The 90 Minute Wall: 60% Rates of TIMI Grade 3 Flow % TIMI 3 Flow.

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  • The 90 Minute Wall:60% Rates of TIMI Grade 3 Flow% TIMI 3 Flow

  • What Do We Need to Do to Achieve Another 1% Mortality Reduction in AMI?% TIMI Grade 3 FlowMortality (%)A 20% improvement in TIMI Grade 3 flow led to a 1% improvement in mortality in GUSTO 154%32%6.3%7.4%

  • Microvascular Dysfunction Following AMIMicrovascular ObstructionPlatelet microembolizationThrombosisReperfusion InjuryNeutrophil aggregationComplement activationFree radical generationEndothelial dysfunction, spasm, microvascular constriction

  • Paradoxical Activation of Coagulation Following Thrombolytic AdministrationThrombin generationClot bound thrombin exposed as lysis proceedsPlasmin activationRapid flow through a narrow lumen increases shear force & activates plateletsActivated platelets in turn activate plasminogen inactivator (PAI 1)CM Gibson Annals Int Med 1999

  • Motivation for the Development of Combination TherapyImproved lysis of thrombus (more rapid & more complete), better flowReduced reocclusionImproved microvascular functionImproved safety (reduced bleeding due to reduction in dose of thrombolytic agent)CM Gibson Annals Int Med 1999

  • ST Segment Acute MI Trials Involving GP 2b3a InhibitorsCombination TherapyWith Thrombolytic AgentsPCI TrialsFull Dose Lytic + GP 2b3aReduced Dose Lytic + GP 2b3aTAMI 8Impact AMIParadigmSK- EptifibatideTIMI 14SPEEDINTRO AMIFASTERENTIREINTEGRITIGRAPERAPPORT ADMIRAL CADILLACCM Gibson Annals Int Med 1999

  • ST , lytic eligible, < 12 hGroup ItPA < 100 mgGroup II dose tPAGroup III dose SKGroup IVNo lytic Angio (90 min) , In Hospital Events, 30 day F/UNo ReoPro ReoPro: bolus 0.25 mg/kg inf 0.125 g/kg/min x 12 hSTD Heparin (70 U/kg ; 15 U/kg/h) Low Dose Heparin (60 U/kg ; 7 U/kg/h)ASATIMI 14TIMI 14 Study Group, Circulation 1999; 99: 2720.

  • TIMI 14: TIMI 2/3 Flow (Core Lab): 90 min tPA50 mg tPA + ReoPro RP bolus 0.3 mg/kgReoProSK 1.5M U SK + ReoPro% Pts947948TIMI 14795481667581binf 30inf 60inf 6014631429364947284636N =100 mgbolus 0.25 inf 0.125500 K750 K1.25 MU3489TIMI 1 + GUSTO 1TIMI 14 Study Group, Circulation 1999; 99: 2720.

  • TIMI Frame Count: 90 minTIMI 14tPA 100 mg 37tPA (bolus/60 m inf)+ ReoPro 31 ReoPro 100SK + ReoPro 45TFC MedianTIMI 14 Study Group, Circulation 1999; 99: 2720.

  • TIMI-14: TIMI 3 Flow (Core Lab) at 90 Mint-PA 100 mgAllDose Conf.Dose Find t-PA (50 mg*) + AbciximabLow-dose HeparinVery Low-dose Heparin21487615829p < 0.02*(bolus 15 mg; infusion 35 mg x 60 m)TIMI 14 Study Group, Circulation 1999; 99: 2720.

  • Abciximab Improves Myocardial PerfusionComplete (>70%) ST Resolution at 90 Min.Myocardial Perfusion Grade 2/3 at 90 Min.% Patients% PatientsN=125N=221N=33N=66tPArPAtPA + AbxrPA + Abxp
  • TIMI Grade 3 Flow at 6090 MinAngiographic Core Lab Readingn = 107n = 103n = 75n = 66r-PA60 U Hep40 U HepAbciximab AloneAbciximabAbciximabAlone + r-PA 5 + 5+ r-PA 5 + 5Dose escalation and confirmation combinedp = 0.2p 0.06

  • GUSTO-IV AMI: ProtocolAbciximab 0.25 mg/kg bolus 0.125 g/kg/minr-PA 5 + 5 UHeparinPrimary Endpoint: 30-Day Mortality16,600 patients Acute MI ST elevation Symptoms 6 hrsr-PA 10 + 10 UHeparin

  • INTRO AMI: TIMI Grade 3 Flow at 90 Minutes3330313048Integrilin bolus 180 180180 180/90 180/90Integrilin infusion 1.33 1.33 2.0 1.33 1.33tPA bolus 25 15 15 25 15tPA infusion 35 35 35

  • Major Hemorrhage (Investigator)%PtstPAReoPro SK + ReoPro tPA + ReoProMajor Hemorrhage = ICH, Retroperitoneal, or Hg > 5 gm/dLICHInstrSpontN = 164323749516384250365337483500665814675488515500 K750 K1.25 M1.5 M20355065 RP 0.3mg100 mgb 0.25 inf 0.12512ALL SK6143339ALL tPATIMI 14 Study Group, Circulation 1999; 99: 2720.


















  • Advantages of Combination PharmacotherapyQuick and easy to administer, no learning curveWidely available at all times of the night and day at all hospitalsAchieves patency earlyPrejunctive therapy does not preclude mechanical interventionCM Gibson Annals Int Med 1999

  • The New Time Dependent Open Artery and Open Microvascular HypothesisThe Five Laws:Not all TIMI Grade 3 Flow is Created EquallyTIMI Grade 3 Flow is Necessary but not SufficientIt is the Achievement of TIMI Grade 3 Flow in both the Epicardial Artery and the Microvasculature that Optimizes Clinical OutcomesFaster is Better: The Faster Achievement of Faster Flow Optimizes Clinical OutcomesLocation, location, location: Drug efficacy and clinical outocmes must be interpreted in the context of infarct artery locationCM Gibson 2000

    Potential mechanistic explanations for this problem are shown here. Important interactions exist between thrombolytics and platelets. Platelets can be stimulated by thrombolytics ---for example by the exposure of clot bound thrombin. (Point) The narrowed lumen shown on the previous slide generates high shear forces a potent stimulus to platelet activation. On the other hand, activated platelets may inhibit thrombolysis though the release substances that stabilize the clot and also through enhancement of clot retraction---all of which make the clot more resistant to thrombolysis.5The trial is divided into a dose finding phase and dose confirmation phase. The design of the dose finding phase is shown on this slide. All patients are given aspirin and are then randomized into one of 4 groups:1. The control group does not receive ReoPro (POINT) but is treated with front loaded tPA and standard dose heparin consisting of a bolus of 70 U/kg and initial infusion of 15 U/kg/h/2. The three experimental groups(POINT) receive a ReoPro bolus of 0.25 mg/kg followed by a 12h infusion of 0.125 ug/kg/min. Groups II and III receive reduced dose tPA or SK respectively.Group IV does not receive any lyticReoPro treated patients receive low dose heparin using a bolus of 60 U/kg and infusion of 7 U/kg/h/ which represents a 14% reduction in the bolus and a 50% reduction in the infusion. For all groups the heparin is continued for at least 24 hours with a target aPTT of 50-70s.All patients undergo a 90 min angio and are then followed for clinical events in hospital and through 30 days. ________________________________________________________________ Max bolus 4000 U inf Group I = 1200 U/h Groups II-IV = 800 U/hPTCR Grp I = 250 s grp II-IV = 200n s ACT11Plotted on this slide are the rates of TIMI 2 plus 3 flow ( that is patency).TIMI 3 flow is on the bottom and TIMI 2 is on the top of each stacked bar. In white is the tPA alone arm; in blue is the historical reference for 1.5 M SK alone. Several experimental groups of interest are shown in yellow.Note that ReoPro alone achieved a patency rate of 48 % (POINT).The patency rates with reduced dose SK+RP rangaed from 66-81% and with 50 mg tPA +RP from 75-94%. Note that the highest rates of TIMI 3 flow observed occurred in groups where 1/2 the usual dose of tPA was administered in combination with ReoPro.14Plotted here are the corrected TIMI frame counts for 4 representative groups of reperfusion regimens. The dashed vertical line at 28 frames is the upper end of the 95 % CI for normal flow, while the dashed line at 40 frames is the breakpoint between TIMI 3 and TIMI 2 flow as established previously in Dr. Gibsons Core Lab. It is in the zone between these two lines that some distinctions between the groups can be observed.The group receiving a bolus +60 min infusion of tPA +RP, shown in yellow is shifted up and to the left compared to the full dose tPA control arm, in white, indicating a tendency to a higher proportion of pts with faster frame counts. The median TFC was 31 frames as compared with 37 frames in the tPA alone arm.A composite of all the SK + ReoPro groups, in green, is below the tPA control arm indicating slower frame counts--the median TFC was 45 frames. This is followed by the ReoPro alone group in pink with the slowest frame counts.

    The TIMI 14, SPEED, and INTRO AMI phase II angiographic trials were designed to test whether use of an intravenous glycoprotein IIb/IIIa inhibitor would be a potent and safe addition to reperfusion regimens.I will illustrate promising findings from this avenue of clinical investigation with examples from the TIMI 14 trial.Abciximab when combined with 50 mg half the usual dose of tPA facilitated the rate and extent of thrombolysis. A particularly striking observation was the 29% absolute increase in the rate of TIMI 3 flow at 60 minutes from 43% in the full dose tPA alone group shown in white compared with 72% in a regimen containing abciximab and 50 mg of tPA (Pint).When evaluated by the TIMI frame count method, the combination reperfusion group had a cumulative distribution plot shifted up and to the left compared with the control group, indicating a higher proportion of patients with faster flow (Point).

    9916 An Events Committee is in the process of adjudicating clinical endpoints that have occurred during the trial. Shown here is the rate of major hemorrhage defined as an intracranial or retroperitoneal hemorrhage or a bleed that was associated with at least a 5 gm drop of Hg. A 6% rate of Maj Hem was observed in the tPA control group, ReoPro alone group, and all tPA + ReoPro groups combined. The rate of Maj Hem was 12% for all the SK + ReoPro groups combined.There is a a dose related increase in the rate of major hemorrhage as ascending doses of SK are combined with ReoPro eventually culminating in an unacceptable risk as full dose SK was combined with ReoPro.There have been 7 ICHs -- 3 in the tPA control group, 1 out of the 6 patients in the 1.5 M SK group, and three in the 50 mg tPA plus ReoPro tier (POINT). The overall rate of ICH is 1.0%, a value that is similar to one from recent large phase III trials of thrombolysis for MI. ---------------------------------------------------------------------------------------Shown in white is the fact that the majority of hemorrhages were instrumented, as expected in this angiographic trial. The overall rate of major hemorrhage is 7.1 % , a value that is similar to rates reported in recent angiographic trials in acute MI. TIMI 10 A = 6.2 % TIMI 10 B = 6.0 %