1、Combination Lytic Therapy inAcute 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,
2、Myocardial Blush ST Resolution, Myocardial Flow,Facilitates PCI,Reduces Reinfarction*,Recent Clinical Trials,Unfractionated heparinEnoxaparinUnfractionated heparinEnoxaparin,AbciximabAbciximabNoneNone,ENTIRE,ACC/AHA heparin doseLow-dose heparinEnoxaparin,NoneAbciximabNone,ASSENT-3,Standard-dose hepa
3、rinLow-dose heparin,NoneAbciximab,50% TNK-tPA50% TNK-tPA100% TNK-tPA100% TNK-tPA,100% TNK-tPA50% TNK-tPA100% TNK-tPA,100% r-PA50% r-PA,GUSTO-V,Anticoagulant,GP IIb/IIIaReceptor Inhibitor,Lytic,Trial,Clinical Trials: Ongoing,Low-dose heparinLow-dose heparinLow-dose heparin,EptifibatideEptifibatideEpt
4、ifibatide,50% TNK-tPA75% TNK-tPA100% TNK-tPA,INTEGRITI,Low-dose heparinLow-dose heparinLow-dose heparin,TirofibanTirofibanTirofiban,50% TNK-tPA75% TNK-tPA100% TNK-tPA,FASTER,Anticoagulant,GP IIb/IIIaReceptor Inhibitor,Lytic,Trial,54%,32%,GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yiel
5、d 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 Flo
6、w,GUSTO-I90 min,T14 t-PA90 min,T14 r-PA90 min,SPEED60-90 min,INTRO-AMI60 min,Pooled60-90 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 flowIf a 20% i
7、mprovement 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
8、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 days2 end point: clinical and safety events at 30 d
9、ays,2 x 5 U bolus (30)Half-dose r-PA,Standard Heparin: 5000 U bolus followed by800 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
10、(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 + Hal
11、f-dose r-PA superior,Full-dose r-PAsuperior,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,
12、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, unadjudicatedThe GUSTO-V In
13、vestigators. Lancet. 2001;357:1905-1914.,0,1,3,4,2,Myocardial Infarction (%),Any,Q-wave,Enzymatic,Ischemic STChange*,3.5,0.5,1.6,2.7,r-PA,r-PA + Abx,P 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*,12/1088,24/1149,28/7179,37/7172,2
14、5/2030,31/2135,21/6193,24/6230,*,*,*,*,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 PC
15、I,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
16、, 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
17、 thrombocytopeniaA higher rate of ICH in elderly patients over the age of 75 years,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 reinfarction
18、s:ASSENT-PlusAMI-SKWilson, 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-tPAPlus Enoxaparin,Half-dose TNK-tPAPlus AbciximabPlus Low-dose Heparin,Full-dose TNK-tPAPlus Wei
19、ght-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-ho
20、spital 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
21、,*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 Age,*There was a statistically significant interaction between treatment with abciximab and age such that patients over the age of
22、75 had poorer outcomes with abciximab (P=.001).,% Risk of 30-Day Efficacyand 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
23、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 Point,0,15,25,30,TNK-tPA + Enox,TNK-tPA + Abx,TNK-tPA + UFH,13
24、.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:
25、In-Hospital Recurrent MI,% Risk of In-HospitalRecurrent 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-DayRefractory 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:
26、 Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complications,*While 3-way P-value is significant, Enox vs UFH comparison P=NS,EnoxAbxUFHP-Value(n=2040) (n=2017)(n=2038)3-way,Any thrombocytopenia1.23.21.3.0001Thrombocytopenia.000120,000 cells/L0.10.50.220,000 to 50,000 cells/L0.2
27、0.60.250,000 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*4.22.3.0032,ASSENT-3: In-Hospital Stroke Rates,*Including hemorrhagic conversion,Patients Undergoing PCI: Mortality,ASSENT-3: In-Hospital PCI,GUSTO-V: Urgen
28、t 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
29、 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 e
30、stimating 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
31、, 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 obt
32、ained 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 abcixim
33、ab 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 a
34、ttractive 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),UFH60 U/kg bolus12 U/kg/h infusion 36 h,ENOXvarying doses+/- IV bolusIndex Hosp ( 8 d),ASA, ENOXvarying dose
35、s+/- 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. 2001;22:15. Abstract 145., UFH 40 U/kg bolus7 U/kg/h infusion 36 h,Outstanding Issues,Should enoxaparin replace UFH as the opti
36、mal 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 p
37、lus 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 Targets,Large embolii: FiltersSmall embolii (thrombii): Filters & GP IIb/IIIa inhibitors, p-selectin inhibitorsVasoconstric
38、tor 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,
