课件：急性心肌梗塞的溶栓治疗.ppt

Combination Lytic Therapy in Acute Myocardial Infarction,C. Michael Gibson, M.D.,Pathophysiology of Combination Therapy in AMI,*Gibson et al. J Am Coll Cardiol. 1995;25:582-589. Gibson et al. Circulation. 2001;103:2550-2554.,Combination Therapy, Thrombus, % Stenosis Minimum Diameter, Epicardial Flow, Myocardial Blush ST Resolution, Myocardial Flow,Facilitates PCI,Reduces Reinfarction*,Recent Clinical Trials,Unfractionated heparin Enoxaparin Unfractionated heparin Enoxaparin,Abciximab Abciximab None None,ENTIRE,ACC/AHA heparin dose Low-dose heparin Enoxaparin,None Abciximab None,ASSENT-3,Standard-dose heparin Low-dose heparin,None Abciximab,50% TNK-tPA 50% TNK-tPA 100% TNK-tPA 100% TNK-tPA,100% TNK-tPA 50% TNK-tPA 100% TNK-tPA,100% r-PA 50% r-PA,GUSTO-V,Anticoagulant,GP IIb/IIIa Receptor Inhibitor,Lytic,Trial,Clinical Trials: Ongoing,Low-dose heparin Low-dose heparin Low-dose heparin,Eptifibatide Eptifibatide Eptifibatide,50% TNK-tPA 75% TNK-tPA 100% TNK-tPA,INTEGRITI,Low-dose heparin Low-dose heparin Low-dose heparin,Tirofiban Tirofiban Tirofiban,50% TNK-tPA 75% TNK-tPA 100% TNK-tPA,FASTER,Anticoagulant,GP IIb/IIIa Receptor Inhibitor,Lytic,Trial,54%,32%,GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality Reduction,The GUSTO Angiographic Investigators. N Engl J Med. 1993;329:1615-1622.,0,30,50,60,40,20,% TIMI Grade 3 Flow,t-PA,SK,10,t-PA,5,7.4%,6.3%,SK,8,7,6,TIMI Grade 3 Flow Pooled Data From Dose Confirmation Phases of Recent Trials,0,40,80,100,60,20,% Patients With TIMI Grade 3 Flow,GUSTO-I 90 min,T14 t-PA 90 min,T14 r-PA 90 min,SPEED 60-90 min,INTRO-AMI 60 min,Pooled 60-90 min,54,73,70,47,40,56,78,73,54,56,64,292,63,87,98,81,329,58,88,100,75,321,Lytic alone,Combination,SPEED: Results of Dose-Confirmation Phase,There was a 7.4% improvement in the rate of TIMI Grade 3 flow If 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. Circulation. 2000;101:2788-2794.,0,40,80,100,r-PA 10+10 U,r-PA 5+5 U + Abx,60,20,Patency (%),TIMI-2,TIMI-3,n=109,n=115,21.6,54.9,47.5,28.7,GUSTO-V: Study Design,The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,ST , lytic eligible, 6 h (n=16,588),ASA,No Abciximab,2 x 10 U bolus (30) Full-dose r-PA,Abciximab,Low-dose Heparin: 60 U/kg bolus followed by 7 U/kg/h infusion,1 end point: mortality at 30 days 2 end point: clinical and safety events at 30 days,2 x 5 U bolus (30) Half-dose r-PA,Standard Heparin: 5000 U bolus followed by 800 U/h ( 80 kg) or 1000 U/h ( 80 kg) infusion,Primary End Point: 30-Day Mortality,The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,0,% Mortality,Days,0,5,10,15,20,25,30,P=.43 for superiority,Non-Inferiority RR 0.95 (95% CI, 0.84-1.08),Std. Reteplase (n = 8260),Abx + Dose Reteplase (n = 8328),4,6,2,5.9%,5.6%,GUSTO-V: Noninferiority Analysis,Adapted with permission from the GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,Non-Inferiority RR 0.95 (95% CI, 0.84-1.08),1.11,OR and 95% CI,0.0,2.0,1.0,Abciximab + Half-dose r-PA superior,Full-dose r-PA superior,Upper Boundary of 95% CI for Noninferiority,A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V Trials,The GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123. The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,0,3,7,8,5,1,2,6,4,GUSTO III,GUSTO V,10,138,8,260,Death,P.001,0,40,50,20,30,10,GUSTO III,GUSTO V,48%,37%,10,138,8,260,Anterior MI,0,0.5,0.9,1.0,0.7,0.3,0.4,0.8,0.6,0.2,GUSTO III,GUSTO V,0.91%,0.59%,10,138,8,260,ICH,P=.015,0.1,0.2,1.2,1.7,2.3,GUSTO-V: Causes of Reinfarction,*Unblinded, unadjudicated The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,0,1,3,4,2,Myocardial Infarction (%),Any,Q-wave,Enzymatic,Ischemic ST Change*,3.5,0.5,1.6,2.7,r-PA,r-PA + Abx,P.0001,Non-Intracranial Bleeding Through Discharge/Day 7,The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,0,% of Patients,15,25,30,20,r-PA,r-PA + Abx,10,Severe Bleeding,Moderate Bleeding,Mild Bleeding,Any Bleeding,Receiving Transfusions,10,0.5,1.1,1.8,3.5,11.4,20.0,13.7,24.6,4.0,5.7,ICH by Age Group,*Significant treatment interaction for the age 75 dichotomy; P=.033. The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,0,1,3,2,% of Patients, 70 yrs, 70 yrs, 75 yrs, 75 yrs,0.4,1.2,0.5,1.1,1.5,0.4,2.1,r-PA (n=8260),r-PA + Abx (n=8328),0.3,P=.66,P=.53,P=.27*,P=.069*,12/1088,24/1149,28/7179,37/7172,25/2030,31/2135,21/6193,24/6230,*,*,*,*,GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7,*P.0001. The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.,5.6,25.4,27.9,8.6,0,15,25,30,20,10,PCI (%),Urgent,Through Day 7,5,r-PA,r-PA + Abx,2.8,9.0,5.4,GUSTO-V: Event Rates in Those Requiring Urgent PCI,Heartwire News. September 2, 2001. GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI?,6.7,4.8,9.6,0,4,10,12,8,Myocardial Infarction (%),r-PA,r-PA + Abx,n=1173,Death,Repeat MI,Death Plus Repeat MI,2,6,GUSTO-V: Conclusions,Compared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in A mortality rate that was not inferior to r-PA monotherapy Fewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation) A lower rate of urgent revascularization More noncerebral bleeding complications, transfusions, and thrombocytopenia A higher rate of ICH in elderly patients over the age of 75 years,ASSENT-3: Rationale for Use of Enoxaparin,TNK-tPA plus enoxaparin Favorable effects of LMWHs in recent small-scale thrombolysis trials Higher late patency: HART-2 ASSENT-Plus AMI-SK Less reocclusion: HART-2 Fewer reinfarctions: ASSENT-Plus AMI-SK Wilson, et al. ASSENT-3 is the first large-scale trial to test LMWH,ASSENT-3: Study Design,ST-Segment Elevation AMI (n=6095 patients),150 to 325 mg ASA (daily),Randomized,Full-dose TNK-tPA Plus Enoxaparin,Half-dose TNK-tPA Plus Abciximab Plus Low-dose Heparin,Full-dose TNK-tPA Plus Weight- adjusted UFH,The ASSENT-3 Investigators. Lancet. 2001;358:605-613.,ASSENT-3: Primary End Points,Primary 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, Refractory Ischemia,0,5,10,15,20,% Risk of 30-Day D/MI/Ref Isch,TNK-tPA + Enox,TNK-tPA + Abx,TNK-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 P.0001 for the abx vs UFH comparison.,11.4,11.1,15.4,3-way P=.0001,P=.0002*,P=.0009*,ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICH,% Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH,*P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0037 for the enox vs UFH comparison, and P=.0142 for the abx vs UFH comparison.,0,5,10,15,20,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,13.8,14.2,3-way P=.0062,P=.0057*,P=.0146*,Kaplan-Meier Curves,UFH,Abx*,5,10,15,20,25,30,0,2,4,6,8,10,12,14,16,20,18,0,Enox*,log-rank P=.0001 *vs UFH,Days to death, reinfarction, or refractory ischemia,Primary Efficacy End Point,Probability (%),Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:605-613.,5,10,15,20,25,30,0,2,4,6,8,10,12,14,16,20,18,0,log-rank P=.0062 *vs UFH + Abx,Days to death, reinfarction, refractory ischemia, ICH, or major bleeding,Primary Efficacy Plus Safety End Point,Probability (%),UFH,Abx,Enox*,ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding 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 Efficacy and Safety End Point,0,15,25,35,45,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,25.5,36.9,P=.001*,5,20,30,40,10,ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding 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 Efficacy and Safety End Point,0,15,25,30,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,13.9,22.3,P=.007*,5,20,10,ASSENT-3: 30-Day Mortality,0,4,8,10,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,5.4,6.6,3-way P=.25,6,2,% Risk of 30-Day Mortality,ASSENT-3: 30-Day Death or MI,% Risk of 30-Day Death or MI,0,4,8,10,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,6.8,7.3,3-way P=.0198,6,2,ASSENT-3: In-Hospital Recurrent MI,% Risk of In-Hospital Recurrent MI,0,2,4,5,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,2.7,2.2,3-way P=.0009,3,1,ASSENT-3: In-Hospital Refractory Ischemia,% Risk of 30-Day Refractory Ischemia,0,4,8,10,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,4.6,3.2,3-way P.0001,6,2,ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complications,*While 3-way P-value is significant, Enox vs UFH comparison P=NS,Enox Abx UFH P-Value (n=2040) (n=2017) (n=2038) 3-way,Any thrombocytopenia 1.2 3.2 1.3 .0001 Thrombocytopenia .0001 20,000 cells/L 0.1 0.5 0.2 20,000 to 50,000 cells/L 0.2 0.6 0.2 50,000 to 100,000 cells/L 0.9 2.0 1.0 Bleeding episodes Total 25.6* 39.7 21.1 .0001 Major 3.0* 4.3 2.2 .0005 Minor 22.6* 35.4 18.8 .0001 Blood transfusion 3.4* 4.2 2.3 .0032,ASSENT-3: In-Hospital Stroke Rates,*Including hemorrhagic conversion,Patients Undergoing PCI: Mortality,ASSENT-3: In-Hospital PCI,GUSTO-V: Urgent PCI,0,5,7,8,6,3,Mortality (%),4,2,1,2.5,3.7,2.7,5.4,6.7,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,r-PA + UFH,r-PA + Abx,How Does Actual Weight Compare to Estimated Weight?,Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.,Correlation Between Estimated and Actual Patient Weight in TIMI 10B,40.5,36.4,188.5,Actual Patient Weight (kg),Estimated Patient Weight (kg),R2=0.93, P.0001,181,Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and 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. 2001;37:323A.,ASSENT-3: Study Group Conclusions Regarding TNK-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. 2001;358:605-613.,ASSENT-3: Study Group Conclusions Regarding Enoxaparin,“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. 2001;358:605-613.,ENTIRE TIMI-23: Study Design,ST MI 6h (n=461),UFH 60 U/kg bolus 12 U/kg/h infusion 36 h,ENOX varying doses +/- IV bolus Index Hosp ( 8 d),ASA, ENOX varying doses +/- IV bolus Index Hosp ( 8 d),Combination Reperfusion: Half-dose TNK-tPA + Abx (0.27