056) Age median67 years67 years Men 68% 69% Hypertension 33% 33% Diabetes mellitus 14% 12% Previous MI 30% 27% Chest pain at rest 82% 80% ST-depression at entry 46% 50% Troponin-T > 0.1 ng/ml 57% (n=574) 60% (n=611) Fragmin vs Placebo Lancet 1999; 354: 701-07

9. FRISC II Important Exclusion Criteria Increased risk of bleeding Thrombolysis indication or administered within last 24 hours PTCA within the last 6 months Waiting for coronary angiogram or revascularization Other severe illness Anticipated problems of cooperation Fragmin vs Placebo Lancet 1999; 354: 701-07

10. FRISC II Contraindication to Early Revascularization Only randomized to Fragmin® or Placebo Previous open heart surgery Advanced age (> 75 years) Other concomitant disease or condition that makes early revascularization inappropriate Fragmin vs Placebo Lancet 1999; 354: 701-07

11. Primary Endpoint and Components at 90 days (during Double - Blind Phase) Fragmin vs Placebo FRISC II- (Preliminary Data) 8.0 1.6 1.5 6.7 1.3 0.9 0.0 2.0 4.0 6.0 8.0 10.0 Death or MIDeathCardiac Death % of Patients Placebo (n=1056)Fragmin (n=1049) p=0.17 Lancet 1999; 354: 701-07

12. Death or MI at 30 and 90 days (during Double - Blind Phase) Fragmin vs Placebo FRISC II- (Preliminary Data) 5.9 8.0 3.1 6.7 0.0 2.0 4.0 6.0 8.0 10.0 Death or MI (30 days)Death or MI (90 days) % of Patients Placebo (n=1056)Fragmin (n=1049) p=0.002 p=0.17 47%  Lancet 1999; 354: 701-07 16% 

13. Results during Double-Blind Phase (Death or MI) Fragmin vs Placebo TimeFragminPlacebo RR (95% CI) p 90 days 6.7%8.0%0.82 (0.60-1.10) 0.17 30 days 3.1%5.9%0.53 (0.35-0.80)0.002 There was a 47% reduction in Death or MI at 30 days with Fragmin compared to placebo which was highly significant ( p = 0.002). However, there was not a significant reduction in events at 90 days (primary endpoint). FRISC II- (Preliminary Data) Lancet 1999; 354: 701-07

14. FRISC II TimeFragminPlacebo RR (95% CI) p 90 days 6.7% 8.0%0.81 (0.60-1.10) 0.17 30 days 3.1% 5.9%0.53 (0.35-0.80)0.002 Death or MI at 90 Days (during DB Phase) Lancet 1999; 354: 701-07 p=0.002 p=0.17

15. Death or MI through 1, 3 and 6 Months (including open acute phase) Fragmin vs Placebo FRISC II - 8.4 11.2 13.1 6.2 10.0 13.3 0.0 5.0 10.0 15.0 20.0 30 Day D/MI3 Month D/MI6 Month D/MI % of Patients PlaceboFragmin p=0.048 Lancet 1999; 354: 701-07 p=0.34p=0.93 n= 1121 1129 n= 1103 1115 n= 1121 1129

16. D/MI or Revascularization through 1, 3, or 6 Months (including open acute phase) Fragmin vs Placebo FRISC II - 25.7 33.4 39.9 19.5 29.1 38.4 0.0 10.0 20.0 30.0 40.0 50.0 30 Day Events3 Month Events6 Month Events % of Patients PlaceboFragmin p=0.001 Lancet 1999; 354: 701-07 p=0.031p=0.50 n= 1121 1129 n= 1103 1115 n= 1121 1129

17. 30 Day Death or MI based on Troponin Status (during Double - Blind Phase) Fragmin vs Placebo FRISC II - 6.4 9.3 6.1 6.4 0.0 2.0 4.0 6.0 8.0 10.0 12.0 Troponin < 0.1 ng/mlTroponin > 0.1 ng/ml % of Patients Placebo (n=1056)Fragmin (n=1049) p=NS p=0.07 Lancet 1999; 354: 701-07 30%  n= 574 611n= 425 404

18. FRISC II Adverse Events Fragmin vs Placebo (Double-Blind Treatment Period) VariableFragminPlacebo n=1049 n=1056 Major 3.3% 1.5% Minor 23.0% 8.4% Stroke total 1.0% 0.8% Hemmorhagic 0.8% 0.0% Other Stroke 0.2% 0.8% Thrombocytopenia (<100K) 0.0% 0.5% Allergic Reactions 2.3% 1.8% Lancet 1999; 354: 701-07

19. FRISC II Conclusions In UCAD patients, treatment with Fragmin® in addition to aspirin and anti-anginal treatment: Significantly reduced cardiac events (D/MI) by 47% (p=0.002) through 30 days. However, the primary endpoint (reduction in 90 day D/MI) was not significant. Significantly reduced D/MI/Revascularization at 30 and 90 days. Allows time for planning of invasive procedures. Shows comparable risk of bleeding to placebo Troponin-T positive (> 0.01 ng/ml) patients had a 30% reduction in D/MI at 90 days if they were randomized to Fragmin (p=0.07). Lancet 1999; 354: 701-07

20. Fragmin® and Fast Revascularization during InStablity in Coronary artery disease FRISC II

21. Trial Design Compare an early invasive with a non-invasive treatment strategy in patients with unstable coronary artery disease –Enrolled 2457 patients with unstable coronary artery disease –Patients recruited from June, 1996 - May 1998 –58 Scandinavian Centers –Randomized –Double Blind –Placebo Controlled –Intention to Treat Analysis Lancet 1999; 354: 708-15

22. FRISC II Study Design for Secondary Objective * Randomized to Invasive or Non-Invasive Strategy within 72 hours of enrollment † Randomized to receive placebo or Fragmin® for 3 months 1  Endpoint of Death or MI Measured at 6 Months: Both Invasive arms compared to Both Non-Invasive Arms UCAD Patients w/ symptoms < 48 hours eligible for revascularization* All Patients receive Fragmin® for 5 to 7 days in the open acute phase after enrollment Invasive Strategy PCI or CABG within 7 days † (n=1222) Stepwise Selective (Non-Invasive) Revascularization Strategy † ‡ (n=1235) Fragmin® or Placebo s.c twice daily for 3 months ‡ PCI or CABG only if driven by refractory clinical symptoms Invasive vs. Non-Invasive Lancet 1999; 354: 708-15

23. FRISC II Secondary Objectives In patients eligible for an early invasive strategy: –Compare a direct invasive approach with early coronary angiography and revascularization (invasive) vs. a stepwise selective approach with coronary angiography and revascularization only if driven by refractory clinical symptoms (non-invasive) concerning: death or MI –(1  Endpoint for this phase is D/MI at 6 months) revascularization bleeding Invasive vs. Non-Invasive Lancet 1999; 354: 708-15

24. FRISC II Baseline Characteristics Variable InvasiveNon-invasive (n=1222) (n=1235) Age median66 years 65 years Men 71% 68% Hypertension 30% 31% Diabetes mellitus 13% 12% Previous MI 23% 22% ST-depression at entry 45% 46% Troponin-T > 0.1 ng/ml 57% 58% LVEF < 45% 14% 12% Invasive vs Non-Invasive Lancet 1999; 354: 708-15

25. FRISC II Coronary Procedures by Arms Variable InvasiveNon-invasive (n=1222) (n=1235) Coronary Angiography 98% 47% Time to Angiography 4 days 17 days PCI n (%) 522 (43%) 220 (18%) Time to PCI 4 days 16.5 days Stents 61% 70% Abciximab 10% 10% CABG n (%) 430 (35%) 233 (19%) Time to CABG 7 days 28 days Invasive vs Non-Invasive Lancet 1999; 354: 708-15

26. FRISC II Important Exclusion Criteria Increased risk of bleeding Thrombolysis indication or administered within the last 24 hours PTCA within the last 6 months Waiting for coronary angiogram/revascularization Contraindication to early revascularization –Previous open heart surgery –Advanced age (> 75 years) –Other severe disease Invasive vs Non-Invasive Lancet 1999; 354: 708-15

27. FRISC II Randomization for Secondary Objective Invasive vs Non-Invasive Open acute treatment phase – All patients were administered open Fragmin® 120 IU/kg twice daily for 5 to 7 days Patients should be randomized within 72 hours of this treatment Day 1 is the start of the open acute treatment phase Lancet 1999; 354: 708-15

28. FRISC II Randomization for Secondary Objective (cont.) Invasive direct strategy –Coronary angiogram/revascularization < 7 days in all patients –PCI/CABG at > 70% stenosis in major coronary arteries: PTCA preferred for 1-2 vessel disease CABG preferred for 3 vessel or left main disease Invasive vs Non-Invasive Non-invasive selective strategy – Coronary angiography and revascularization only at : recurring or incapacitating symptoms or severe ischemia at exercise test Patients without contra-indications to an early invasive strategy are randomized to either an: Lancet 1999; 354: 708-15

29. Primary Endpoint: Death or MI at 6 months* Invasive vs. Non-Invasive FRISC II - 12.1 9.4 0.0 5.0 10.0 15.0 Death or MI % of Patients Non-Invasive (n=1226)Invasive (n=1207) 22 %  p=0.031 * Does not include patients contraindicated to revascularization Lancet 1999; 354: 708-15

30. FRISC II Death or MI at 6 months (inv vs non-inv) Patients Eligible for Revascularization Lancet 1999; 354: 708-15 p=0.031

31. FRISC II Death and MI through 6 months Patients Eligible for Revascularization Lancet 1999; 354: 708-15 p=0.045 p=0.10

32. FRISC II Death or MI at 6 months* * Does not include patients contraindicated to revascularization Lancet 1999; 354: 708-15

33. 6 Months Death or MI by Gender* Invasive vs. Non-Invasive FRISC II- (Preliminary Data) 13.9 8.3 8.9 10.5 0.0 5.0 10.0 15.0 20.0 MaleFemale % of Patients Non-InvasiveInvasive RR 1.26 (0.80-1.97) 21%  RR 0.64 (0.49-0.84) 36%  n= 828 863 n= 398 344 * Does not include patients contraindicated to revascularization Lancet 1999; 354: 708-15

34. FRISC II Adverse Events Invasive vs Non-Invasive Variable InvasiveNon-invasive (n=1222) (n=1235) % (n) % (n) Major Bleeding 1.6% (19) 0.7% (9) Minor Bleeding 7.6% (93) 5.8% (72) Total Stroke 0.2% (2) 0.2% (3) Thrombocytopenia (<100K) 0.1% (1) 0.1% (1) * Does not include patients contraindicated to revascularization Lancet 1999; 354: 708-15

35. FRISC II Conclusions In unstable angina/non Q wave MI patients, the early invasive strategy: Reduces the incidence of 6 month death or MI by 22% (p=0.031) –reduced the incidence of 6 month death or MI in men by 36%; RR 0.53 (0.45-0.65) –increased the incidence of 6 month death or MI in women by 21%; RR 1.26 (0.80-1.97) Reduces symptoms of angina Reduces re-admissions and late procedures Invasive vs Non-Invasive Lancet 1999; 354: 708-15

36. FRISC II Conclusions Early revascularization reduced the incidence of 6 month death or MI by 22% compared with a stepwise selective revascularization strategy: –Only 10% of all patients received abciximab. “The increasing use of abciximab in association with percutaneous coronary intervention and stenting will lower the rate of events related to percutaneous coronary interventions by 50%” –The superiority of an early invasive approach in reducing death or MI through 6 months was driven by a 36% reduction in men. Female patients had a non-significant increase in 6 month death or MI with an early invasive approach compared to a non- invasive strategy. Lancet 1999; 354: 708-15 In unstable angina/non Q wave MI patients

37. FRISC II Conclusions Female patients may benefit from a non-invasive treatment strategy compared to an early invasive strategy. –In female patients treated with a non-invasive treatment strategy, long-term anti-thrombotic treatment with Fragmin® reduced death or MI by 23% through 90 days. In unstable angina/non Q wave MI patients receiving a non-invasive treatment strategy: Troponin-T + (> 0.1  g/ml) patients receiving a non-invasive treatment strategy had a trend in the reduction of death and MI through 90 days when treated with long-term Fragmin® compared to placebo (9.3% vs. 6.6%; p=0.07). Long-term anti-thrombotic treatment with Fragmin® reduces death or MI by 47% through 30 days which is useful if early interventional procedures are inappropriate.