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Combination Lytic Therapy inCombination Lytic Therapy inAcute Myocardial InfarctionAcute Myocardial InfarctionC.Michael Gibson,M.D.C.Michael Gibson,M.D.Pathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMI*Gibson et al.*Gibson et al.J Am Coll Cardiol.J Am Coll Cardiol.2019;25:582-589.2019;25:582-589.Gibson et al.Gibson et al.Circulation.Circulation.2019;103:2550-2554.2019;103:2550-2554.Combination TherapyCombination Therapy ThrombusThrombus%Stenosis%Stenosis Minimum Diameter Minimum Diameter Epicardial FlowEpicardial Flow Myocardial Blush Myocardial Blush ST Resolution ST Resolution Myocardial Flow Myocardial FlowFacilitates PCIFacilitates PCIReduces Reduces Reinfarction*Reinfarction*Recent Clinical TrialsRecent Clinical TrialsUnfractionated heparinEnoxaparinUnfractionated heparinEnoxaparinAbciximabAbciximabNoneNoneENTIREACC/AHA heparin doseLow-dose heparinEnoxaparinNoneAbciximabNoneASSENT-3Standard-dose heparinLow-dose heparinNoneAbciximab50%TNK-tPA50%TNK-tPA100%TNK-tPA100%TNK-tPA100%TNK-tPA50%TNK-tPA100%TNK-tPA100%r-PA50%r-PAGUSTO-VAnticoagulantGP IIb/IIIaReceptor InhibitorLyticTrialClinical Trials:OngoingClinical Trials:OngoingLow-dose heparinLow-dose heparinLow-dose heparinEptifibatideEptifibatideEptifibatide50%TNK-tPA75%TNK-tPA100%TNK-tPAINTEGRITILow-dose heparinLow-dose heparinLow-dose heparinTirofibanTirofibanTirofiban50%TNK-tPA75%TNK-tPA100%TNK-tPAFASTERAnticoagulantGP IIb/IIIaReceptor InhibitorLyticTrial54%54%32%32%GUSTO-I:A 20%Increase in TIMI Grade 3 Flow is GUSTO-I:A 20%Increase in TIMI Grade 3 Flow is Needed to Yield a 1%Mortality ReductionNeeded to Yield a 1%Mortality ReductionThe GUSTO Angiographic Investigators.The GUSTO Angiographic Investigators.N Engl J Med.N Engl J Med.1993;329:1615-1622.1993;329:1615-1622.03050604020%TIMI Grade 3 Flowt-PASK10t-PA57.4%7.4%6.3%6.3%SK876TIMI Grade 3 Flow Pooled Data From Dose TIMI Grade 3 Flow Pooled Data From Dose Confirmation Phases of Recent TrialsConfirmation Phases of Recent Trials040801006020%Patients With TIMI Grade 3 FlowGUSTO-I90 minT14 t-PA90 minT14 r-PA90 minSPEED60-90 minINTRO-AMI60 minPooled60-90 min54737047405678735456642922926363878798988181329329585888881001007575321321Lytic aloneCombinationSPEED:Results of Dose-Confirmation PhaseSPEED:Results of Dose-Confirmation PhaseThere was a 7.4%improvement in the rate of TIMI Grade 3 flowIf a 20%improvement is required to improve mortality by 1%,then a 7.4%improvement would be predicted to improve mortality by 0.3%The SPEED Study Group.The SPEED Study Group.Circulation.Circulation.2000;101:2788-2794.2000;101:2788-2794.04080100r-PA 10+10 Ur-PA 5+5 U+Abx6020Patency(%)TIMI-2TIMI-3n=109n=109n=115n=11521.621.654.954.947.547.528.728.7GUSTO-V:Study DesignGUSTO-V:Study DesignThe GUSTO-V Investigators.Lancet.2019;357:1905-1914.ST ,lytic eligible,6 h(n=16,588)ASANo Abciximab2 x 10 U bolus(30)Full-dose r-PA AbciximabLow-dose Heparin:60 U/kg bolus followed by 7 U/kg/h infusion1 end point:mortality at 30 days2 end point:clinical and safety events at 30 days2 x 5 U bolus(30)Half-dose r-PAStandard Heparin:5000 U bolus followed by800 U/h(80 kg)or 1000 U/h(80 kg)infusionPrimary End Point:30-Day Mortality Primary End Point:30-Day Mortality The GUSTO-V Investigators.Lancet.2019;357:1905-1914.0%MortalityDays051015202530P=.43 for superiorityNon-Inferiority RR 0.95(95%CI,0.84-1.08)Std.Reteplase(n=8260)Abx+Dose Reteplase(n=8328)4625.9%5.6%GUSTO-V:Noninferiority AnalysisGUSTO-V:Noninferiority AnalysisAdapted with permission from the GUSTO-V Investigators.Lancet.2019;357:1905-1914.Non-Inferiority RR 0.95(95%CI,0.84-1.08)1.111.11OR and 95%CI0.00.02.02.01.01.0Abciximab+Abciximab+Half-dose r-PA superiorHalf-dose r-PA superiorFull-dose r-PAFull-dose r-PAsuperiorsuperiorUpper Boundary of 95%CI for NoninferiorityUpper Boundary of 95%CI for NoninferiorityA Comparison of the Outcomes With r-PA A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V TrialsMonotherapy in GUSTO-III vs GUSTO-V TrialsThe GUSTO-III Investigators.N Engl J Med.2019;337:1118-1123.The GUSTO-V Investigators.Lancet.2019;357:1905-1914.037851264GUSTO IIIGUSTO V7.4%5.9%10,13810,1388,2608,260DeathP.00104050203010GUSTO IIIGUSTO V48%37%10,13810,1388,2608,260Anterior MI00.50.91.00.70.30.40.80.60.2GUSTO IIIGUSTO V0.91%0.59%10,13810,1388,2608,260ICHP=.0150.10.21.21.72.3GUSTO-V:Causes of ReinfarctionGUSTO-V:Causes of Reinfarction*Unblinded,unadjudicatedThe GUSTO-V Investigators.Lancet.2019;357:1905-1914.01342Myocardial Infarction(%)AnyQ-waveEnzymaticIschemic STChange*3.50.51.62.7r-PAr-PA+AbxP 70 yrs 75 yrs 75 yrs0.41.20.51.11.50.42.1r-PA(n=8260)r-PA+Abx(n=8328)0.3P=.66P=.53P=.27*P=.069*12/108812/108824/114924/114928/717928/717937/717237/717225/203025/203031/213531/213521/619321/619324/623024/6230*GUSTO-V:PCI Within 6 Hours(Urgent)GUSTO-V:PCI Within 6 Hours(Urgent)and Through Day 7and Through Day 7*P.0001.The GUSTO-V Investigators.Lancet.2019;357:1905-1914.5.65.625.425.427.927.98.68.601525302010PCI(%)UrgentThrough Day 75r-PAr-PA+Abx2.89.05.4GUSTO-V:Event Rates in Those Requiring Urgent GUSTO-V:Event Rates in Those Requiring Urgent PCIPCIHeartwire News.September 2,2019.GUSTO-V:Combination half-dose fibrinolytic plus IIb/IIIa blocker.An Alternative approach to MI?6.74.89.60410128Myocardial Infarction(%)r-PAr-PA+Abxn=1173DeathRepeat MIDeath Plus Repeat MI26GUSTO-V:ConclusionsGUSTO-V:ConclusionsCompared with r-PA monotherapy,combination therapy with r-PA and abciximab resulted in A mortality rate that was not inferior to r-PA monotherapyFewer nonfatal reinfarctions(primarily a reduced incidence of recurrent ST elevation)A lower rate of urgent revascularizationMore noncerebral bleeding complications,transfusions,and thrombocytopeniaA higher rate of ICH in elderly patients over the age of 75 yearsASSENT-3:Rationale for Use of Enoxaparin ASSENT-3:Rationale for Use of Enoxaparin TNK-tPA plus enoxaparinFavorable effects of LMWHs in recent small-scale thrombolysis trialsHigher late patency:HART-2ASSENT-PlusAMI-SKLess reocclusion:HART-2Fewer reinfarctions:ASSENT-PlusAMI-SKWilson,et al.ASSENT-3 is the first large-scale trial to test LMWHASSENT-3:Study DesignASSENT-3:Study DesignST-Segment Elevation AMI(n=6095 patients)150 to 325 mg ASA(daily)RandomizedFull-dose TNK-tPAPlus EnoxaparinHalf-dose TNK-tPAPlus AbciximabPlus Low-dose HeparinFull-dose TNK-tPAPlus Weight-adjusted UFHThe ASSENT-3 Investigators.Lancet.2019;358:605-613.ASSENT-3:Primary End PointsASSENT-3:Primary End PointsPrimary Efficacy End Point:Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia.Primary Efficacy Plus Safety End Point: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.ASSENT-3:30-Day Mortality,Recurrent MI,ASSENT-3:30-Day Mortality,Recurrent MI,Refractory IschemiaRefractory Ischemia05101520%Risk of 30-Day D/MI/Ref IschTNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH*P-values are the Bonferroni P-values after correcting for multiple comparisons.The uncorrected P-values were P=.0002 for the enox vs UFH comparison,and P75 Years of AgeBleeding 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=.001).%Risk of 30-Day Efficacyand Safety End Point015253545TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH25.536.928.0P=.001*520304010ASSENT-3:Primary Efficacy and Safety End Point of ASSENT-3:Primary Efficacy and Safety End Point of Death,Reinfarction or Refractory Ischemia,ICH or Major Death,Reinfarction or Refractory Ischemia,ICH or Major Bleeding in Patients with DiabetesBleeding in Patients with Diabetes*There was a statistically significant interaction between treatment with abciximab and diabetes,such that diabetics had poorer outcomes with abciximab therapy(P=.0007).%Risk of 30-Day Efficacyand Safety End Point0152530TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.922.316.5P=.007*52010ASSENT-3:30-Day MortalityASSENT-3:30-Day Mortality04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH5.46.66.03-way P=.2562%Risk of 30-Day MortalityASSENT-3:30-Day Death or MIASSENT-3:30-Day Death or MI%Risk of 30-Day Death or MI04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH6.87.39.13-way P=.019862ASSENT-3:In-Hospital Recurrent MIASSENT-3:In-Hospital Recurrent MI%Risk of In-HospitalRecurrent MI0245TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH2.72.24.23-way P=.000931ASSENT-3:In-Hospital Refractory IschemiaASSENT-3:In-Hospital Refractory Ischemia%Risk of 30-DayRefractory Ischemia04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH4.63.26.53-way P.000162ASSENT-3:Incidence of In-Hospital Thrombocytopenia ASSENT-3:Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complicationsand Noncerebral Bleeding Complications*While 3-way P-value is significant,Enox vs UFH comparison P=NSEnoxAbxUFHP-Value(n=2040)(n=2019)(n=2038)3-wayAny thrombocytopenia1.23.21.3.0001Thrombocytopenia.000120,000 cells/L0.10.50.220,000 to 50,000 cells/L0.20.60.250,000 to 100,000 cells/L0.92.01.0Bleeding episodesTotal25.6*39.721.1.0001Major3.0*4.32.2.0005Minor22.6*35.418.8.0001Blood transfusion3.4*4.22.3.0032ASSENT-3:In-Hospital Stroke RatesASSENT-3:In-Hospital Stroke Rates*Including hemorrhagic conversionUnclassifiedHemorrhagic conversionIschemic stroke*Intracranial hemorrhageTotal strokes0.150.150.070.070.400.640.940.881.491.62Abx(n=2019)Enox(n=2040)0.590.050.770.000.570.540.980.930.941.52P-ValueUFH(n=2038)Patients Undergoing PCI:MortalityPatients Undergoing PCI:MortalityASSENT-3:In-Hospital PCIGUSTO-V:Urgent PCI057863Mortality(%)4212.53.72.75.46.7TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFHr-PA+UFHr-PA+AbxHow Does Actual Weight Compare to How Does Actual Weight Compare to Estimated Weight?Estimated Weight?Reprinted with permission from Cannon CP,et al.J Am Coll Cardiol.2019;37:323A.Correlation Between Estimated and Actual Patient Weight in TIMI 10BCorrelation Between Estimated and Actual Patient Weight in TIMI 10B40.536.4188.5Actual Patient Weight(kg)Estimated Patient Weight(kg)R2=0.93,P.0001181Weight-Based Dosing of Thrombolysis:How Well Do We Weight-Based Dosing of Thrombolysis:How Well Do We Estimate Weight?How Often Would This Translate Into Estimate Weight?How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and Errors With Administration of Thrombolytic Drugs and Adverse Outcomes?Adverse Outcomes?Errors in estimating weight are uncommon,especially those that would lead to a dose change(1.3%or 49/3730 for TNK-tPA and 4.5%or 13/290 for t-PA).No adverse outcomes were seen among patients who received an incorrect dose,suggesting a broad safety profile for the new single-bolus agent TNK-tPA.Cannon CP,et al.J Am Coll Cardiol.2019;37:323A.ASSENT-3:Study Group Conclusions Regarding ASSENT-3:Study Group Conclusions Regarding TNK-tPA+Abciximab TherapyTNK-tPA+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.”“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.”“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.”The ASSENT-3 Investigators.Lancet.2019;358:605-613.ASSENT-3:Study Group Conclusions Regarding ASSENT-3:Study Group Conclusions Regarding EnoxaparinEnoxaparin“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.”The ASSENT-3 Investigators.Lancet.2019;358:605-613.ENTIRE TIMI-23:Study DesignENTIRE TIMI-23:Study DesignST MI 6h(n=461)UFH60 U/kg bolus12 U/kg/h infusion 36 h ENOXvarying doses+/-IV bolusIndex Hosp(8 d)ASA ENOXvarying doses+/-IV bolusIndex Hosp(8 d)Combination Reperfusion:Half-dose TNK-tPA+Abx(0.27 mg/kg)Standard Reperfusion:Full-dose TNK-tPA(0.53 mg/kg)Antman E,et al.Eur Heart J.2019;22:15.Abstract 145.UFH 40 U/kg bolus7 U/kg/h infusion 36 hOutstanding IssuesOutstanding IssuesShould enoxaparin replace UFH as the optimal antithrombin agent for AMI?Will similar improvements in efficacy and safety occur if enoxaparin is combined with a less fibrin-specific agent such as r-PA?Will physicians accept the use of enoxaparin in selected patients with ST-elevation MI who may require rescue PCI?Will trials of TNK-tPA plus the small molecule GP IIb/IIIa receptor inhibitors produce results similar to ASSENT-3?What is the optimal strategy for facilitated PCI?Future Trials:Potential Downstream TargetsFuture Trials:Potential Downstream TargetsLarge embolii:FiltersSmall embolii(thrombii):Filters&GP IIb/IIIa inhibitors,p-selectin inhibitorsVasoconstrictor release:GP IIb/IIIa inhibitorsSpasm:Adenosine,Ca channel blockers,alpha blockers,avoid over sizing with PCI,high pressure inflations,serotonin inhibitors,endothelin inhibitorsEndothelial&Myocardial swelling:Myocardial cooling,Ca channel blockers,DHEA,Na/H pump inhibitors,anti-inflammatory approaches
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