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  1. High Risk Patients with ACS — EuroPCR 2008, Barcelona, Spain Introduction and ObjectivesIssues and challenges in ACS Philippe Gabriel Steg INSERM U-698 Hôpital Bichat – Claude Bernard Université Paris VII – Denis Diderot

  2. Disclosures Speaker’s name: Philippe Gabriel Steg I have the following potential conflicts of interest to report: Consulting/Advisory Board: AstraZeneca, Boehringer-Ingelheim, BMS, GSK, MSD, Nycomed, sanofi-aventis, Servier, Takeda, The Medicines Company  Research Grant: sanofi-aventis Speaker’s Bureau: Boehringer-Ingelheim, BMS, GSK, Nycomed, sanofi-aventis, Servier, ZLB-Behring  I do not have any potential conflict of interest

  3. The Landscape • A changing pattern of care for all high-risk ACS

  4. Trends in Management of STEMI in the GRACE Registry Fox KAA et al. JAMA 2007;297:1892-1900

  5. The Landscape • A changing pattern of care for all high-risk ACS • …and outcomes which are improving

  6. In-Hospital and 6-Month Outcomes in Patients With STEMI or LBBB Fox KAA et al. JAMA 2007;297:1892-1900.

  7. CRUSADE In-Hospital Outcomes: Data from 2006 Death 3.6% (Re)-Infarction 1.8% CHF 6.6% Cardiogenic Shock 2.2% Stroke 0.7% RBC Transfusion* 9.1% *Excluding CABG-related transfusions CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)

  8. The Landscape • A changing pattern of care for all high-risk ACS • …and outcomes which are improving • A growing level of complexity

  9. Antithrombotics for ACSMore and More Choices (and Combinations) Fonda Direct TIs Lytics Clopidogrel GP IIb/IIIa inhibitors LMWH Heparin Aspirin

  10. Choices Impacting Antithrombotic Therapy Anticoagulants: UFH LMWH Fonda Bival Antiplatelets: ASA (dose) Clopidogrel (time/dose) IV antiplatelets: None Abcix Ept/Tiro (timing) Cath strategy: Early Delayed Never 72 Different Combinations!

  11. Treatment of ACS is a Jungle ! Anticoagulant Rx UFH Enoxaparin Bivalirudin Fondaparinux Warfarin ? Anti X ? Anti II Timing Antiplatelet Rx ASA Clopidogrel ? Prasugrel ? AZD 6140 GpIIb/IIIA IV blockers ? Cangrelor ? TRA Revascularization PCIBMS DES CABG Patient Bleeding risk Comorbidities Risk of thrombotic event

  12. The Landscape • A changing pattern of care for all high-risk ACS • …and outcomes which are improving • A growing level of complexity • Use and timing of interventions impact therapeutic choices

  13. The Landscape • A changing pattern of care for all high-risk ACS • …and outcomes which are improving • A growing level of complexity • Use and timing of interventions impact therapeutic choices • Fortunately, we have guidelines to assist us !

  14. Objectives • Know the current guidelines for the management of STEMI and NSTE ACS • Understand their implications for patient management

  15. New Horizons for Patients with ST-Elevation Myocardial Infarction Gregg W. Stone MD Columbia University Medical Center Cardiovascular Research Foundation

  16. Potential Conflicts of Interest Speaker’s name: Gregg W. Stone, MD I have the following potential conflicts of interest to report:  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company Grant/Research Support: The Medicines Company and Boston Scientific  I do not have any potential conflict of interest

  17. Major bleeding(with or without blood product transfusions) has emerged as a powerful independent predictor of early and late mortality in pts with NSTEMI, STEMI and in those undergoing PCI FACT Ndrepepa et al. JACC 2008;51:690–7

  18. Impact of Major Bleed and MI after Elective and Urgent PCI1-Year Mortality (N=6,012) With major bleed 8.8% 5.7% With MI Cumulative % Mortality 2.0% Without major bleed 1.9% Without MI Time from Randomization in Days Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

  19. Predictors of 1-year Mortality after Elective and Urgent PCI Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.

  20. 1-year MortalityAll 6,012 Patients (ITT) 2.5% P value = 0.16 1.9% Cumulative Deaths Days Lincoff AM et al. JAMA 2004;292:696–703

  21. Major Bleed only (without MI) (N=551) 12.5% MI only (without Major Bleed) (N=611) 8.6% No MI or Major Bleed (N=12,557) Both MI and Major Bleed (N=94) 28.9% 3.4% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 1 yearEstimate 30 25 20 Mortality (%) 15 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. ACC 2007

  22. Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Influence of Major Bleeding and MI in the First 30 Days on the Risk of Death within 30 Days Of 13,819 enrolled pts, 704 (5.1%) had a MI, 644 (4.7%) had a major bleed (non CABG), and 206 (1.5%) died within 30 days Attributable deaths HR ± 95% CI HR (95% CI) P-value 42.0* 38.2** *20.4% of all deaths **18.5% of all deaths Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Stone GW. ACC 2008

  23. Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year Of 13,819 enrolled pts, 524 (3.8%) died within 1 year Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates Attributable deaths HR ± 95% CI HR (95% CI) P-value 51.5* 66.5** *9.8% of all deaths **12.7% of all deaths Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR Mehran RM et al. Submitted

  24. ACUITY: Early and Late MortalityLandmark analysis 30 day P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa 1.4% — Bivalirudin + IIb/IIIa 0.53 1.6% Bivalirudin alone 0.39 1.6% 30d - 1 year P (log rank) Estimate 3.1% — 0.54 2.7% 0.21 2.3% 4 3 Mortality (%) 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW. JAMA 2007;298:2497-506

  25. Harmonizing Outcomes with Revascularization and Stents in AMI ≥3400* pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… R 1:1 R 1:3 CABG – – Primary PCI Medical Rx 3000 pts eligible for stent randomization TAXUS paclitaxel-eluting stent Bare metal stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years *To rand 3000 stent pts

  26. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin Monotherapy N=1800 Randomized 9 15 • • • Withdrew • • • • • • Lost to FU • • • 10 13 N=1778 (98.7%) N=1777 (98.7%) 30 day FU* ITT population N=1802 N=1800 * Range ±7 days Stone GW et al. In press.

  27. Primary Outcome Measures (ITT) Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.005 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 0.95 1 endpoint 1 endpoint • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke

  28. 30 Day Bleeding Endpoints* *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

  29. Thrombocytopenia P = 0.002 P = 0.04 P = 0.02 <100,000 cells/mm3 <50,000 cells/mm3 <20,000 cells/mm3 Stone GW et al. In press.

  30. 30 Day MACE Components* *CEC adjudicated Stone GW et al. In press.

  31. 30 Day Mortality Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 3.1% Death (%) 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630 Stone GW et al. In press.

  32. 30 Day Mortality: Cardiac and Non Cardiac Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 2.9% Death (%) Cardiac 1.8% Non cardiac 0.3% 0.2% Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630 Stone GW et al. In press.

  33. 30 Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated

  34. 30 Day Mortality: PCI Cohort Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) HR [95%CI] = 0.63 [0.40, 0.99] P=0.049 2.8% Death (%) Cardiac 1.8% Non cardiac 0.2% 0.1% Time in days Number at risk Bivalirudin 1678 1647 1640 1635 1632 1620 1563 Heparin + GPIIb/IIIa1662 1631 1615 1604 1598 1583 1512 Stone GW et al. In press.

  35. Predictors of 30 Day Mortality32 Candidate Baseline Variables* Demographic:Age; sex; race; US vs. OUS; HTN, hyperlipidemia, smoking, diabetes, diabetes on insulin, MI, PCI, CABG, CAD, angina, CHF, major cardiac rhythm/rate disturbances, PVD Medication use at home previous 5 days:aspirin, beta blocker, thienopyridines, calcium channel blocker, ACE/ARB, diuretic Time from symptom onset to hospital ER Physical exam:BMI; KILLIP class Baseline labs: Estimated CrCl, anemia, platelet count Medications in hospital prior to angiography:Randomized treatment (bivalirudin vs. heparin + GPI; pre-procedure heparin; clopidogrel load * Angiographic variables not yet available; - treatment related variables not used

  36. Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Attributable Ischemic EventsHR (95% CI) P deaths* C-stat Reinfarction 11.09 [5.44,22.59] <0.001 9.1 [8.2,9.6] 0.83 Ischemic TVR 6.91 [3.36,14.18] <0.001 7.7 [6.3,8.4] 0.83 Stent thrombosis, definite** - any10.71 [3.93,29.18] <0.001 4.5 [3.7,4.8] 0.83 - acute (<24 hours)5.88 [0.78,44.30] 0.09 0.8 [-0.3,1] 0.82 Stroke 5.44 [1.67,17.69] 0.005 2.4 [1.2,2.8] 0.82 * Of 93 total deaths; ** in 3,124 successfully stented pts ***Only 2 pts with acute stent thrombosis died within 30 days, 1 in each randomized group

  37. Time-updated covariate adjusted Cox model relating single 30-day adverse events to 30-day mortality Attributable Bleeding EventsHR (95% CI) P deaths* C-stat Major bleed (non-CABG) 4.43 [2.67, 7.33] <0.001 20.1 [16.3,22.5] 0.85 Major bleed (all) 5.92 [3.73, 9.41] <0.001 29.1 [25.6,31.3] 0.86 Transfusion 3.88 [2.09, 7.20] <0.001 11.9 [8.4,13.8] 0.83 Thrombocytopenia** - <100,000 cells/mm33.89 [2.22, 6.84] <0.001 11.1 [8.2,12.8] 0.78 - <50,000 cells/mm36.44 [2.93,14.18] <0.001 5.9 [4.6,6.5] 0.78 - <20,000 cells/mm34.98 [1.20,20.66] 0.03 1.6 [0.3,1.9] 0.77 * Of 93 total deaths; ** 88 deaths in 3550 patients Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

  38. Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality- Complete model with MACE components and major bleeding - Risk Factor HR [95% CI] P-value Reinfarction 9.75 [2.72,34.91] <0.001 <0.001 Major bleeding (non CABG) 4.66 [2.84, 7.63] Ischemic TVR 1.11 [0.29, 4.21] 0.88 2.64 [0.71, 9.75] 0.15 Stroke 0.01 0.1 1 10 100 Hazard Ratio [95% CI] C-statistic = 0.87.

  39. Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality- Complete model with MACE components and major bleeding - Attributable Deaths Risk Factor HR [95% CI] P-value Reinfarction Incidence 69 (2.2%) 10 deaths with event 9.75 [2.72,34.91] 9.0* [6.3, 9.7] <0.001 Major bleeding (Non CABG) Incidence 238 (6.8%) 26 deaths with event 4.66 [2.84, 7.63] 20.4** [16.8, 22.6] <0.001 *9.7% of 93 total deaths **21.9% of 93 total deaths 0.01 0.1 1 10 100 Hazard Ratio [95% CI] C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

  40. Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortality- Complete model in 3,124 pts with successfully implanted stents - Attributable Deaths Risk Factor HR [95% CI] P-value Stent thrombosis (definite) Incidence 57 (1.8%) 5 deaths with event 10.62 [3.96, 28.48] 4.5* [3.7, 4.8] <0.001 Major bleeding (non CABG) Incidence 195 (6.2%) 18 deaths with event 6.22 [3.33, 11.60] 15.1** [12.6, 16.4] <0.001 *8.3% of 54 total deaths **28.0% of 54 total deaths 0.01 0.1 1 10 100 Hazard Ratio [95% CI] C-statistic = 0.87. Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR

  41. 1. Major bleeding is a powerful independent determinant of mortality in ACS, STEMI, and in pts undergoing PCI, at least as important as MI/reinfarction. Conclusions 2. In high risk pts with STEMI undergoing primary PCI, treatment with bivalirudin compared to heparin + GPI results in a significant reduction in bleeding, thrombocytopenia and transfusions, with similar rates of reinfarction, stent thrombosis, iTVR and stroke. 3. This favorable balance of adverse events results in lower 30-day mortality in primary PCI pts treated with bivalirudin rather than heparin + GPI, representing a new standard of care for pts with STEMI.

  42. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ SWITCH Changing Anticoagulants in Midstream — What Are the Benefits and Risks? Harvey White Green Lane Cardiovascular Service and Cardiovascular Research Unit Auckland City Hospital; Auckland, New Zealand

  43. Potential conflicts of interest Speaker’s name: Harvey D. White I have the following potential conflicts of interest to report: Research Grants: Sanofi Aventis, The Medicines company, Eli Lilly, Roche,Schering Plough, Pfizer, Johnson and Johnson, Astra Zenica, Merck Sharpe and Dohme and NIH Consulting Fees: The Medicines Company  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  I do not have any potential conflict of interest

  44. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ Background • ACS patients • 87% of patients receive either UFH or Enox within 24 hours after admission1 • 72% of patients in SYNERGY and 50 % of patients in OASIS- 5received prior antithrombin2,3 • Published studies and perceptions • Patients in SYNERGY who crossed over between UFH and Enox had an increase in bleeding complications2 • This activity occurred at various times through the study period: At times in response to clinical or clinician perception • Consistent therapy is better4 1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al, NEJM 2006; 4 Cohen et al, JACC 2006;

  45. Switching Concern about switching antithrombins in patients with ACS (lessons from SYNERGY) European guidelines Why should switching to bivalirudin monotherapy be reasonable? Mechanistic rationale for switching SWITCH REPLACE 2 ACUITY Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ

  46. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ ESC Non-STEACS Guidelines • At PCI procedures, the initial anticoagulant should also be maintained during the procedure regardless of whether this treatment is UFH (I-C), enoxaparin (IIb-B), or bivalirudin (I-B) EHJ 2007;28:1598-60

  47. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ SWITCH • Switch: Protocol mandated change in antithrombotic therapy at randomization • Crossover : Post randomization change in antithrombotic therapy due to physician choice Definitions

  48. ACUITY — SWITCH Hypothesis Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation Is it better to switch to bivalirudin or remain on consistent therapy? Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ White HD. In Press JACC

  49. ACUITY – Primary Results UFH/Enoxaparin + GPI vs. Bivalirudin Alone UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612) PNI <0.0001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.0001 PSup <0.0001 11.7% 30 day events (%) 10.1% 7.8% 7.3% 5.7% 3.0% Net clinical outcome Ischemic composite Major bleeding