1. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3 Efficacy and Safety of Tenecteplase in Combination with Enoxaparin, Abciximab or Unfractionated Heparin: the ASSENT-3 Randomised Trial in Acute Myocardial Infarction The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators

2. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Inclusion Criteria Inclusion criteria were identical to those of the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-2 trial:Inclusion criteria were identical to those of the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-2 trial:  Age 18 years or older  Onset of symptoms within 6 hours before randomization  ST-segment elevation of 1 mm or more in two or more limb leads, or 2 mm or more in two or more contiguous precordial leads or left bundle-branch block.

3. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Exclusion Criteria Exclusion criteria on admission were: Systolic blood pressure of more than 180 mm HgSystolic blood pressure of more than 180 mm Hg Diastolic blood pressure of more than 110 mm Hg, or both on repeated measurementsDiastolic blood pressure of more than 110 mm Hg, or both on repeated measurements Use of abciximab or other glycoprotein IIb/IIIa inhibitors within the preceding seven daysUse of abciximab or other glycoprotein IIb/IIIa inhibitors within the preceding seven days Major surgery, biopsy of a parenchymal organ or substantial trauma within two monthsMajor surgery, biopsy of a parenchymal organ or substantial trauma within two months Any head or other trauma occurring after onset of current myocardial infarction; any known history of stroke, transient ischemic attack or dementia; any known structural damage to the central nervous systemAny head or other trauma occurring after onset of current myocardial infarction; any known history of stroke, transient ischemic attack or dementia; any known structural damage to the central nervous system Current therapy with oral anticoagulants; treatment with unfractionated heparin 5,000 U or a therapeutic subcutaneous dose of low-molecular-weight heparin within 6 hoursCurrent therapy with oral anticoagulants; treatment with unfractionated heparin 5,000 U or a therapeutic subcutaneous dose of low-molecular-weight heparin within 6 hours

4. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Exclusion Criteria (continued) Exclusion criteria on admission were (continued): Known thrombocytopenia (100,000 cells/l)Known thrombocytopenia (100,000 cells/l) Known renal insufficiency (serum creatinine 2.5 mg% for men and 2.0 mg% for women)Known renal insufficiency (serum creatinine 2.5 mg% for men and 2.0 mg% for women) Sustained cardiopulmonary resuscitation (more than 10 min) in previous two weeksSustained cardiopulmonary resuscitation (more than 10 min) in previous two weeks Pregnancy, lactation, or parturition in the previous 30 daysPregnancy, lactation, or parturition in the previous 30 days Active participation in another investigative drug or device study in the previous 30 days; previous enrolment in this studyActive participation in another investigative drug or device study in the previous 30 days; previous enrolment in this study Inability to follow the protocol and to comply with the follow-up requirementsInability to follow the protocol and to comply with the follow-up requirements

5. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. UFH IV bolus enoxaparin IV bolus UFH IV bolus Wt adj TNK-tPA full-dose IV bolus abciximab IV bolus UFH IV infusion for up to 48 hours enoxaparin SC injections every 12 hours up to discharge or revascularization (max of 7 days) Wt adj TNK-tPA half-dose IV bolus abciximab IV infusion for 12 hours UFH IV infusion for up to 48 hours randomization 1:1:1 ASSENT 3: Trial Design An international, multicenter, randomized (1:1:1), open-label, controlled, parallel- group study in patients with ST-elevation AMI presenting within 6 hours of symptom onset, treated with 1 of 3 different reperfusion regimens

6. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Primary Endpoints Primary Efficacy Endpoint: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia. Primary Efficacy Plus Safety Endpoint: Composite of 30-day mortality or in-hospital reinfarction or in- hospital refractory ischemia plus in-hospital intracranial haemorrhage or in-hospital major bleeding other than intracranial.

7. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Patients Randomized (ITT) Female, (%) Age (median years) Previous MI (%) Anterior MI (%) Diabetes (%) ASSENT II 97-98 ASSENT II 97-98 16949 23 61 16 40 16 2.8 GUSTO V 99-01 GUSTO V 99-01 16588 25 61 15 37 16 2.7 GUSTO III 95-97 GUSTO III 95-97 15059 27 63 18 48 16 2.7 InTIME II 97-99 InTIME II 97-99 15060 25 62 16 42 14 2.9 Median Time (hrs) Between Symptom and First Study Rx Median Time (hrs) Between Symptom and First Study Rx GUSTO I 90-93 GUSTO I 90-93 30647 25 62 17 39 15 2.8 ASSENT 3 00-01 ASSENT 3 00-01 2040 23 61 14 39 19 2.7 ASSENT 3 00-01 ASSENT 3 00-01 2017 24 61 13 39 18 2.7 ASSENT 3 00-01 ASSENT 3 00-01 2038 23 61 14 38 18 2.8 Baseline Demographics of Large Scale Thrombolytic Trials

8. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Primary Composite Endpoints at Hospital Discharge and at 30 Days Unfractionated 3 way EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) 30-day mortality or11.411.115.4<0.0001 in-hospital reinfarction or in-hospital refractory ischemia 30-day mortality or13.814.217.00.0081 in-hospital reinfarction or in-hospital refractory ischemia or in-hospital ICH or in-hospital major bleeds (other than ICH) Data are percentages and 95% confidence intervals. ICH, intracranial hemorrhage.

9. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Days to Death or Reinfarction or Refractory Ischemia Days to Death or Reinfarction or Refractory Ischemia Probability (%) 0 2 4 6 8 10 14 12 16 18 20 51015202530 UnfractionatedHeparin Enoxaparin Abciximab Log-rank test: P=0.0001 0 15.4% 11.4% 11.1%

10. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Days to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleeding Days to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleeding Probability (%) 0 2 4 6 8 10 14 12 16 18 20 51015202530 UnfractionatedHeparin Abciximab Enoxaparin Log-rank test: P=0.0062 0 13.8% 14.2% 17.0%

11. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: 30 Day Mortality, Recurrent MI, Refractory Ischemia Enoxaparin Abciximab % Risk of 30 Day D / MI / Ref Isch 3 way P=0.0001 p=0.0002* p=0.0009* *P values are the Bonferroni p-values after correcting for multiple comparisons. The uncorrected p-values were p=0.0002 for the enox vs UFH comparison, and <0.0001 for the abcix vs UFH comparison.

12. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: 30 Day Mortality, Recurrent MI, Refractory Ischemia Enoxaparin Abciximab 3 way p=0.0062 ASSENT 3: 30 Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding, ICH % Risk of 30 Day D / MI / Ref Isch / Maj Bleed / ICH p=0.057* p=0.0146* *P values are the Bonferroni p-values after correcting for multiple comparisons. The uncorrected p-values were p=0.0037 for the enox vs UFH comparison, and 0.0142 for the abcix vs UFH comparison.

13. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Death at 30 Days orENOX or In-Hospital Reinfarction orENOX orRelative RiskABCIXUFH Refractory Ischemia (%)UFHABCIX(95% CI)BetterBetter ASSENT 3: Odds Ratios for Death at 30 Days or In- Hospital Reinfarction or Refractory Ischemia 0.512 ENOX vs UFH ABCIX vs UFH UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab. Overall event rate15.411.40.74 (0.63, 0.87) 11.10.72 (0.61, 0.84) Gender Male14.810.40.70 (0.58, 0.84) 9.80.66 (0.55, 0.80) Female17.415.10.87 (0.65, 1.17) 14.80.85 (0.64, 1.14) Infarct location Anterior19.414.60.75 (0.60, 0.94) 13.60.70 (0.56, 0.88) Other13.09.50.72 (0.58, 0.91) 9.50.73 (0.58, 0.91) Time to TNK-tPA (h) 0-216.813.00.77 (0.59, 1.01) 8.90.53 (0.38, 0.74) >2-414.29.80.69 (0.53, 0.84) 10.90.76 (0.60, 0.96) >416.312.60.77 (0.56, 1.06) 13.30.82 (0.60, 1.10)

14. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Odds Ratio for Death at 30 Days or In- Hospital Reinfarction or Refractory Ischemia (Cont.) ENOX vs UFH ABCIX vs UFH UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab. Death at 30 Days orENOX or In-Hospital Reinfarction orENOX orRelative RiskABCIXUFH Refractory Ischemia (%)UFHABCIX(95% CI)BetterBetter Age (years) ≤7513.810.00.73 (0.61, 0.87) 9.00.65 (0.54, 0.78) >7526.220.90.80 (0.59, 1.09) 26.61.02 (0.76, 1.36) Diabetes Yes13.812.40.90 (0.62, 1.30) 18.01.31 (0.93, 1.84) No15.811.20.71 (0.60, 0.85) 9.50.60 (0.50, 0.72) 0.512 * There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (p=0.0004). *

15. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Death at 30 Days or In-HospitalENOX or Reinfarction or Refractory IschemiaENOX orRelative RiskABCIXUFH or ICH or Major Bleeding (%)UFHABCIX(95% CI)BetterBetter Overall event rate17.013.70.81 (0.70, 0.93) 14.20.84 (0.73, 0.97) Gender Male16.211.90.73 (0.61, 0.88) 12.550.77 (0.65, 0.92) Female19.920.11.01 (0.78, 1.31) 20.01.01 (0.78, 1.30) Infarct location Anterior20.516.00.78 (0.63, 0.96) 16.60.83 (0.67, 1.02) Other15.012.30.82 (0.67, 1.00) 12.80.85 (0.70, 1.03) Time to TNK-tPA (h) 0-218.316.20.88 (0.69, 1.14) 13.00.71 (0.53, 0.95) >2-415.811.90.75 (0.60, 0.94) 13.50.87 (0.70, 1.07) >418.013.90.77 (0.57, 1.05) 16.90.94 (0.71, 1.23) ASSENT 3: Odds Ratios for Days to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleeding 0.512 ENOX vs UFH ABCIX vs UFH UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab.

16. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Odds Ratio for Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding (Cont.) Death at 30 Days or In-HospitalENOX or Reinfarction or Refractory IschemiaENOX orRelative RiskABCIXUFH or ICH or Major Bleeding (%)UFHABCIX(95% CI)BetterBetter Age (years) ≤7515.412.00.78 (0.66, 0.92) 11.20.74 (0.63, 0.88) >7528.025.50.91 (0.69, 1.20) 36.91.30 (1.01, 1.68) Diabetes Yes16.513.90.84 (0.60, 1.19) 22.31.35 (1.00, 1.82) No17.213.70.80 (0.68, 0.94) 12.50.74 (0.62, 0.87) 0.512 ENOX vs UFH ABCIX vs UFH UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab. *There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (p=0.0007), and likewise, patients over the age of 75 had poorer outcomes with abciximab (p=0.0010).

17. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Enoxaparin Abciximab ASSENT 3: 30 Day Mortality % Risk of 30 Day Efficacy & Safety Endpoint ASSENT 3: Primary Efficacy and Safety Endpoint of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients > 75 Years of Age *There was a statistically significant interaction between treatment with abciximab and age such that patients over the age of 75 had poorer outcomes with abciximab (p=0.0010). *p=0.001

18. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Enoxaparin Abciximab ASSENT 3: Primary Efficacy and Safety Endpoint of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with Diabetes % Risk of 30 Day Efficacy & Safety Endpoint *There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (p=0.0007). *p=0.0007

19. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Frequency of Individual Endpoints at Hospital Discharge and at 30 Days Unfractionated 3 way EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) Death at 30 days5.46.66.00.25 In-hospital reinfarction2.72.24.20.0009 In-hospital refractory4.63.26.5<0.0001 ischemia In-hospital ICH0.90.90.90.98 Major bleeding3.04.32.20.0005 (other than ICH) Data are percentages. ICH, intracranial hemorrhage.

20. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Enoxaparin Abciximab ASSENT 3: 30 Day Mortality ASSENT 3: Risk of Major Bleeding % Risk of Major Hemorrhage 3 Way p = 0.005 p=0.0002 p=NS

21. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complications Unfractionated EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038)3 way Any thrombocytopenia1.23.21.3<0.0001 Thrombocytopenia<0.0001 <20,000 cells/µL0.10.50.2 20,000 to 50,000 cells/µL0.20.60.2 50,000 to <100,000 cells/µL0.92.01.0 Bleeding episodes Total25.639.721.1<0.0001 Major3.04.32.20.0005 Minor22.635.418.8<0.0001 Blood transfusion3.44.22.30.0032 * * * * * While 3 way p value is significant, Enoxaparin vs UFH comparison p=NS

22. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Abciximab ASSENT 3: 30 Day Mortality ASSENT 3: Risk of Major Bleeding in Patients Over 75 Years % Risk of Major Hemorrhage

23. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. Abciximab ASSENT 3: 30 Day Mortality ASSENT 3: Risk of Major Bleeding in Patients With Diabetes % Risk of Major Hemorrhage

24. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Study Group Conclusions Regarding TNK + Abciximab Therapy “The results obtained with half-dose tenecteplase plus abciximab are very similar to those with half-dose reteplase and abciximab seen in GUSTO-V.”“The results obtained with half-dose tenecteplase plus abciximab are very similar to those with half-dose reteplase and abciximab seen in GUSTO-V.” “In both trials, these benefits are obtained at the cost of a higher rate of major bleeding complications and blood transfusions”.“In both trials, these benefits are obtained at the cost of a higher rate of major bleeding complications and blood transfusions”. “No benefit and perhaps even harm was observed in patients above 75 years and in diabetics”.“No benefit and perhaps even harm was observed in patients above 75 years and in diabetics”. “Taken together they suggest that caution should be exercised regarding the use of conjunctive therapy with abciximab in elderly patients with an acute myocardial infarction treated with a fibrinolytic agent.”“Taken together they suggest that caution should be exercised regarding the use of conjunctive therapy with abciximab in elderly patients with an acute myocardial infarction treated with a fibrinolytic agent.”

25. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Conclusions Regarding Enoxaparin “In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase”.“In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase”.

26. The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13. ASSENT 3: Unanswered Questions “Whether enoxaparin is a desirable anticoagulant in conjunction with less fibrin-specific agents or whether enoxaparin can replace unfractionated heparin in combination with a platelet glycoprotein IIb/IIIa inhibitor and what role various pharmacologic combinations will ultimately have in conjunction with early coronary intervention needs to be determined”.“Whether enoxaparin is a desirable anticoagulant in conjunction with less fibrin-specific agents or whether enoxaparin can replace unfractionated heparin in combination with a platelet glycoprotein IIb/IIIa inhibitor and what role various pharmacologic combinations will ultimately have in conjunction with early coronary intervention needs to be determined”.