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Characteristics of the Ideal Fibrinolytic Agent

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

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Characteristics of the Ideal Fibrinolytic Agent

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  1. 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 Gibson CM. Ann Intern Med. 1999;130:841-847.

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

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

  4. TNK-tPA: Molecular and Biochemical Properties N Domain Gln for Asn at 117 : Increased fibrin specificity Kringle 1 Kringle 2 T Domain Asn for Thr at 103: Reduces clearance; single bolus K Domain Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299: More resistant to PAI 1, enzyme which breaks down lytic agents EGF Finger NH2 HOOC

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

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

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

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

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

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

  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 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 P=0.18 % of Patients TNK TNK tPA tPA tPA TNK H Barron AHA 1999; Circulation 1999; 100: I-1

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

  17. Weight Optimizing Reduces ICH Rates : ASSENT II Multivariate Model Odds Ratio 1.788 0.760 1.024 1.513 0.300 95% Confidence Ratio (1.529, 2.091) (0.668, 0.864) (1.013, 1.036) (1.096, 2.088) (0.092, 0.977) Age Weight Diastolic Blood Pressure Hypertension TNK Treatment by high-risk females* * Females >75 years and <67 kgs 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. Weight Optimized Dosing of TNK Improves Rate of Opening by 60 Minutes Dose of 0.53 mg / kg selected for ASSENT 2 based upon logistic regression of Frame Count data p = 0.02 vs low dose % of Patients Med High Low N=177 N=174 N=178 Gibson CM, et al. Am J Cardiol. 1999;84:976-980.

  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 Gibson CM, et al. Am J Cardiol. 1999; 84:976-980.

  21. ASSENT-2 Trial Design 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 Randomization t-PA-accelerated regimen (weight-adjusted) TNK-tPA single bolus (weight-adjusted) Adapted from ASSENT-2 Investigators. Lancet. 1999;354:716-722.

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

  23. Comparison Among Equivalency Analyses for 30-Day Mortality Absolute Other Mortality t-PA Difference P Value for (%) (95% CI) Better Better Equivalence n-PA t-PA 0.17 InTIME-2 0.047 6.77 6.60 (1.0, 0.68) TNK-tPA t-PA 0.02 0.006 ASSENT-2 (0.59, 0.62) 6.16 6.18 r-PA t-PA 0.23 GUSTO-III NS (1.11, 0.66) 7.47 7.24 +1 0 -1 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.

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

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

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

  27. 1.00 (0.89, 1.12) 1.017 (0.799 - 1.296) 1.157 (0.970, 1.379) 0.766 (0.617. 0.952) ASSENT-2: Improved Survival forTNK-tPA in Late-Treated Patients TNK-tPA t-PA Relative Risk TNK-tPA t-PA P Value (n=8,461) (n=8,488) (95% CI) Better Better Total population (%) 6.16 6.18 0.975 Time to therapy (h) 0-2 (%) 5.0 4.9 0.897 >2-4 (%) 6.3 5.5 0.106 >4 (%) 7.0 9.2 0.018 0.4 1 1.4 ASSENT-2 Investigators. Lancet. 1999;354:716-722.

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

  29. ASSENT-2: Significantly Fewer Noncerebral Bleeding Events With TNK-tPA TNK-tPA t-PA P Value (n=8,461) (n=8,488) 26.4 29.0 0.0003 Total bleeds (%) 4.7 5.9 0.0002 Major bleeds (%) 21.8 23.0 0.0553 Minor bleeds (%) Units transfused 4.3 5.5 0.0002 Any - 1-2 units 2.6 3.2 - >2 units 1.7 2.2 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 CM Gibson, GW symposium, AHA 2000

  31. Why Not Use a Fixed 40 mg Dose in All 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. 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. 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 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

  34. Confusion in Reperfusion: 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 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”? CM Gibson, GW symposium, AHA 2000

  37. Safety and Efficacy of 50 mg of TNK Differences Between TIMI 10B and ASSENT 2 • 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 CM Gibson, GW symposium, AHA 2000

  38. Wide Range of Weights Among Pts. Given 50 mg TNK in TIMI 10B • 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 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 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 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 P=0.003 P =NS P=NS P=NS 0.57* ICH (%) 2P<0.02 TNK tPA t-PA SK r-PA t-PA r-PA Placebo SK t-PA n-PA 50 mg TNK in ASSENT 2 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 P<0.00001 P=0.0003 Mortality % 4.78* TNK t-PA Placebo SK t-PA SK r-PA t-PA r-PA t-PA n-PA SK t-PA 50 mg TNK ASSENT 2 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 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? 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 CM Gibson, GW symposium, AHA 2000

  46. Low Body Weight As A Risk Factor For Adverse Outcomes • 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 CM Gibson, GW symposium, AHA 2000

  47. 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 CM Gibson, GW symposium, AHA 2000

  48. Association Between Recording of Weight on Case Report Form and 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? 10.1% 6.16% Mortality

  49. Among rPA Treated Patients Missing Weight is Associated with Higher Mortality: A Textbook Case of Statistical Confounding Weight not recorded in 11% of INJECT Trial patients • 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 19.5% 16.3% Mortality (%) 10.2% N = 242 N = 48 N = 65 Deaths > 60 Kg < 60 Kg Missing weight FDA PLA 95-1167, July 15, 1996, page 33

  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 CM Gibson, GW symposium, AHA 2000

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