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  • The TIMI Trials1984 - 1999Brigham and Womens HospitalHarvard Medical SchoolBoston, MAPART I.RESULTS OF TIMI 1 - TIMI 17PART II.TRIAL DESIGNS FOR TIMI 18-24

  • IV HeparinBaseline AngioPatient with Acute ST Elevation MI < 6 hours t-PA 80 mg / 3 hrsStreptokinase1.5 MU / 60 minsAngio 10, 20, 30, 45, 60, 75, 90 MinsDouble-blindTIMI 1Protocol Design

  • TIMI Study Group N Engl J Med 1985;312:397- 401TIMI 1Primary OutcomeComparison of t-PA and Streptokinase

  • TIMI 1Impact of 90 Minute Patency on Mortality081624324048Weeks from Randomization05101520Mortality (%)Patent (N=161)Occluded (N=128)Open Artery TheoryDalen, et. al. Am J Cardiol 1988; 62:179-85

  • TIMI Grade Flow Scoring SystemMonitoring ReperfusionTIMI 1TIMI 0 Complete occlusion TIMI 1 Penetration of obstruction by contrast but no distal perfusion TIMI 2 Perfusion of entire artery but delayed flow TIMI 3 Full perfusion, normal flowFlygenring BP et al. JACC 1991;17:275Mortality at 42 DaysP < 0.005

  • IV t-PARandomize6 week ETT / RVGImmediate Invasive:Cath 2 hrsN=195Acute MI < 4 hours onsetPrimary Endpoint:Pre-D/C EFFollow-up 1 yearDelayed Invasive:Cath 18-48 hrsN=194Pre-D/C Angio and RVGTIMI IIAProtocol DesignConservative:Cath if +ETT or ischemiaN=197

  • TIMI IIA Immediate PTCA vs. Delayed Invasive vs. Conservative Strategy post ThrombolysisManagement StrategyTIMI IIA Invest. JAMA 1988;260:2849. Rogers, et al. Circulation 1990;81:1457-76 Patency at Discharge (%)Death or MI by 6 weeks (%)

  • IV t-PAHeparin, ASARandomizePre-D/C ETT / RVGAcute MI < 4 hours onsetConservative:Cath if +ETT or ischemiaPrimary Endpoint:Death or MIFollow-up 1 yearInvasive:Cath 18-48 hrsRevasc if feasible6 week ETT / RVGTIMI IIBProtocol Design

  • TIMI Study Group. NEJM 1989;320:618. Williams DO, Circulation 1992;85:533-42.PTCA or CABG to 1 Year07142128354252Weeks020406080% of PatientsInvasiveConservative07142128354252Weeks05101520% of PatientsP=NS15.2%14.7%ConservativeInvasive*P
  • 1000 Pts370 Caths saved400 PTCAs saved$3,200,000 saved With no difference in outcomeWilliams DO, et al. Circulation 1992;85:533-42. $3000 per Cath$4000 per PTCATIMI IIBCost Implications of Invasive StrategyManagement Strategy

  • Roberts et al. Circulation 1991;83:422-37.TIMI IIBIV Beta-Blockade Following ThrombolysisAdjunctive TherapyReinfarction (%)Recurrent Ischemia (%)P = 0.02P = 0.005

  • IV Heparin, (ASA), Beta-blockers, Nitrates, Ca++ blockersRandomizeAngio 18-36 hrst-PA0.8 mg/kg over 90 mins391 Patients with Unstable Angina / NQWMIPlaceboPrimary Endpoint:Death, MI,Positive ETT 6 weeksFollow-up 6 weeksCirculation 1993;87:38-52Baseline AngioAngio Exclusion: no CAD or LMainTIMI IIIAProtocol Design

  • Apparent thrombus35%Possible thrombus30%No thrombus35%Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NSTIMI IIIA Investigators. Circulation 1993;87:38-52.TIMI IIIAEffects of tPA on Coronary LesionsPrimary ResultsBASELINE ANGIORAPHY:ANGIORAPHY AFTER tPA:

  • ASA, IV Heparin, Beta-blockers, Nitrates, Ca++ blockersRandomizeETT 6 weeksEarly Invasive:Cath 18-48 hPTCA/CABG prn1473 Patients with Unstable Angina / NQWMIEarly Conservative:ST Holter, ETT Thallium Cath/PTCA if +ischemia1o Endpoint Inv-Cons:Death, MI,Positive ETT - 6 weeksFollow-up 1 yearCirculation 1994;89:1545-562x2 Factorial:t-PA vs. Placebo1o Endpoint t-PA:Death, MI, Rec Isch,+ ETT, Thallium or ST Holter TIMI IIIBProtocol Design

  • TIMI IIIB Investigators. Circulation 1994;89:1545-56 TIMI IIIBtPA vs. Placebo in Non-ST Elevation ACSPrimary ResultsComposite EndpointDeath or MIICH% of PatientsP = NSP = 0.05P = 0.05

  • Events at 42d Invasive Conservativep valueNo. Pts 740 733Death (%) 2.4 2.5 NSMI (%) 5.1 5.7 NSD/MI/+ETT (%) 16.2 18.1 NS

    Rehosp Angina (%) 7.8 14.1

  • All consecutive patients admitted with unstable angina were screened.Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MIExclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedurePatients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year. TIMI III REGISTRYProtocol Design

  • 2.63.6110.86.622.91.63.76.81.63.78.2In-Hospital6 Weeks1 Year0510152025% of PatientsST deviation >0.1 mVLBBBTw changeNo ECG changes_Stone PH, TIMI III Registry Study Group. JAMA 1996;275:1104-1112.Cannon CP et al for ECG Substudy Investigators. JACC 1997;30:133-40. TIMI III REGISTRYAdmission ECG as a prognostic indicatorRisk StratificationDeath or MI

  • Antman et al. NEJM 1996; 335:1342-9Enrolled 0-6 hrs

    Enrolled 6-24 hrs

    Enrolled 0-24 hrs

    P

  • Pt. with AMI < 6 hrsHeparin, ASA90 min Angio18-36 hr AngioMIBI scanRVG, MIBI scanFollow-up 6 wks, 1 yr tPA Combination APSAC TIMI 4Protocol Design

  • Unsatisfactory OutcomeOne Year MortalityCannon CP, et al., TIMI 4 Investigators J Am Coll Cardiol 1994;24:1602-10 0306090120150180210240270300330365Days from Randomization0.70.80.91Survival (% of Pts) t-PA Comb. APSAC*p=0.07t-PA vs. APSACp=0.13t-PA vs. Comb. TIMI 4Benefit of front-loaded tPAPrimary Results*P = 0.06*

  • Pt. with AMI < 6 hrsDay 5-6: RVG, MIBI scan4 Ascending Hirudin Doses:0.15 B, 0.05 IV0.1 B, 0.1 IV0.3 B, 0.1 IV0.6 B, 0.2 IV5000 U Bolus,1000 U/h IVAPTT 65-90 secs TIMI 5Protocol DesignHeparinHirudin ASA, tPAF/U 6 Weeks, 1 yr90 min angio18-36 hr angioMIBI Scan

  • TIMI 5Hirudin vs. Heparin: Angiographic ResultsPrimary ResultsHeparin N = 84HirudinN = 162Heparin N = 79HirudinN = 157Heparin N = 60HirudinN = 123TIMI 3 Flow at 90TIMI 3 Flow at 90 and 18-36 hReocclusionCannon CP, et al. J Am Coll Cardiol 1994;23:993-1003.

  • Pt. with AMI < 6 hrsDay 5-6: RVG, MIBI scan3 Ascending Hirudin Doses:0.15 B, 0.05 IV0.3 B, 0.1 IV0.6 B, 0.2 IV5000 U Bolus,1000 U/h IVAPTT 65-90 secs TIMI 6Protocol DesignHeparinHirudinASA, SKF/U 6 Weeks

  • TIMI 6Heparin vs. Hirudin and stability of APTTAdjunctive TherapyHirudin DoseLee VL et al. for the TIMI 6 Investigators. Am J Cardiol 1995;75:7-13. APTT range 30 seconds*p < 0.001*

  • ASARandomize30 Day Follow-upHirulog0.25 mg/kg/hPatient with Unstable AnginaHirulog0.5 mg/kg/hHirulog1.0 mg/kg/hHirulog0.02 mg/kg/hTIMI 7Protocol Design

  • TIMI 7Hirulog in Unstable AnginaPrimary ResultsFuchs, Cannon for the TIMI 7 Investigators Circulation 92 : 727, 1995P = 0.008P = 0.009

  • UA/NQMI < 24 hrsPrimary Endpoint: Death or MIASAHirulog

    Followup: 30 daysHeparin (aPTT 50-70s)TIMI 8Protocol Design

  • Pt. with AMI < 12 hrsThrombolytic Therapy (accel tPA or SK)Death, MI, CHF/Shock 30 days F/UHEPARIN Bolus 5000 UInf 1000 U/h1300 u/h >80kgHIRUDIN Bolus 0.6 mg/kg Inf 0.2 mg/kg/h

    Major BleedingASA96 H RxaPTT 60-90 sTIMI 9AProtocol Design

  • Pt. with AMI < 12 hrs Sample Size =3000 pts (Power 90%, a .05, 25% Rx effect)Thrombolytic Therapy (accel tPA or SK)Death, MI, CHF/Shock 30 daysHEPARIN Bolus 5000 UInf 1000 U/hHIRUDIN Bolus 0.1 mg/kg Inf 0.1 mg/kg/h

    Major BleedingASA96 H RxaPTT 55-85 sProtocol DesignTIMI 9B

  • 05101520253002468101214HIRUDINHEPARINUNSATISFACTORY OUTCOMEDEATH + REINFARCTION%PtsDays post randomizationp=NS12.911.99.79.5TIMI 9B E. Antman for The TIMI 9B Investigators Circulation 1996;94: 911.Primary ResultsHirudin vs. Heparin with tPA for MI

  • TIMI 9Influence of Heparin/Hirudin Dosing Safety ObservationsAntman et al. Circulation 1994 and 1996Major Hemorrhage:TIMI 9A (N=713)TIMI 9B (N = 2929)

  • TIMI 9 REGISTRYInitial Management Strategy in AMICritical Pathways All Patients Pts presenting 12 hrsCannon CP et al. J Am Coll Cardiol 1995;231-232A.

  • TIMI 9BRisk StratificationPrediction of Mortality at 30 Days Age > 70, Prior MI Anterior MI, Atrial fibrillation Rales Hypotension and HR Female gender DiabetesP
  • TIMI 10AProtocol Design TNK- tPA Bolus ASA + IV Heparin (APTT 55-85) Follow-up Hosp. Discharge to 30 days Pt. with Acute MI < 12hEnd Points:PharmacokineticsCoagulation parametersTIMI grade 3 flow at 90'TIMI frame countMajor hemorrhageAllergic Events8 Ascending TNK-tPA Doses:5, 7.5, 10, 15, 20, 30, 40, 50 mgCannon CP et al. Circulation 1995;92:I-415.

  • TIMI 10ATIMI Flow Grade at 90 Minutes Primary ResultsCannon CP, TIMI 10A Investigators. Circulation 1997;95:351-6TNK-tPA Dose

  • ASA, IV HeparinRandomize30 Day Follow-upTNK-tPA 30mgPatient with Acute ST Elevation MI < 12 hours TNK-tPA 40mgTNK-tPA 50mg*t-PA100 mgAngio 60, 75, 90 Mins*Stopped earlyReplaced with 40 mgTIMI 10BProtocol Design

  • TIMI 10BTIMI Flow Grade at 90 Minutes Primary ResultsCannon CP for the TIMI 10B Investigators. Circulation 1998;98:2805-14*77%79%88%82%N = 311 304 146 76

  • ASA, IV HeparinRandomize30 Day Follow-upTNK-tPA 30mgPatient with Acute ST Elevation MI < 12 hours TNK-tPA 40mgTNK-tPA 50mg**Stopped earlyReplaced with 40 mgASSENT IProtocol Design

  • ASSENT IPrimary ResultsIncidence of Stroke at 30 Days Van de Werf F, Cannon CP for the ASSENT 1 Investigators Am Heart J 1999;137:786-91

  • p = 0.046p = 0.4p = 0.01Giugliano RP, Circ 1997;96:I-535 (abstract)TIMI 10B/ASSENT IICH Pre/post Reduction in Heparin Adjunctive Therapy

  • Dose 2 N=309Dose 1N=320 IV BolusWgt AdjFixed Dose 30 mg 30 mg 1.25 mg/kgQ 12 h (2-8d) 1.0 mg/kgQ 12 h (2-8d)< 65 kg> 65 kg40 mg60 mgQ12 h40 mg60 mgQ12 hTotal Rx Period = 14 days< 65 kg> 65 kgHospital PhaseHome RxTIMI 11A