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 Trial Design ST-Segment Elevation AMI (6095 patients) Randomized 150-325 mg Aspirin (daily) Half-Dose TNK-tPA Plus Abciximab Plus Low-Dose Heparin Full-Dose TNK-tPA Plus Weight-Adjusted Heparin Full-Dose TNK-tPA Plus Enoxaparin

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: Rationale for Inclusion of TNK-tPA Monotherapy and Unfractionated Heparin TNK-tPA plus UFH (fully weight-adjusted)TNK-tPA plus UFH (fully weight-adjusted) –In spite of several 100,000s of patients studied in thrombolysis trials, the optimal dose of concomitant UFH remains unknown –InTIME-II data with t-PA suggest lower ICH rates with reduced, fully weight-adjusted UFH, and earlier aPTT monitoring –AHA/ACC-recommended fully weight-adjusted dose of UFH never tested prospectively in a large-scale trial

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. Pathophysiology of Combination Therapy in AMI *Gibson et al. J Am Coll Cardiol. 1995;25:582-589. Gibson et al. Circulation. 2001;103:2550-2554. Combination Therapy  Thrombus  % Stenosis  Minimum Diameter  Epicardial Flow  Myocardial Blush  ST Resolution  Myocardial Flow Facilitates PCI Reduces Reinfarction*

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. Ohman et al. Circulation. 1990;82:781-791. Angiographic Predictors of Reocclusion Incidence of reocclusion (%) 0 2 4 6 8 10 12 TIMI 2 TIMI 3 10.4 2.2 P=0.003 P=0.03 P=0.009 P=0.06 TIMI Flow CollateralsUlcer P=0.04 Thrombus % Stenosis Clinical Impact of Reocclusion: 810 patients, cath 90 min & 7 days later: 12.4% reocclude, 58% symptomatic, in-hospital mortality 11.0% vs 4.5% (P=0.01). Gibson et al. J Am Coll Cardiol. 1995;25:582-589. 71 72 73 74 75 76 79 + – 77.9 73.9 18.2 5.6 0 2 4 6 8 10 12 + – 10.7 3.0 + – 8.4 3.3 0 4 10 14 18 20 2 8 12 16 0 2 4 6 891 3 5 7 77 78 6 + –

6. When a small camera is placed in the artery (angioscopy), all 40 thrombolytic patients in a study by Van Belle et al had some remaining form of thrombus (shown in red here). While thrombolysis reduces thrombus burden, thrombus remains, & thrombolysis exposes underlying ulcerated lesions. The high frequency of persistent thrombotic lesions underscores the need for effective antithrombotic therapy following thrombolytic administration. Thrombus Remains Following Thrombolysis: The Need For Aggressive Antithrombotic / Antiplatelet Therapy Van Belle et al. Circulation. 1998;97:26-33.

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. ASSENT 3: Rationale for Use of Enoxaparin TNK-tPA plus enoxaparinTNK-tPA plus enoxaparin –Favorable effects of LMWHs in recent small-scale thrombolysis trials –Higher late patency:HART-2 ASSENT-Plus AMI-SK –Less reocclusion:HART-2 –Fewer reinfarctions:ASSENT-Plus AMI-SK Wilson et al ASSENT 3 is the first large-scale trial to test LMWHASSENT 3 is the first large-scale trial to test LMWH

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: Rationale for Use of Enoxaparin Enoxaparin AdvantagesEnoxaparin Advantages –Reduced bleeding (because it binds less strongly to circulating plasma, proteins, etc.) –Superior bioavailability at lower doses –Longer half-life –Does not require aPTT monitoring, due to more predictive dose response –Possible long-term cost advantage due to lower frequency of aPTT monitoring –Delivered subcutaneously with potential for even longer durations of administration –Enoxaparin has unique anti-Xa:anti-IIa ratio that distinguishes it from others in its class

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: Rationale for Half Dose TNK-tPA Plus Full- Dose Abciximab Trial arm based on hypothesis that a thrombolytic agent plus GP llb/llla inhibitor might result in improved patency with enhanced safety Hypothesis based onHypothesis based on –Phase II angiographic trials that suggest there may be improved patency with half-dose lytic plus GP llb/llla inhibitor –Enhanced safety profile of TNK-tPA, reduced risk of major complications, especially in the elderly (ASSENT 2)

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: 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.

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: 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

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: 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

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. ASSENT 3: TNK-tPA Weight-Adjusted Dosing Weight (kg)Full dose (mg)Half dose (mg) (in combination with abcix) <60 (<132 lbs)30.015.0 ≥60 to <70 (133-154 lbs)35.017.5 ≥70 to <80 (155-176 lbs)40.020.0 ≥80 to <90 (177-198 lbs)45.022.5 ≥90 (>199 lbs)50.025.0

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. 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

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. 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.

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: Statistical Analysis Plan Statistical analysis was by intention-to-treat.Statistical analysis was by intention-to-treat. A two-sided 95% confidence interval was calculated and an overall chi-square test, comparing the three treatment groups, was performed.A two-sided 95% confidence interval was calculated and an overall chi-square test, comparing the three treatment groups, was performed. Between groups pair wise comparisons are presented using the two- sided 95% confidence interval of the relative risk.Between groups pair wise comparisons are presented using the two- sided 95% confidence interval of the relative risk. Non-parametric, covariate-adjusted rates were calculated for each end point. Covariates used were gender, age, weight, infarct location, previous infarct, Killip class, heart rate, time to tenecteplase treatment and systolic blood pressure.Non-parametric, covariate-adjusted rates were calculated for each end point. Covariates used were gender, age, weight, infarct location, previous infarct, Killip class, heart rate, time to tenecteplase treatment and systolic blood pressure. Since the results of the adjusted and non-adjusted analyses were very similar only non-adjusted results are presented.Since the results of the adjusted and non-adjusted analyses were very similar only non-adjusted results are presented.

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. ASSENT 3: Statistical Power The study had 80% power to exclude with 95% confidence (one-sided) a 1% higher incidence of these end points in comparison with the control groupThe study had 80% power to exclude with 95% confidence (one-sided) a 1% higher incidence of these end points in comparison with the control group

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. ASSENT 3: Endpoint Adjudication Stroke: Reviewed blinded to treatment allocation by the same stroke committee that reviewed the stroke data in the ASSENT-2 trial.Stroke: Reviewed blinded to treatment allocation by the same stroke committee that reviewed the stroke data in the ASSENT-2 trial. Reinfarction, refractory ischemia, bleeding complications: No central adjudication. However, definitions were provided to the investigators who, in addition, had to reconfirm the occurrence of these end points on a special form.Reinfarction, refractory ischemia, bleeding complications: No central adjudication. However, definitions were provided to the investigators who, in addition, had to reconfirm the occurrence of these end points on a special form.

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: Endpoint Definitions Reinfarction in the first 18 hours: Recurrent symptoms of ischemia at rest accompanied by new or recurrent ST-segment elevations of 0.1 mV or more in at least two contiguous leads, lasting at least 30 min.Reinfarction in the first 18 hours: Recurrent symptoms of ischemia at rest accompanied by new or recurrent ST-segment elevations of 0.1 mV or more in at least two contiguous leads, lasting at least 30 min. Reinfarction after 18 hours: New Q waves in two or more leads and/or enzyme evidence of reinfarction (re-elevations of CK-MB troponins or total CK above the upper limit of normal and increased over the previous value).Reinfarction after 18 hours: New Q waves in two or more leads and/or enzyme evidence of reinfarction (re-elevations of CK-MB troponins or total CK above the upper limit of normal and increased over the previous value). Refractory ischemia: Symptoms of ischemia with ST-segment deviation or T wave inversion persisting for at least 10 min despite medical management and not fulfilling the diagnosis of reinfarction.Refractory ischemia: Symptoms of ischemia with ST-segment deviation or T wave inversion persisting for at least 10 min despite medical management and not fulfilling the diagnosis of reinfarction. Non-cerebral bleeding complications were defined as major (requiring transfusion, intervention because of hemodynamic compromise or both) or minor.Non-cerebral bleeding complications were defined as major (requiring transfusion, intervention because of hemodynamic compromise or both) or minor.

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. ASSENT 3: Randomization and Study Treatments 6095 patients with ST-segment elevation acute myocardial infarction 2017 assigned half-dose TNK-tPA plus weight-adjusted, reduced dose, unfractionated heparin plus abciximab 2038 assigned full-dose TNK-tPA plus weight-adjusted unfractionated heparin 2040 assigned full-dose TNK-tPA plus enoxaparin At least 1 component of study medication not given: 21 At least 1 component of study medication not given: 61 At least 1 component of study medication not given: 24 Primarycomposite end points unavailable: 3 Primarycomposite end points unavailable: 1 Primarycomposite end points unavailable: 2 2037 completed follow-up 2016 completed follow-up 2036 completed follow-up

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: Concomitant Use of Medications In-Hospital Unfractionated EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) Calcium channel blockers IV nitrates Beta-blockers ACE inhibitors Angiogenesis II inhibitors StatinsAspirin ≤12h or upon randomization in-hospitalTiclopidine/Clopidogrel Oral anticoagulants Abciximab Other GP IIb/IIIa inhibitors Low-molecular-weight heparins Thrombolytics 4.34.85.20.41 6.54.28.9<0.0001 6.83.77.1<0.0001 16.0 26.029.0<0.0001 16.0 26.029.0<0.0001 2.01.92.90.08 1110110.82 7371730.25 8484830.73 6260630.18 3.12.93.10.87 5250510.24 9797970.53 9695950.40 3028320.014

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. ASSENT 3: Baseline Characteristics Unfractionated 3 way EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) Age (years)6161610.41 Age >75 years1312130.21 Women2324230.40 Weight (kg)7979 79 0.73 Height (cm)170 170 170 0.51 Time from onset of symptoms to randomization (h)2.7 2.72.80.33 Time from randomization to TNK-tPA (h)0.260.400.27<0.0001 Killip class0.61 I898888 II/III101112 IV0.30.40.4 Systolic blood pressure (mm Hg)134 133 133 0.66 Data are mean (SD) or percentages. CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

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. ASSENT 3: Baseline Characteristics (Cont.) Unfractionated EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) Infarct location0.91 Anterior393938 Inferior565657 Other4.64.85.0 Heart rate (bpm)75 75 74 0.23 Hypertension4141410.99 Diabetes1918180.66 Previous myocardial infarction1413140.52 Prior CABG3.63.32.60.19 Prior PCI6.26.06.40.86 Current smoker4447470.16 Data are mean (SD) or percentages. CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

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. 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

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: 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.

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: 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%

27. 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%

28. 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.

29. 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.

30. 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)

31. 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). *

32. 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.

33. 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).

34. 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

35. 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

36. 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.

37. 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 3 way p=0.25 ASSENT 3: 30 Day Mortality % Risk of 30 Day Mortality ASSENT 3: 30 Day Mortality

38. 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 3 way p=0.0198 ASSENT 3: 30 Day Mortality % Risk of 30 Day Death or MI ASSENT 3: 30 Day Death or MI

39. 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 3 way p=0.0009 ASSENT 3: 30 Day Mortality ASSENT 3: In-Hospital Recurrent MI % Risk of In-Hospital Recurrent MI

40. 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 3 way p< 0.0001 ASSENT 3: 30 Day Mortality ASSENT 3: In-Hospital Refractory Ischemia % Risk of 30 Day Refractory Ischemia

41. 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 p=NS ASSENT 3: 30 Day Mortality ASSENT 3: In-Hospital ICH % Risk of Intracranial Hemorrhage

42. 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

43. 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

44. 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

45. 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

46. 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 In-Hospital Cardiac Events and Procedures Unfractionated EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) IABP, intra-aortic balloon pump; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention. Sustained hypotension2.12.82.80.27 Pulmonary edema and/or5.25.25.60.78 cardiogenic shock Major arrhythmias8.59.310.50.11 Invasive cardiac procedures Any32.532.135.30.06 IABP2.61.52.80.01 Urgent CABG1.71.51.70.94 Non-urgent CABG2.42.93.50.10 Urgent PCI11.99.114.4<0.0001 Non-urgent PCI17.419.416.50.04

47. 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 In-Hospital Cardiac Events and Procedures (Cont.) Unfractionated EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) Pericarditis0.71.00.60.23 Acute mitral regurgitation0.10.30.30.35 Pulmonary embolism0.10.30.10.19 Tamponade0.40.30.30.89 Acute ventricular septum defect0.50.40.50.85 Electromechanical dissociation1.31.51.40.84 Killip class >14.54.94.80.82 Anaphylaxis000.10.67 IABP, intra-aortic balloon pump; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

48. 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: In-Hospital Stroke Rates Unfractionated EnoxaparinAbciximabHeparinP Value (n=2040)(n=2017)(n=2038) Total strokes1.621.491.520.94 Intracranial hemorrhage0.880.940.930.98 Ischemic stroke*0.640.400.540.57 Hemorrhagic conversion0.070.070.000.77 Unclassified0.150.150.050.59 *Including hemorrhagic conversion

49. 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.”

50. 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”.

51. 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”.