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在非ST段抬高的急性冠状动脉综合征(NSTACS) 中早期应用血小板糖蛋白IIbIIIa受体拮抗剂: 一项评估NSTACS治疗中早期应用依替巴肽 临床效果的随机、双盲、安慰剂对照试验 Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation.

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Presentation on theme: "在非ST段抬高的急性冠状动脉综合征(NSTACS) 中早期应用血小板糖蛋白IIbIIIa受体拮抗剂: 一项评估NSTACS治疗中早期应用依替巴肽 临床效果的随机、双盲、安慰剂对照试验 Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation."— Presentation transcript:

1 在非ST段抬高的急性冠状动脉综合征(NSTACS) 中早期应用血小板糖蛋白IIbIIIa受体拮抗剂: 一项评估NSTACS治疗中早期应用依替巴肽 临床效果的随机、双盲、安慰剂对照试验
Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome: A Randomized, Double-blind, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-loaded Eptifibatide in the Treatment of Patients with Non-ST-segment Elevation Acute Coronary Syndromes

2 Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome: A Randomized, Double-blind, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-loaded Eptifibatide in the Treatment of Patients with Non-ST-segment Elevation Acute Coronary Syndromes

3 Disclosures Funded by Millennium Pharmaceuticals and Schering Plough
Individual disclosures Armstrong Braunwald Califf Gibson Giugliano Harrington Montalescot Newby Strony Van de Werf

4 Study Structure—figure with the below components
Exec Comm Steering Committee Sponsor Coordinating Centers—DCRI, TIMI, CVC DSMB Sites CEC

5 Primary Objective To demonstrate the superiority of a strategy of early, routine eptifibatide begun shortly after presentation compared with a strategy of delayed, provisional use of eptifibatide pre-PCI in reducing the composite of death, MI, recurrent ischemia, and thrombotic bail-out within 96 hours in patients with high-risk NSTE ACS managed with an invasive strategy

6 Study Design High-risk NSTE ACS
2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) High-risk NSTE ACS n = 10,500 (9500) Early, routine eptifibatide (180/2/180) Placebo / provisional eptifibatide pre-PCI Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization 1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout 2 Endpoint: 30-d Death/MI Fade in safety endpoints at 120 hours (bleeding (GUSTO and TIMI scales), transfusions, stroke, non-hemorrhagic SAEs

7 Key Exclusion Criteria
Increased bleeding risk active bleeding or recent bleed Recent surgery or trauma Prior ICH or recent ischemic stroke Serious concomitant illness or pregnancy ESRD with dialysis < 30 days Recent or planned use of direct thrombin inhibitor, fXa inhibitor, abciximab/tirofiban amendment 1: bivalirudin at PCI amendment 2: acute fondaparinux or bivalirudin

8 Blinded Study Drug Administration
Double bolus and infusion regimen 180 ug/Kg IV eptifibatide (or matching placebo) bolus as soon as possible after randomization Immediate initiation of 2 ug/Kg/min eptifibatide (or matching placebo) infusion (1 ug/Kg/min if CrCl <50 cc/min) Second 180 ug/Kg IV eptifibatide (or matching placebo) bolus 10 minutes after initial bolus Provisional, blinded transition to open label eptifibatide at time of PCI using blinded bolus kit PCI active if transition before wire crossed lesion PCI bailout if after wire crossed the lesion

9 Statistical Methods Power = 85% to detect a 22.5% reduction in the primary quadruple composite assuming an event rate of 5.8% with placebo at alpha after single interim efficacy analysis Power = 85% for the key secondary efficacy endpoint of death or MI at 30 days (15% RRR, placebo rate 12.7%); also at alpha 0.048, using step down testing procedure where formally tested only if primary endpoint significant Power after sample size reduction to 9500 patients 98% for 96-hour primary composite endpoint 81% for 30-day key secondary endpoint of death or MI Prespecified subgroups Proper: Age, baseline troponin, hospital type, diabetes, early clopidogrel, UFH vs enoxaparin, TIMI Risk Score Post-randomization (improper): By management strategy (PCI, CABG, medical)

10 Enrollment Use map of world with enrollment by country on the map
Recognize top 20 (?30) enrollers worldwide—could be a “build” on top of the map

11 Study Conduct Patients randomized 9492
Patients excluded for site conduct 64 Patients without informed consent 22 Intent-to-treat population Patients who received no study drug 77 As-treated safety population 9329 Lost to follow-up 11

12 Baseline Characteristics
ERE (n=4722) DPE (n=4684) Age (years) 67 (60, 75) 68 (60, 75) Female (%) Region (%) Most of World North America Diabetes mellitus (%) Hypertension (%) Dyslipidemia (%) Prior MI (%) Prior PCI (%) Prior CABG (%) Creatinine Clearance (cc/min) 75 (56, 96) 74 (56, 96) Troponin or CKMB positive (%) ST-segment shifts (%) Presentation to rand (hours) 5.4 (3.3, 8.8) 5.7 (3.4,8.8)

13 In-hospital Management
ERE (n=4722) DPE (n=4684) Cardiac Catheterization (%) Randomization to cath (hours) (16.9, 34.2) (16.7, 31.0) PCI (%) Active provisional (%) Bailout (%) CABG (%) Medically Treated only (%) Use of Evidence-based Rx (%) ASA UFH or enoxaparin Beta-blocker Statin ACEI / ARB Clopidogrel (intended early) Clopidogrel (any)

14 96-Hour Primary Efficacy Results
ERE DPE OR P (n=4722) (n=4684) (95% CI) Death, MI, RIUR, TBO ( ) Death ( ) Death / MI ( ) Death / MI / RIUR ( )

15 Kaplan-Meier Curves for Primary Endpoint
Death, MI, RIUR or TBO (%) 5 10 15 Time Since Randomization (Hours) 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 10.0% 9.3% Delayed provisional eptifibatide 4684 469 25.9 (18.7, 48.4) Early routine 4722 439 31.1 (18.8, 62.2) P = 0.23 (stratified for intended early clopidogrel use) N # Events Hours to Event Delayed provisional eptifibatide Early routine eptifibatide

16 30-Day Secondary Efficacy Results
ERE DPE OR P (n=4722) (n=4684) (95% CI) Death or MI ( ) Death ( ) Death, MI, RIUR

17 Kaplan-Meier Curves for 30-day Death or MI
5 10 15 Time Since Randomization (Days) 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 12.4% 11.2% P = 0.079 (stratified for intended early clopidogrel use) Delayed provisional eptifibatide 4684 578 2.1 (1.0, 5.8) Early routine 4722 528 2.7 (1.0, 4.9) N # Events Days to Event Delayed provisional eptifibatide Early routine eptifibatide

18 96-hour Primary Efficacy Results By Prespecified Subgroups
0.70 0.80 0.50 0.60 0.90 1.00 2.00 Baseline Characteristic Odds Ratio for Upstream Eptifibatide (95% CI) Early Routine Eptifibatide, % Delayed Provisional Overall Men Women Age < 75 yr Age > 75 yr Troponin positive Troponin negative Diabetes No Diabetes Randomized < 4 hours Randomized > 4 hours High TIMI Risk Score (5 - 7) Intermediate TIMI Risk Score (3 4) Low TIMI Risk Score (0 2) Unfractionated heparin only Low molecular weight heparin only Primary Care Hospital Tertiary Care Hospital 9.3 10.0 9.1 9.8 9.7 10.4 8.6 9.5 11.4 10.6 7.7 6.8 8.9 10.5 10.8 9.4 10.1 8.0 11.0 9.9 9.0 Early Eptifibatide Better Delayed Provisional Eptifibatide Better Upfront clopidogrel intended No upfront clopidogrel intended 8.8 11.5 North America Western Europe Eastern Europe 10.3 7.3 11.2 Middle East, Africa and Asia 10.9

19 30-day Death or MI By Prespecified Subgroups
0.70 0.80 0.50 0.60 0.90 1.00 2.00 Overall 11.2 12.3 Men 11.4 12.0 Women 10.7 13.0 Age < 75 yr 10.2 11.6 Age > 75 yr 14.0 14.6 Troponin positive Troponin negative 8.1 8.4 Diabetes 11.7 13.8 No Diabetes 10.9 Randomized < 4 hours 11.1 12.8 Randomized > 4 hours 12.1 High TIMI Risk Score (5 - 7) 13.2 13.3 Intermediate TIMI Risk Score (3 4) Low TIMI Risk Score (0 2) 9.1 Unfractionated heparin only 11.3 Low molecular weight heparin only Primary Care Hospital Tertiary Care Hospital 12.4 Upfront clopidogrel intended 10.3 No upfront clopidogrel intended 13.7 13.4 Baseline Characteristic Odds Ratio for Upstream Eptifibatide (95% CI) Early Routine Eptifibatide, % Delayed Provisional Early Eptifibatide Better Delayed Provisional Eptifibatide Better North America Western Europe Eastern Europe 14.5 8.8 15.2 Middle East, Africa and Asia 11.0

20 Safety Results (through 120 hours)
ERE DPE OR(95%CI) P (n=4686) (n=4643) Bleeding (overall) TIMI Major ( ) 0.015 TIMI major or minor ( ) <0.001 GUSTO Severe ( ) 0.97 GUSTO Moderate or Severe ( ) <0.001 PRBC transfusion ( ) 0.001 Bleeding (CABG) Re-operation for bleeding ( ) 0.24 Chest tube output (mL/24 H) Thrombocytopenia (nadir <100K) Stroke ( ) 0.36

21 Conclusions Among high-risk NSTE ACS patients, a strategy of early, routine eptifibatide compared with delayed provisional eptifibatide at PCI did not significantly reduce the primary composite of D/MI/RIUR/TBO at 96h (9.3% vs. 10.0%, OR 0.92; ; p = 0.234) resulted in a trend toward reduction in death or MI at 30 days (11.2% vs. 12.3%; OR 0.89; ; p = 0.079), but no difference in 30-day mortality (x.x% vs. y.y%; OR 0.xx; 0.yy-0.zz; p = 0.aa) resulted in significantly higher rates of non-life-threatening bleeding and transfusions

22 Implications The results of EARLY ACS do not support a strategy of early, routine eptifibatide use among NSTE ACS patients managed with an invasive strategy It may be reasonable to consider early eptifibatide use in selected high-risk subsets of ACS patients with low risk of bleeding who are scheduled to undergo PCI In selected high-risk NSTE ACS patients who are also at increased bleeding risk, a delayed provisional eptifibatide strategy pre-PCI would be reasonable

23 Back-up slides

24 Primary and Key Secondary Efficacy Results By Clopidogrel Strata at Randomization
ERE DPE OR (95% CI) 96-hr Death, MI, RIUR, TBO Clopidogrel intended ( ) No Clopidogrel intended ( ) 30-day Death / MI Clopidogrel intended ( ) No Clopidogrel intended ( )


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