Panelist Gilles Montalescot MD PhD
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  • Figure 5a
  • Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI. A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesis All patients were to receive ASA. Randomization was stratified by UA/NSTEMI vs STEMI DB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg - OR prasugrel with a LD of 60 mg and MD of 10 mg DB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 months The primary composite EP was CV death, MI, or Stroke through the end of the study Key secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleeds Two key substudies are evaluating pharmacokinetics and genomics
  • Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI. A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesis All patients were to receive ASA. Randomization was stratified by UA/NSTEMI vs STEMI DB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg - OR prasugrel with a LD of 60 mg and MD of 10 mg DB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 months The primary composite EP was CV death, MI, or Stroke through the end of the study Key secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleeds Two key substudies are evaluating pharmacokinetics and genomics
  • Figure 1. Incidence of Non-CABG-Related Major or Minor Bleeding during the First 48 Hours. The 95% CIs for adjusted differences between groups for non-CABG-related major or minor bleeding during the first 48 hours were -4.7 to -0.6% for comparison of the group given 0.5 mg of enoxaparin per kilogram with the group given unfractionated heparin and -4.0% to 0.0% for the comparison of the group given 0.75 mg of enoxaparin per kilogram with the group given unfractionated heparin, with a noninferiority margin of 2.6%.

Panelist Gilles Montalescot MD PhD Panelist Gilles Montalescot MD PhD Presentation Transcript

  • Lost in translation: US & European guidelines for the pharmacologic management of ACS Panelist Gilles Montalescot MD PhD Professor of Cardiology Institut de Cardiologie Hospital la Pitié-Salpêtrière Paris, France Panelist Charles V Pollack Jr MA MD Chairman Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Chair E Magnus Ohman MD Professor of Medicine and Director Program for Advanced Coronary Disease Duke University Medical Center Durham, North Carolina Panelist Keith A A Fox MB ChB Professor of Cardiology Cardiovascular Research, Division of Medical & Radiological Science University of Edinburgh Edinburgh, Scotland
  • ACS patients Invasive strategy Angio Before angiography ACC/AHA Guidelines UA/NSTEMI J Am Coll Cardiol . 2007;50:e1-e157 . Enoxaparin Fondaparinux UFH Bivalirudin B A B A Clopidogrel (with load) or IIb/IIIa (eptifibatide or tirofiban) Abciximab only if no delay and PCI likely IIb/IIIa plus clopidogrel (with load) Abciximab only if no delay and PCI likely ASA [alternative - Clopidogrel ] w/ Hx GI bleed - PPI A A B A B B B Fibrinolytic Rx Abciximab if PCI not planned A A Class I Class IIa Class IIb Class III
  • CABG rates non-STE ACS Stone GW, et al. N Engl J Med . 2006;355:2203-2216. The Crusade Registry 2005. Fox KA, et al. Heart . 2007;93:177-182.
  • CURE study N=12,562 ACS within 24 hour no ST-segment ↑ > 1 mm Clopidogrel (n=6259 ) 300 mg load/ 75 mg/day Placebo (n=6303) No PCI (n=4946) PCI (n=1313) No PCI (n=4958 ) PCI (n=1345 ) Yusuf S, et al. N Engl J Med . 2001;345:494-502 . ASA Clopidogrel group significant reduction in: CV death/MI/stroke 20% CV death/MI/stroke/refrac isch 14%
  • CRUSADE: timing of PCI Tricoci P, et al. Am J Cardiol . 2007;99:1389-1393 .
  • TRITON TIMI 38: study design Anatomy known to be suitable for PCI ACS (STEMI or UA/NSTEMI) & planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD N=13,608 1 o endpoint: CV death, MI, stroke 2 o endpoints: CV death, MI, stroke, rehosp-rec isch CV death, MI, UTVR Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, life-threatening bleeds
  • TRITON TIMI 38: efficacy & safety
    • Efficacy: significant reduction in
    • CV death/MI/stroke 19%
    • Stent thrombosis 52%
    • uTVR 34%
    • MI 24%
    • Safety: significant increase in:
    • Serious bleeding* 32%
    • Avoid in patients with prior CVA/TIA
    • * TIMI major bleeding (non-CABG)
    Wiviott SD, et al. N Engl J Med . 2007;357:2001-2015.
  • TRITON TIMI 38 n=3534 Within 14 days med Rx for STEMI Within 12 hours of symptom onset STEMI cohort Wiviott SD, et al. N Engl J Med . 2007;357:2001-2015. Findings expected ESC 2008
  • Anticoagulant options
    • Enoxaparin/LMWH
      • more often used in Europe vs United States
    • Fondaparinux
      • rarely used in United States
    • UFH
    • Bivalirudin
  • OASIS-5 results at 9 days N Engl J Med . 2006;354:1464-1476. P < 0.001 Greater reduction in bleeding in patients who did not undergo PCI Fondaparinux or enoxaparin given for hospital duration or up to 8 days 67% thienopyridine N=20,078 39.5% underwent PCI
  • Fondaparinux
      • Class I (level of evidence b) for early invasive and selective invasive in US guidelines
    • Insufficient as sole anticoagulant in PCI
      • catheter thrombosis an issue
      • some centers combine with UFH
    • Sometimes used in medically managed patients
      • no FDA label for use in ACS
  • CRUSADE: chronic kidney disease
    • 45,343 non-STE ACS patients
      • 6560 (14.5%) moderate-to-severe CKD
        • SCr >2.0 mg/dL or need for dialysis
    • Moderate-to-severe CKD
      • 50% increase in mortality
      • 70% increase in likelihood of transfusion
    Han JH, et al. Am J Med . 2006;119:248-254 .
  • Example of enoxaparin regimen
    • IV enoxaparin 0.5 mg/kg for PCI
      • 1 shot ± IIb/IIIa inhibitors
      • no ACT monitoring
      • stable anticoagulation for 2 hours (duration of PCI)
  • ACUITY 30-day Stone GW. N Engl J Med . 2006;355:2203-2216. *bivalirudin monotherapy vs heparin + IIb/IIIa, † noninferior N=13,819 moderate- to high-risk ACS early invasive in all UFH/LMWH + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone P value* Death/MI/revasc 7.3 7.7 7.8 0.32 † Major bleeding 5.7 5.3 3.0 <0.001 Net clinical outcome 11.7 11.8 10.1 0.02
  • ISAR REACT 3 Kastrati A. SCAI-ACCi2 2008 Biomarker negative stable and unstable angina patients undergoing PCI; All received 600 mg clopidogrel Bivalirudin (n=2289) UFH 140 U/kg (n=2281) P value Death, MI, UTVR, major bleeding (%) 8.3 8.7 0.57 Major bleeding (%) 3.1 4.6 0.008 Minor bleeding (%) 6.8 9.9 0.0001 Transfusion (%) 1.3 1.8 0.15
  • Montalescot G, et al. N Engl J Med . 2006;355:1006-1017. © 2006 Massachusetts Medical Society. All rights reserved. STEEPLE: non-CABG-related major/minor bleeding during first 48 hours
  • EARLY ACS: study design High-risk NSTE ACS n=10,500 1  endpoint: 96-hr death/MI/urgent revasc/thrombotic bailout 2  endpoint: 30-d death/MI Placebo Eptifibatide (180/2/180) Randomize within 8 hours Early invasive strategy: ≥ next calendar day
    • 2 of 3 criteria:
    • Age > 60 years
    • + CKMB or TNT/I
    • ST  or transient ST 
    Expected AHA 2008 or ACC 2009