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Abciximab in Patients with AMI Undergoing Primary PCI After Clopidogrel Pretreatment

ClinicalTrials.gov Identifier: NCT00133250. Abciximab in Patients with AMI Undergoing Primary PCI After Clopidogrel Pretreatment. BRAVE-3 Trial B avarian R eperfusion A lternati V es E valuation-3 Trial.

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Abciximab in Patients with AMI Undergoing Primary PCI After Clopidogrel Pretreatment

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  1. ClinicalTrials.gov Identifier: NCT00133250 Abciximab in Patients with AMI Undergoing Primary PCI After Clopidogrel Pretreatment BRAVE-3 Trial Bavarian Reperfusion AlternatiVes Evaluation-3 Trial J. Mehilli, A. Kastrati, K. Huber, S. Schulz, J. Pache, C.Markwardt, S. Kufner, F. Dotzer, K. Schlotterbeck, J. Dirschinger, A. Schömig

  2. Financial Disclosure No financial relationship to disclose

  3. Background • Glycoprotein IIb/IIIa inhibitors (GPI) may improve the results of primary PCI in acute STEMI • Pretreatment with a 300mg loading dose of clopidogrel improved the outcome of patients undergoing primary PCI in the setting of the CLARITY trial • A higher, 600mg loading dose of clopidogrel further enhances and accelerates platelet inhibition

  4. Objective ..to assess whether abciximab further reduces the infarct size in patients with acute ST-elevation myocardial infarction undergoing primary PCI after pre-treatment with 600 mg clopidogrel

  5. Inclusion Criteria • Patients with acute ST-elevation myocardial infarction presenting within 24 hours from the onset of symptoms • chest pain lasting more than 20 min • ≥0.1 mV of ST-segment elevation in ≥2 limb leads or ≥0.2 mV in ≥2 contiguous precordial leads or new left bundle branch block on surface ECG • Written, informed consent

  6. Exclusion Criteria • Age > 80 or < 18 years • Malignancies with a life expectancy <1 year • Cardiogenic shock or prolonged cardiopulmonary resuscitation • Increased risk of bleeding Previous stroke within the last 3 months Active bleeding or bleeding diatheses Recent trauma or major surgery within the last 30 days Suspected aortic dissection Recent use of GPI within 14 days Oral anticoagulation therapy with coumarin derivatives Severe uncontrolled hypertension (>180mmHg, unresponsive to therapy) • Relevant hematologic deviations (hemoglobin < 100g/L or hct < 34%, platelet count < 100 x 109/L) • Coronary intervention within the last 30 days • Known allergy to study medication, Pregnancy, Prior inclusion in the study

  7. Myocardial perfusion % 0% 100% 50% Endpoints Primary endpoint: • SPECT study (5-7days after • randomization) • Final infarct size • (% of the left ventricle) Secondary endpoints: • Death • Myocardial reinfarction • Urgent revascularization • Stroke • Major and minor bleeding (TIMI criteria) • Profound thrombocytopenia

  8. Sample Size Calculation Assumptions: • Infarct size of the LV in placebo group: 16.9% ± 13.9% • Reduction of infarct size with abciximab by 20% • -level: 0.05 (two-sided); -error: 0.10 Sample size: • 353 patients per group with SPECT study • to accommodate for possible missing SPECT studies: 400 patients per group planned

  9. BRAVE-3 Study Sides & Investigators • Deutsches Herzzentrum, Munich, Germany PI: M. Seyfarth • Klinikum rechts der Isar, Munich, Germany • PI: J. Dirschinger • Klinikum Traunstein, Traunstein, Germany • PI: K. Schlotterbeck • Wilhelminenspital Vienna, Vienna, Austria • PI: K. Huber • Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany PI: F. Dotzer Study Chair: A. Schömig Study Principal Investigator: A. Kastrati Data Co-ordinator: J. Mehilli

  10. Study Therapy (randomized, double-blind) Clopidogrel 600 mg oral Aspirin 500 mg i.v. or oral Unfractionated Heparin 5000 IU Abciximab n=401 Bolus: 0.25 mg/kg Infusion: 0.125 μg/kg/min/12h Placebo n=399 Additional UFH bolus of 70U/kg Placebo infusion for 12h Aspirin 200mg/day indefinitely Clopidogrel 2 x 75mg/day for 3 days Clopidogrel 75mg/day for at least 4 weeks

  11. Abciximab (n=401) Placebo (n=399) 62.4±11.7 61.8±12.2 24 27 42 44 70 71 19 16 42 41 27.1±3.8 27.0±4.1 10 11 4 2 Baseline Characteristics Age, yrs Women, % Hypercholesterolemia, % Arterial hypertension, % Diabetes mellitus, % Current smoker, % Body mass index, kg/m2 Previous MI, % Previous CABG, % Mean±SD

  12. Infarct Characteristics Abciximab (n=401) Placebo (n=399) Infarct localization, % 42 44 anterior 43 43 inferior lateral 15 13 Killip Class, % I 76 77 II 18 18 III 4 3 IV 2 2 Arterial blood pressure, mmHg 138±23 139±22 systolic diastolic 79±13 80±14 Heart rate, beats/min 73±17 73±16 Mean±SD or %

  13. Abciximab (n=401) Placebo (n=399) 210[110;420] 216[110;467] 25[15;43] 20[14;40] 73[54;104] 75[53;105] 78[59;109] 80[58;110] Time Intervals Symptom to admission Admissiontostudydrug Clopidogrel loading to PCI Admission to PCI Median [25th, 75th percentiles] in minutes

  14. Abciximab (n=401) Placebo (n=399) 47.7±11.5 48.0±10.6 65 61 43 45 16 15 39 38 0 1 2 1 Angiographic Characteristics LV- ejection fraction, % Multivessel disease, % Infarct related coronary artery, % LAD LCx RCA LMA Bypass graft Mean±SD

  15. Infarct-Related Artery TIMI Flow Rates TIMI 1 TIMI 2 TIMI 0 TIMI 3 After PCI Prior to PCI 100 100 % % 60 60 20 20 Abciximab Placebo Abciximab Placebo

  16. 100 % 60 20 Abciximab Placebo Rentrop class 1 Rentrop class 2 No collaterals Rentrop class 3 Collateral Distribution IRA TIMI Flow rate <2

  17. Abciximab (n=401) Placebo (n=399) 2.93±0.54 2.91±0.56 0.46±0.56 0.44±0.57 84.1±19.4 84.3±20.6 3.26±0.53 3.26±0.52 1.11±0.09 1.12±0.12 13.5±2.6 13.4±2.5 2.62±0.67 2.63±0.65 13.8±16.4 13.6±15.2 QCA Measurements Vessel size, mm MLD prior PCI, mm DS prior PCI, % Balloon diameter, mm Balloon-to-vessel ratio Maximal balloon pressure, atm MLD after PCI, mm DS after PCI, % Mean±SD

  18. Reperfusion Strategy 100 Drug-eluting stents % Bare metal stents PTCA 60 Medical treatment 20 Abciximab Placebo

  19. Primary Endpoint Final infarct size Mean Final infarct size Median[25th; 75th percentile] 40 P =.76 P = .47 % LV % LV 30 20 10 10 9 0 Abciximab Placebo Abciximab Placebo

  20. All ≤ 62.5 yrs > 62.5 yrs female male yes no anterior non-anterior ≤ 210 min > 210 min ≤ 47 min > 47 min Primary Endpoint - Subgroup analysis - Difference in Final Infarct Size (%) Age Sex Diabetes Infarct localization Interval pain onset to admission Interval study drug to PCI Interval clopidogrel to PCI ≤ 74.5 min > 74.5 min -8 -6 -4 -2 0 2 4 6 8 Abciximab better Placebo better

  21. 30-Day Mortality P= .53 6 % Abciximab 4 Cumulative Incidence Placebo 2 0 0 5 10 15 20 25 30 Days after randomization

  22. Clinical Adverse Events- 30 days - P= .46 P= .48 P= .39 % Abciximab Placebo

  23. Clinical Adverse Events- 30 days - 6 P = .99 P= .09 P = .03 % 3.7 4 1.8 1.8 1.8 2 1.5 0 0 TIMI major TIMI minor <20,000/µl Thrombocytopenia Bleeding Abciximab Placebo

  24. Conclusion In patients with acute STEMI undergoing primary PCI after pre-treatment with a 600mg loading dose of clopidogrel, the additional use of abciximab is notassociated with further reduction in infarct size

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