1. Gibson CM. Ann Intern Med. 1999;130:841-847. Characteristics of the Ideal Fibrinolytic Agent Longer half-life/single-bolus administration Increased fibrin specificity/decreased bleeding and ICH More rapid and consistent achievement of TIMI grade 3 flow No effect on blood pressure No antigenicity Lower reocclusion rates Greater resistance to PAI-1 Compatible with other intravenous agents Low cost Longer half-life/single-bolus administration Increased fibrin specificity/decreased bleeding and ICH More rapid and consistent achievement of TIMI grade 3 flow No effect on blood pressure No antigenicity Lower reocclusion rates Greater resistance to PAI-1 Compatible with other intravenous agents Low cost

2. Fibrin Specificity Molecular Structures of Fibrinolytics TNK-tPA t-PA r-PA / n-PA SK TNK t-PA (tenecteplase) r-PA (reteplase) t-PA (alteplase) n-PA (lanoteplase)

3. TenecteplaseTenecteplase (TNK-tPA)(TNK-tPA) LanoteplaseLanoteplase (n-PA)(n-PA) StaphylokinaseStaphylokinaseSaruplaseSaruplase Half-life (minutes) 20 37 6 6 9 9 Dosing Single bolus 2 boluses 30 min apart Bolus + 60- min infusion Provides patient- specific weight- based dosing Yes ?? Fibrin specificity +++ + + + + PAI-1 resistance Increased ?? Antigenic No Yes Plasminogen activation Direct Indirect Direct Fibrinolytics in Development: Comparative Overview

4. TNK-tPA: Molecular and Biochemical Properties K Domain Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299: More resistant to PAI 1, enzyme which breaks down lytic agents K Domain Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299: More resistant to PAI 1, enzyme which breaks down lytic agents NH 2 HOOC EGF Finger Kringle 1 Kringle 2 T Domain Asn for Thr at 103: Reduces clearance; single bolus N Domain Gln for Asn at 117 : Increased fibrin specificity

5. n=312 n=304 n=146 n=76 *P=0.047, TNK-tPA 30 mg vs t-PA; all others, P=NS. TIMI-10B: TIMI Grade Flow at 90 Minutes Percent of Patients Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814.

6. 0.2 0.3 0.4 0.5 0.6 0.7 P=0.028 Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814. TIMI-10B: TIMI Grade 3 Flow at 90 Minutes by Dose/Weight No further improvement In flow above 0.53 mg/kg No further improvement In flow above 0.53 mg/kg

7. Gibson CM, et al. Am J Cardiol. 1999;84:976-980. TIMI Frame Count TIMI-10B: Relationship Between TIMI Frame Count & Dose / Weight N=166 N=174 N=171 N=104 N=107 N=127 0.52 to 1.24 mg/kg 0.52 to 1.24 mg/kg 0.40 to 0.51 mg/kg 0.40 to 0.51 mg/kg 0.20 to 0.39 mg/kg 0.20 to 0.39 mg/kg High Dose = 0.52 to 1.24 mg / Kg. Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of CTFC High Dose = 0.52 to 1.24 mg / Kg. Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of CTFC p = 0.007 p = 0.002 Low Med High 0.20 to 0.39 mg/kg 0.20 to 0.39 mg/kg Low 0.40 to 0.51 mg/kg 0.40 to 0.51 mg/kg Med 0.52 to 1.24 mg/kg 0.52 to 1.24 mg/kg High

8. Pathophysiology of Improved Flow With Weight Optimized TNK Dosing: Weight Optimizing Reduces Thrombus Burden & Improves Percent Stenosis Gibson CM, et al. Am J Cardiol. 1999;84:976-980. N=166 N=174 N=171 % Stenosis % Patients p = 0.06 p = 0.03 Low Med High Low High N=173

9. Gibson CM, et al. Am J Cardiol. 1999;84:976-980. TIMI Frame Count TIMI-10B: Weight Optimized Dosing “Facilitates Adjunctive PCI” N=46 N=39 N=20 0.52 to 1.24 mg/kg 0.52 to 1.24 mg/kg 0.40 to 0.51 mg/kg 0.40 to 0.51 mg/kg 0.20 to 0.39 mg/kg 0.20 to 0.39 mg/kg Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of Frame Count data p = 0.05 Low Med High

10. TNK-tPATNK-tPA (n=8,461)(n=8,461) t-PAt-PA (n=8,488)(n=8,488) Relative Risk (95% CI) P Value P Value Total stroke (%) 1.78 1.66 1.07 (0.856-1.349) 0.555 Intracranial hemorrhage (%) 0.93 0.94 0.991 (0.727-1.350) 1.000 Ischemia 0.72 0.64 1.13 (0.787-1.632) 0.514 With hemorrhagic conversion (%) 0.07 0.09 0.752 (0.261-2.168) 0.790 Unknown type (%) 0.13 0.08 1.576 (0.611-4.065) 0.358 ASSENT-2 Investigators. Lancet. 1999;354:716-722. ASSENT-2: Similar Incidence of Stroke for TNK-tPA and t-PA

11. Confusion in Reperfusion: The “Old Old” (>75 yrs) Highest risk for complications, but potentially have the most to gain from treatment Understudied in randomized trials, but now over 1/3 rd of MIs are > 75 years Heterogeneous group, multiple risk factors at play, potential for interactions Tend to present late Highest risk for complications, but potentially have the most to gain from treatment Understudied in randomized trials, but now over 1/3 rd of MIs are > 75 years Heterogeneous group, multiple risk factors at play, potential for interactions Tend to present late CM Gibson, GW symposium, AHA 2000

12. ICH Risk is Eight Time Higher in Elderly Females following t-PA Gurwitz et al. 1998 Annals Int Med. 129; 597-604.

13. Unadjusted Dose Rises Rapidly in People of Low Body Weight CM Gibson, GW symposium, AHA 2000

14. New Answers to the Old Old Question How might weight optimized dosing of TNK favorably alter outcomes in this very high risk group of low body weight women over 75 years of age? CM Gibson, 2000

15. Weight Optimizing Reduces ICH Rates : ASSENT II TNK tPA % of Patients P=0.18 H Barron AHA 1999; Circulation 1999; 100: I-1

16. ICH Rates Among Women > 75 Years who are 75 Years who are < 67 Kg in ASSENT II TNK-tPA tPA P <0.05 Weight Optimizing Reduces ICH Rates : ASSENT II H Barron AHA 1999; Circulation 1999; 100: I-1

17. Age Age Weight Weight Diastolic Diastolic Blood Pressure Blood Pressure Hypertension Hypertension TNK Treatment by TNK Treatment by high-risk females* high-risk females* Age Age Weight Weight Diastolic Diastolic Blood Pressure Blood Pressure Hypertension Hypertension TNK Treatment by TNK Treatment by high-risk females* high-risk females* Odds Ratio 1.7880.7601.0241.5130.300 1.7880.7601.0241.5130.300 95% Confidence Ratio (1.529, 2.091) (0.668, 0.864) (1.013, 1.036) (1.096, 2.088) (0.092, 0.977) 95% Confidence Ratio (1.529, 2.091) (0.668, 0.864) (1.013, 1.036) (1.096, 2.088) (0.092, 0.977) * Females >75 years and <67 kgs Multivariate Model Weight Optimizing Reduces ICH Rates : ASSENT II Multivariate Model H Barron AHA 1999; Circulation 1999; 100: I-1

18. Weight Optimizing TNK Reduces the ICH Risk Among High Risk Patients In women > 75 years of age and < 67 kg weight optimizing TNK reduces the risk of ICH by 70% compared with t- PA H Barron AHA 1999; Circulation 1999; 100: I-1

19. Gibson CM, et al. Am J Cardiol. 1999;84:976-980. % of Patients N=177 N=178 N=174 Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of Frame Count data p = 0.02 vs low dose Low Med High Weight Optimized Dosing of TNK Improves Rate of Opening by 60 Minutes

20. Weight Optimized Dosing of TNK Improves Microvascular Function Improved flow in all 3 arteries (even in those without a stenosis) In a multivariate model correcting for % stenosis, thrombus & early opening by 60 minutes, weight optimized dose group was 5 frames faster Following relief of the stenosis by PCI, weight optimized dose arm was faster Improved flow in all 3 arteries (even in those without a stenosis) In a multivariate model correcting for % stenosis, thrombus & early opening by 60 minutes, weight optimized dose group was 5 frames faster Following relief of the stenosis by PCI, weight optimized dose arm was faster Gibson CM, et al. Am J Cardiol. 1999; 84:976-980.

21. t-PA-accelerated regimen (weight-adjusted) t-PA-accelerated regimen (weight-adjusted) TNK-tPA single bolus (weight-adjusted) Adapted from ASSENT-2 Investigators. Lancet. 1999;354:716-722. Patients with AMI and ST-segment elevation, symptom onset  6 h (n = 16,950; 1,021 hospitals) Objective: demonstrate “equivalence” Primary endpoint: all-cause 30-day mortality Aspirin (150-325 mg) IV heparin >67 kg: 5000-U bolus, 1000 U/h <67 kg: 4000-U bolus, 800 U/h Aspirin (150-325 mg) IV heparin >67 kg: 5000-U bolus, 1000 U/h <67 kg: 4000-U bolus, 800 U/h RandomizationRandomization ASSENT-2 Trial Design

22. Superiority: Does the 95% CI contain zero?  Equivalence: Does the 95% CI lie between  1% and +1%?  1% 0%0% +1%+1% 0%0%+1%+1% To left of  1% is clinically meaningful To left of  1% is clinically meaningful Between  1% and +1% is not clinically meaningful Between  1% and +1% is not clinically meaningful To right of  1% is clinically meaningful To right of  1% is clinically meaningful Understanding Equivalence CM Gibson, 2000

23. 0 +1 Mortality (%) Absolute Difference (95% CI) Other BetterBetter P Value for Equivalence InTIME-2 6.776.60   0.17 (  1.0, 0.68) 0.047 ASSENT-2 6.166.18 0.02 (  0.59, 0.62) 0.006 GUSTO-III 7.477.24  0.23 (  1.11, 0.66) NS Comparison Among Equivalency Analyses for 30-Day Mortality ASSENT-2 Investigators. Lancet. 1999;354:716-722; Adapted from GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123. Adapted from Giugliano RP, et al. Circulation. 1999;100:I-651. n-PA TNK-tPA r-PA t-PA t-PA t-PA t-PA

24. Major Trials Comparing 30- or 35-Day Mortality Among Fibrinolytics SK SK t-PA SK r-PA t-PA r-PA t-PA n-PA Agents * * P=NS P=0.0003 P=0.006 Mortality % TNK - tPA Placebo t-PA P=NS P=0.047 2P<0.00001 P=NS P=0.001 P=NS *Lower major bleeds for TNK-tPA (4.7% vs 5.9%; P=0.0002). Equivalency: P=NS Equivalency Demonstrated Superiority Demonstrated Superiority: *Higher ICH rate for n-PA (0.62% vs 1.13%; P=0.003). CM Gibson, 2000

25. Age (years) <75 >75 4.6 17.4 4.3 19.3 1.063 (0.915-1.235) 0.903 (0.754-1.081) 0.425 0.286 Sex Male Female 5.0 10.0 4.8 10.6 1.039 (0.894-1.209) 0.943 (0.784-1.134) 0.627 0.563 ASSENT-2: 30-Day Mortality By Age and Sex TNK-tPATNK-tPA (n=8,461)(n=8,461) t-PAt-PA (n=8,488)(n=8,488) Relative Risk (95% CI) Value Value PP ASSENT-2 Investigators. Lancet. 1999;354:716-722.

26. Infarct location Anterior Other 8.0 5.0 8.2 4.8 0.975 (0.830-1.146) 1.026 (0.865-1.218) 0.789 0.783 Previous AMI Yes No 9.8 5.5 8.6 5.7 1.137 (0.897-1.441) 0.965 (0.843-1.105) 0.318 0.609 Previous CABG Yes No 9.8 6.0 7.7 6.1 1.280 (0.776-2.111) 0.987 (0.875-1.115) 0.406 0.844 ASSENT-2 Investigators. Lancet. 1999;354:716-722. ASSENT-2: 30-Day Mortality By Infarct Location, Previous AMI, or Previous CABG; Killip Class; and History of Hypertension or Diabetes TNK-tPA (n=8,461) t-PA(n=8,488)t-PA(n=8,488) Relative Risk (95% CI) Relative Risk (95% CI) P Value P Value I I II III IV 4.7 13.5 29.0 51.4 4.8 13.4 24.5 61.1 0.983 (0.851-1.134) 1.011 (0.797-1.281) 1.185 (0.740-1.899) 0.842 (0.556-1.273) 0.818 0.944 0.516 0.477 Hypertension Yes No 8.0 5.0 7.6 5.2 1.050 (0.888-1.241) 0.962 (0.816-1.135) 0.578 0.657 Diabetes Yes No 8.8 5.6 8.7 5.7 1.002 (0.786-1.278) 0.993 (0.868-1.136) 1.000 0.942 Killip Class

27. TNK-tPA (n=8,461) t-PA (n=8,488) Relative Risk (95% CI) TNK-tPA Better t-PA Better P Value P Value Total population (%) 6.166.18 1.00 (0.89, 1.12) 0.975 Time to therapy (h) 0-2 (%) 5.04.9 1.017 (0.799 - 1.296) 0.897 >2-4 (%) 6.35.5 1.157 (0.970, 1.379) 0.106 >4 (%) 7.09.2 0.766 (0.617. 0.952) 0.018 0.4 1 1 1.4 ASSENT-2 Investigators. Lancet. 1999;354:716-722. ASSENT-2: Improved Survival for TNK-tPA in Late-Treated Patients

28. Cannon CP, Gibson CM, McCabe CH et al. Circulation. 1998;98:2805-2814. Percent Changes in Parameters (median) Percent Changes in Parameters (median) TIMI-10B: Clinical Evidence of Increased Fibrin Specificity in TNK-tPA A A A A A A 50 30 40 A A A A A A 50 30 40 1 1 1 1 Hours Post-Dose Fibrinogen Plasminogen TNK-tPA alteplase (t-PA)

29. TNK-tPATNK-tPA (n=8,461)(n=8,461) t-PAt-PA (n=8,488)(n=8,488) P Value Total bleeds (%) 26.4 29.0 0.0003 Major bleeds (%) 4.7 5.9 0.0002 Minor bleeds (%) 21.8 23.0 0.0553 Units transfused Any 1-2 units >2 units 4.3 2.6 1.7 5.5 3.2 2.2 0.0002 - - - - ASSENT-2: Significantly Fewer Noncerebral Bleeding Events With TNK-tPA ASSENT-2 Investigators. Lancet. 1999;354:716-722.

30. How Does Weight Optimized Dosing Improve Patient Care? Improves efficacy (earlier & better flow, less thrombus, less stenosis & better outcomes) in heavier patients Improves safety (lower intracranial hemorrhage) in high risk patients Improves efficacy (earlier & better flow, less thrombus, less stenosis & better outcomes) in heavier patients Improves safety (lower intracranial hemorrhage) in high risk patients CM Gibson, GW symposium, AHA 2000

31. Why Not Use a Fixed 40 mg Dose in All Patients? In light patients: These patients receive relatively more drug. Weight optimized dosing may reduce the risk of serious bleeding events and reduce the risk of intracranial hemorrhage rate in lower- weight patients. In heavy patients: These patients receive relatively less drug. Weight optimized dosing may improve rates of TIMI grade 3 flow & TIMI Frame Counts, and thereby lower mortality. CM Gibson, GW symposium, AHA 2000

32. Other Acute MI Regimens Use Weight Adjusted Dosing Heparin Reopro Integrilin Aggrastat Low Molecular weight heparinoids Dopamine, dobutamine As TNK is combined with heparin & glycoprotein 2b3a inhibitors, safety & efficacy will hopefully be improved as a result of weight optimized dosing Heparin Reopro Integrilin Aggrastat Low Molecular weight heparinoids Dopamine, dobutamine As TNK is combined with heparin & glycoprotein 2b3a inhibitors, safety & efficacy will hopefully be improved as a result of weight optimized dosing CM Gibson, GW symposium, AHA 2000

33. TNK-tPA Dosing Regimen Dosing categories are about 22 lb wide –Minimizes the possibility of dosing errors < 60 kg (< 132 lbs)  6 mL 61 - 70 kg (133-154 lbs)  7 mL 71 - 80 kg(155-176 lbs)  8 mL 81 - 90 kg(177-198 lbs)  9 mL > 90 kg(> 199 lbs)  10 mL Dosing categories are about 22 lb wide –Minimizes the possibility of dosing errors < 60 kg (< 132 lbs)  6 mL 61 - 70 kg (133-154 lbs)  7 mL 71 - 80 kg(155-176 lbs)  8 mL 81 - 90 kg(177-198 lbs)  9 mL > 90 kg(> 199 lbs)  10 mL

34. Confusion in Reperfusion: Dose Errors Do dose errors cause death ? Or Does death cause dose errors ? Do dose errors cause death ? Or Does death cause dose errors ? CM Gibson, GW symposium, AHA 2000

35. Dosing Errors to be Studied Timing of dose –No potential for error with a single bolus agent such as TNK Duration of injection –Little or no real potential for error with a 5 second administration of TNK Compatibility with other drugs –Little potential for error with TNK Timing of dose –No potential for error with a single bolus agent such as TNK Duration of injection –Little or no real potential for error with a 5 second administration of TNK Compatibility with other drugs –Little potential for error with TNK CM Gibson, GW symposium, AHA 2000

36. Two Common Questions Asked About the 50 mg Dose of TNK Is the 50 mg dose safe? Is there an excess risk of intracranial hemorrhage and bleeding associated with 50 mg? Is the 50 mg dose efficacious? Is 50 mg of TNK in heavy patients (I.e. those > 90 Kg) adequate? In other words, are very heavy patients being “under dosed”? Is the 50 mg dose safe? Is there an excess risk of intracranial hemorrhage and bleeding associated with 50 mg? Is the 50 mg dose efficacious? Is 50 mg of TNK in heavy patients (I.e. those > 90 Kg) adequate? In other words, are very heavy patients being “under dosed”? CM Gibson, GW symposium, AHA 2000

37. In TIMI 10B, 50 mg of TNK was given to patients of all weights In ASSENT 2, 50 mg of TNK was given only to patients weighing over 90 Kg In TIMI 10B, 50 mg of TNK was given to patients of all weights In ASSENT 2, 50 mg of TNK was given only to patients weighing over 90 Kg Safety and Efficacy of 50 mg of TNK Differences Between TIMI 10B and ASSENT 2 CM Gibson, GW symposium, AHA 2000

38. In TIMI 10B there were a small number of patients (78) who received 50 mg of TNK, the majority of whom were of lighter weights (under 90 Kg) Only 22.4% of pts. in TIMI 10B weighed > 90 Kg, the weight required for therapy with 50 mg of TNK in ASSENT 2 & in clinical practice In TIMI 10B there were a small number of patients (78) who received 50 mg of TNK, the majority of whom were of lighter weights (under 90 Kg) Only 22.4% of pts. in TIMI 10B weighed > 90 Kg, the weight required for therapy with 50 mg of TNK in ASSENT 2 & in clinical practice Wide Range of Weights Among Pts. Given 50 mg TNK in TIMI 10B CM Gibson, GW symposium, AHA 2000

39. Differences Between TIMI 10B and ASSENT 2 in Examining the Safety and Efficacy of 50 mg of TNK In TIMI 10B, only 78 patients received 50 mg of TNK There were 3 intracranial hemorrhages None of the patients in TIMI 10 B with an intracranial hemorrhage weighed over 90 Kg (mean wt. only 77.2 Kg)* These 3 patients all weighed < 90 Kg, and none of them would have received 50mg as a weight adjusted dose in ASSENT 2 or in clinical practice There were 9 major hemorrhages, and only 1 patient weighed over 90 Kg* Thus, 89%* of all patients (8/9) who developed a major hemorrhages at the 50mg dose would not have received this dose had they been enrolled in the ASSENT 2 trial or treated in clinical practice This was in part the motivation for weight adjusting the dose of TNK In TIMI 10B, only 78 patients received 50 mg of TNK There were 3 intracranial hemorrhages None of the patients in TIMI 10 B with an intracranial hemorrhage weighed over 90 Kg (mean wt. only 77.2 Kg)* These 3 patients all weighed < 90 Kg, and none of them would have received 50mg as a weight adjusted dose in ASSENT 2 or in clinical practice There were 9 major hemorrhages, and only 1 patient weighed over 90 Kg* Thus, 89%* of all patients (8/9) who developed a major hemorrhages at the 50mg dose would not have received this dose had they been enrolled in the ASSENT 2 trial or treated in clinical practice This was in part the motivation for weight adjusting the dose of TNK CM Gibson, GW symposium, AHA 2000

40. ASSENT-2: Outcomes With 50 mg TNK vs Lower Doses of TNK Mortality and ICH were both lower with the 50 mg dose The difference in outcome, however, is not significant when adjusting for multiple variables including weight Mortality and ICH were both lower with the 50 mg dose The difference in outcome, however, is not significant when adjusting for multiple variables including weight Alexander et al, AHA 2000

41. Treatment With 50 mg TNK is Associated with low ICH Rates: Major Trials Comparing Intracranial Hemorrhage Rates Among Fibrinolytics Placebo SK SK r-PA t-PA r-PA t-PA n-PA t-PA P =NS 2P<0.02 P=NS P=0.003 ICH (%) TNK tPA 50 mg TNK in ASSENT 2 0.57 * Califf RM, et al. Am Heart J. 1997;133:630-639; ISIS-2 Collaborative Group. Lancet. 1988;2:349-360; GUSTO III Investigators. N Engl J Med. 1997;337:1118-1123; INJECT. Lancet. 1995;346:329-336; Van de Werf F, et al. ACC 1999 CME Online. 1999;1-12. *Data on file, Genentech

42. Treatment with 50 mg TNK is Associated with low Mortality Rates: Major Trials Comparing 30- or 35-Day Mortality Among Fibrinolytics SK SK t-PA SK r-PA t-PA r-PA t-PA n-PA P<0.00001 P=0.0003 Mortality % TNK t- PA Placebo t-PA 50 mg TNK ASSENT 2 4.78 * Califf RM, et al. Am Heart J. 1997;133:630-639; ISIS-2 Collaborative Group. Lancet. 1988;2:349-360; GUSTO III Investigators. N Engl J Med. 1997;337:1118-1123; INJECT. Lancet. 1995;346:329-336; Van de Werf F, et al. ACC 1999 CME Online. 1999;1-12. *Data on file, Genentech

43. Is 50 mg of TNK Administered to Patients with an Estimated Weight > 90 Kg Both Safe & Effective? It is safe: Using the dose schedule in ASSENT 2 (I.e. 50 mg TNK for pts. with estimated wt. > 90 Kg): Risk of ICH in TIMI 10B: 0.0%* Risk of ICH in ASSENT 2: 0.57%* Risk of ICH in TIMI 10B & ASSENT 2 combined: 0.566%* It is effective: Risk of mortality was 4.78% in pts. treated with 50 mg in ASSENT 2, which compares favorably with the 6.18% rate among all patients in the ASSENT 2 study* The 4.78%* mortality observed among the subgroup of pts. treated with 50 mg of TNK is the lowest mortality rate observed among recent thrombolytic trials It is safe: Using the dose schedule in ASSENT 2 (I.e. 50 mg TNK for pts. with estimated wt. > 90 Kg): Risk of ICH in TIMI 10B: 0.0%* Risk of ICH in ASSENT 2: 0.57%* Risk of ICH in TIMI 10B & ASSENT 2 combined: 0.566%* It is effective: Risk of mortality was 4.78% in pts. treated with 50 mg in ASSENT 2, which compares favorably with the 6.18% rate among all patients in the ASSENT 2 study* The 4.78%* mortality observed among the subgroup of pts. treated with 50 mg of TNK is the lowest mortality rate observed among recent thrombolytic trials CM Gibson, GW symposium, AHA 2000

44. Therapeutic Margin of Weight Adjusted Dosing of TNK Questions have been raised about the “margin for error” with weight optimized dosing of TNK What if the estimated weight is off by 10 Kg (22 pounds) which would be one dose category? What if the weight estimate is off by 2 weight categories (20 Kg or 44 pounds)? Is this safe? Dose this pose an undue risk of ICH? Questions have been raised about the “margin for error” with weight optimized dosing of TNK What if the estimated weight is off by 10 Kg (22 pounds) which would be one dose category? What if the weight estimate is off by 2 weight categories (20 Kg or 44 pounds)? Is this safe? Dose this pose an undue risk of ICH? CM Gibson, GW symposium, AHA 2000

45. Low Body Weight As A Risk Factor For Adverse Outcomes Low Body weight has been identified as a risk factor for adverse outcomes following thrombolytic administration, even when the dose is administered correctly Low body weight is a risk factor for adverse outcomes in primary PTCA patients Low body weight is a risk factor for adverse outcomes even among patients who receive no reperfusion strategy Low Body weight has been identified as a risk factor for adverse outcomes following thrombolytic administration, even when the dose is administered correctly Low body weight is a risk factor for adverse outcomes in primary PTCA patients Low body weight is a risk factor for adverse outcomes even among patients who receive no reperfusion strategy CM Gibson, GW symposium, AHA 2000

46. Thus, low body weight is a potential confounder in the analysis of dose errors. Low body weight patients may be more likely to receive excess dosing of a drug, but may simultaneously be at risk for adverse outcomes simply on the basis of their low body weight alone The question becomes “Is it the low body weight of the patient or the dose error that resulted in an adverse outcome” ? To answer this question body weight must be accounted for in the analysis of dose errors Thus, low body weight is a potential confounder in the analysis of dose errors. Low body weight patients may be more likely to receive excess dosing of a drug, but may simultaneously be at risk for adverse outcomes simply on the basis of their low body weight alone The question becomes “Is it the low body weight of the patient or the dose error that resulted in an adverse outcome” ? To answer this question body weight must be accounted for in the analysis of dose errors Low Body Weight As A Risk Factor For Adverse Outcomes CM Gibson, GW symposium, AHA 2000

47. Margin of Safety with TNK Overdoses Margin of Safety with TNK Overdoses Across all dose arms, if an overdose error of 1 to 2 dose categories (up to 20 Kg, 44 pounds) was made, the odds ratio for ICH and death were no different than in the trial as a whole in a multivariate model adjusting for patient weight TNK has a broad therapeutic margin of safety and errors of estimating weight by up to 20 Kg or 44 pounds are well tolerated with no increased risk of ICH or death Across all dose arms, if an overdose error of 1 to 2 dose categories (up to 20 Kg, 44 pounds) was made, the odds ratio for ICH and death were no different than in the trial as a whole in a multivariate model adjusting for patient weight TNK has a broad therapeutic margin of safety and errors of estimating weight by up to 20 Kg or 44 pounds are well tolerated with no increased risk of ICH or death CM Gibson, GW symposium, AHA 2000

48. Association Between Recording of Weight on Case Report Form and Mortality 6.16% 10.1% Mortality Recently concerns have been expressed regarding the need to weigh patients prior to administration of a thrombolytic agent. Dosing in ASSENT 2 was based upon either estimated or actual weights Patients with missing weights had a higher mortality Is this a cause of a higher mortality, or is it a marker of a sicker patient or a patient who died before being weighed? Recently concerns have been expressed regarding the need to weigh patients prior to administration of a thrombolytic agent. Dosing in ASSENT 2 was based upon either estimated or actual weights Patients with missing weights had a higher mortality Is this a cause of a higher mortality, or is it a marker of a sicker patient or a patient who died before being weighed?

49. Among rPA Treated Patients Missing Weight is Associated with Higher Mortality: A Textbook Case of Statistical Confounding Mortality highest if no weight recorded No biologically plausible reason why there should be a higher mortality among patients receiving a fixed lytic dose in whom no weight was recorded Likely explanation is statistical confounding: Missing weight is a marker of a sicker patient, or the patient died before weight obtained Mortality (%) FDA PLA 95-1167, July 15, 1996, page 33 10.2% 16.3% 19.5% Weight not recorded in 11% of INJECT Trial patients Deaths N = 242N = 48N = 65 > 60 Kg < 60 Kg Missing weight

50. Weight Optimized Dosing of TNK: The Advantages TNK dosing is optimized for the patient’s weight so that flow at 90 minutes after its administration is accelerated Weight optimized dosing also improves flow after PTCA / stenting and “facilitates PCI” Weight optimizing TNK dosing improves microvascular function and flow in all 3 arteries While dose is optimized, the range of weights for a given dose is 22 pounds or 10 Kg, which may minimize dosing errors TNK is a single dose agent, TNK is compatible with other medications such as heparin (other lytics may precipitate) TNK is the only agent to demonstrate equivalency to tPA with an acceptable safety profile Weight adjusted dosing of TNK is safe, efficacious, and has a favorable therapeutic margin of safety if errors are made Indeed the safety profile is improved: the risk of bleeding and transfusion is reduced TNK dosing is optimized for the patient’s weight so that flow at 90 minutes after its administration is accelerated Weight optimized dosing also improves flow after PTCA / stenting and “facilitates PCI” Weight optimizing TNK dosing improves microvascular function and flow in all 3 arteries While dose is optimized, the range of weights for a given dose is 22 pounds or 10 Kg, which may minimize dosing errors TNK is a single dose agent, TNK is compatible with other medications such as heparin (other lytics may precipitate) TNK is the only agent to demonstrate equivalency to tPA with an acceptable safety profile Weight adjusted dosing of TNK is safe, efficacious, and has a favorable therapeutic margin of safety if errors are made Indeed the safety profile is improved: the risk of bleeding and transfusion is reduced CM Gibson, GW symposium, AHA 2000