1. 1 ST Elevation MI Management: A Regional Approach Krishnan Ramanathan MB, ChB, FRACP, FRCPC Assistant Professor, University of British Columbia Medical Director Cardiac Intensive Care Unit St. Paul’s Hospital Post Graduate Committee on Cardiology Training Co-Chair Regional STEMI and Provincial ACS group

2. 2 Disclosure No stocks or bonds Speaking honoraria and Consultancy  AstraZeneca  Servier  Schering Plough  GSK  Sanofi aventis

3. 3 VANCOUVER HYPERTENSION September 26-30, 2010

4. 4 2004 Olympics 100m Final 1.USA-Justin Gatlin 2.POR- Obikwelu Francis 3.USA- Maurice Greene 4.USA- Shawn Crawford Superstars

5. 5 Declining Acute MI Mortality Four Decades of Improving Care Adapted from Armstrong et al CJC 1996 changing denominator?

6. 6 PPCI vs Fibrinolysis Higher rates of TIMI 3 flow Faster to initiate

7. 7 Integrated Approach

8. 8 Hospitals with PCI capabilityHospitals without PCI capability VANCOUVER COASTAL HEALTH REGION FRASER HEALTH REGION

9. 9 Reperfusion Confusion No consensus on treatment of STEMI patients: When to refer for PPCI ? Where to refer ? Who to notify ? What adjunctive initial therapy ?

10. 10Stakeholders STEMI Committee Cardiology: Urban/Rural One Acute Network/SET Interventional Cardiology Emergency Dept. BC Ambulance BC Bed Line Regional and Local Pharmacy IMIS/MUSE ED Nursing Cardiac Nursing Cath Lab Nursing GOAL: Regional Integrated Approach to Treating STEMI Health Records

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12. 12 Regional Reperfusion Algorithm – phase 1 Community Hospital PCI Hospital # 911 - ineligible for fibrinolytic - failure to reperfuse - hemodynamic instability - electrical instability

13. 13 STEMI Management Solution Simplifying 12-lead transmission from the field

14. 14 Phase-2 In-Field ECG Diagnosis ALS cars and crews equipped with portable 12-lead ECG recording and transmitting capability suspect STEMI ECGs transmitted to ED with alert ED physician activates reperfusion strategy Patient received at designated hospital in a state of readiness

15. 15 Community Hospital PCI Hospital 911 Regional Reperfusion Algorithm – phase 2 - ineligible for fibrinolytic - failure to reperfuse - hemodynamic instability - electrical instability

16. 16

17. 17 Prehospital (Overall) median times Time (Min) “Prehospital delay” “Intrahospital delay” “Procedural delay”

18. 18 Prehospital & Intrahospital (Overall) median times Time (Min) “Prehospital delay” “Intrahospital delay” “Procedural delay” “43 minutes”

19. 19 Patient Flow (Overall) Time (Min) “Prehospital delay” “Intrahospital delay” “Procedural delay” 43 minutes20 minutes + **

20. 20 Baseline characteristics VARIABLEBefore pECG (N=149) After pECG (N=230) Mean age (yrs) ( + SD)63 + 1265 + 13 Male sex (%)76.580.1 Prior MI (%)14.814.1 Diabetes mellitus (%)17.516.7 Hypertension (%)45.646.7 Current smoking (%)28.933.5 Dyslipidemia43.037.4 Cardiogenic shock (%)10.78.9 Anterior STEMI (%)53.043.0 Initial HR (BPM)81 + 2477 + 23 Initial SBP (mmHg)141 + 30142 + 33 NS

21. 21 Reperfusion times Symptom onset to balloon time First medical contact to balloon time Door to balloon time P=0.002 P<0.0001 Before pECG (N=149) After pECG (N=230) Time (Minutes)

22. 22 Proportion of patients with reperfusion times <90 minutes Before pECG (N=149) After pECG (N=230) % P<0.0001

23. 23 In hospital mortality: pECG vs. no pECG P=0.64 pECG prior to PPCI No pECG prior to PPCI

24. 24 Declining Acute MI Mortality Four Decades of Improving Care

25. 25 2004 Olympics 100m Final 1.USA-Justin Gatlin 2.POR- Obikwelu Francis 3.USA- Maurice Greene 4.USA- Shawn Crawford Superstars

26. 26 USA Lost!! 2004 Olympics 4x100m Relay Oops!!

27. 27 STEMI Reperfusion Sprint Relay #1) STEMI Patient #2) Paramedics/ED triage RN #3) Emergency Dept. Team #4) Cardiac Cath Lab Team Reperfusion Finish Start

28. 28 “Individual commitment to a group effort – that is what makes a team work, a company work, a society work, a civilization work” Vince Lombardi Teamwork

29. New Anti-Platelet Therapies Krishnan Ramanathan MB, ChB FRACP, FRCP(C) Assistant Professor University of British Columbia Director Cardiac Intensive Care Unit St. Paul’s Hospital Co-Chair Regional STEMI Committee Co Chair Provincial ACS Registry Project 29

30. Percent With Event (%) Months LDL-C 106  95 LDL-C 106  62 PROVE-IT Study: 4162 AMI and ACS Patients Incidence of Death, MI, and Revascularization 30

31. 9803mo01, 31 31 Acute Coronary Syndromes Unstable angina RISK Non ST elevation ACS ST elevation ACS Sudden cardiac death Lumin Plaque Thrombus Anti Platelets Thrombolysis Primary PCI Therapy Lipid Lower / ACE inhibitors Early revas vs. initial conservative Anti thrombins Anti ischemic Risk Stratification Anti Platelets Anti thrombins Lipid Lower / ACE inhibitors Beta blockers

32. 9803mo01, 32 32 Sites of Antithrombotic Drug Action Tissue factor Plasma clotting cascade Plasma clotting cascade Prothrombin Thrombin Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A 2 ADP AT Aspirin (OASIS-7) Clopidogrel (OASIS-7) Prasugrel (TRITON/TRILOGY) Ticagrelor (PLATO) Eptifibatide Abciximab Tirofiban Bivalirudin Hirudin Argatroban Factor Xa Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux AT SCH 530348 (TRACER) 32

33. Platelet Activation Mechanism 33

34. ASA in Acute Coronary Syndromes Unstable Angina Acute Myocardial Infarction DEATH/MI p<0.001 DEATH/MI p<0.001 REOCCLUSION p=0.003 REOCCLUSION p=0.003 REINFARCTION p=0.012 REINFARCTION p=0.012 DEATH p<0.01 DEATH p<0.01 397 399 N= 513 419 8587 8600 RISC Group Lancet 1990; 336: 827-30 RISC Group Lancet 1990; 336: 827-30 Roux et al JACC 1992; 19: 671-7 Roux et al JACC 1992; 19: 671-7 ISIS-2 Lancet 1998; 2: 349-60 ISIS-2 Lancet 1998; 2: 349-60 ISIS-2 Lancet 1998; 2: 349-60 ISIS-2 Lancet 1998; 2: 349-60 % of Patients 34

35. Cumulative Hazard Rates for CV Death/MI/Stroke (%) 0 2 4 6 8 10 036912 12 11.4 9.3 Placebo (n=6303) Clopidogrel (n=6259) Months Placebo:63035778466035992378 Clopidogrel : 6259 5064478036402414 p<0.00009 RR 0.80 (0.72-0.90) All patients received ASA and UFH or LMWH CURE Trial Primary End Point N Engl J Med 2001;345:494-502 20% relative Risk Reduction RRR of 30% in PCI- CURE 35

36. Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs. Standard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vs. Low dose (75-100 mg/d) Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Follow up 99.8% Compliance: 36

37. ASA Dose Comparison Death/MI/Stroke at 30 days Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 HR 0.96 (0.85- 1.08) P = 0.489 ASA 81-100 mg ASA 300-325 mg 37

38. Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 036912151821242730 C Std, A Lo C Std, A Hi C Double, A Lo C Double, A Hi Clop Standard Clop Double HRP P Int n ASA 300-325 mg 4.63.80.830.036 0.043 ASA 75-100 mg4.24.51.070.43 Clopidogrel: Double vs. Standard Dose Primary Outcome 38

39. Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 Clopidogrel: Double vs. Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR 0.85 95% CI 0.74-0.99 P=0.036 15% RRR CV Death, MI or Stroke 39

40. Clopidogrel: Double vs. Standard Dose Primary Outcome and Components StandardDoubleHR95% CIPIntn P CV Death/MI/Stroke PCI (2N=17,232)4.53.90.850.74-0.990.036 0.016 No PCI (2N=7855)4.24.91.170.95-1.440.14 Overall (2N=25,087)4.44.20.950.84-1.070.370 MI PCI (2N=17,232)2.62.00.780.64-0.950.012 0.025 No PCI (2N=7855)1.41.71.250.87-1.790.23 Overall (2N=25,087)2.21.90.860.73-1.030.097 CV Death PCI (2N=17,232)1.9 0.960.77-1.190.68 1.0 No PCI (2N=7855)2.82.70.960.74-1.260.77 Overall (2N=25,087)2.22.10.960.81-1.140.628 Stroke PCI (2N=17,232)0.4 0.880.55-1.410.59 0.50 No PCI (2N=7855)0.80.91.110.68-1.820.67 Overall (2N=25,087)0.5 0.990.70-1.390.950 40

41. Clopidogrel Double vs. Standard Dose Bleeding PCI Population Clopidogrel Standard N= 8684 Double N=8548 Hazard Ratio 95% CIP TIMI Major 1 0.5 1.060.70-1.610.79 CURRENT Major 2 1.11.61.441.11-1.860.006 CURRENT Severe 3 0.81.11.391.02-1.900.034 Fatal0.150.070.470.18-1.230.125 ICH0.0350.0461.350.30-6.040.69 RBC transfusion ≥ 2U 0.911.351.491.11-1.980.007 CABG-related Major0.1 1.690.61-4.70.31 1 ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

42. Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR 0.58 95% CI 0.42-0.79 P=0.001 Clopidogrel: Double vs. Standard Dose Definite Stent Thrombosis (Angio confirmed) 42

43. 9803mo01, 43 43 TRITON-TIMI 38 Study Design TRITON-TIMI 38 Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg OD CLOPIDOGREL 300 mg LD/ 75 mg OD 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 Key Substudies:Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600 43

44. 9803mo01, 44 44 Healthy Volunteer Crossover Study -20 0 20 40 60 80 100 IPA at 24 hours (%) Response to Prasugrel 60 mg Response to Clopidogrel 300 mg Clopidogrel Responder Clopidogrel Non-responder Interpatient Variability From Brandt JT AHJ 153: 66e9,2007 N=66

45. 9803mo01, 45 45 0 5 10 15 0306090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel HR 0.80 P=0.0003 HR 0.77 P=0.0001 Days Primary Endpoint (%) 12.1 (781) 9.9 (643) Primary Endpoint TRITON-TIMI 38 CV Death,MI,Stroke NNT= 46 ITT= 13,608 LTFU = 14 (0.1%)

46. 46 0 5 10 15 0306090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 138 events 35 events TRITON-TIMI 38:Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 46

47. 9803mo01, 47 47 TRITON –TIMI 38 : Net Clinical Benefit Bleeding Subgroups Increased risk of bleeding persisted throughout the treatment duration

48. 9803mo01, 48 TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363 0306090180270360450 HR 0.48 (0.36-0.64) P<0.0001 RRR 52% ARR 1.22% Prasugrel Clopidogrel 2.35 1.13 Days Stent Thrombosis (%) Any Stent at Index PCI n=12,844 0 1 2 3 NNT=77 48

49. Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) OH OH O OH N F S N H N N N N F Direct acting – Not a prodrug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y 12 receptor – Greater inhibition of platelet aggregation than clopidogrel Reversibly bound – Degree of inhibition reflects plasma concentration – Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets 49

50. PLATO study design Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 6–12-month exposure Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) NSTEMI-ACS (mod-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack 50

51. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 5,096 5,161 4,047 4,147 060120180240300360 12 11 10 9 8 7 6 5 4 3 2 1 0 13 Cumulative incidence (%) 9.8 11.7 8,219 HR 0.84 (95% CI 0.77–0.92), p=0.0003 Clopidogrel Ticagrelor K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval 51

52. 8,688 8,763 0102030 8 6 4 2 0 Cumulative incidence (%) Clopidogrel Ticagrelor 4.77 5.43 HR 0.88 (95% CI 0.77–1.00), p=0.045 No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,875 8,942 8,763 8,827 Days after randomisation 3190150 210 270330 8 6 4 2 0 Clopidogrel Ticagrelor 5.28 6.60 8,688 8,673 8,286 8,397 6,379 6,480 Days after randomisation * HR 0.80 (95% CI 0.70–0.91), p<0.001 8,437 8,543 6,945 7,028 4,751 4,822 Cumulative incidence (%) Primary efficacy endpoint over time (composite of CV death, MI or stroke) *Excludes patients with any primary event during the first 30 days 52

53. Stent thrombosis Ticagrelor (n=5,640) Clopidogrel (n=5,649) HR (95% CI) p value Stent thrombosis, n (%) Definite Probable or definite Possible, probable, definite 71 (1.3) 118 (2.1) 155 (2.8) 106 (1.9) 158 (2.8) 202 (3.6) 0.67 (0.50–0.91) 0.75 (0.59–0.95) 0.77 (0.62–0.95) 0.009 0.02 0.01 (evaluated in patients with any stent during the study) *Time-at-risk is calculated from first stent insertion in the study or date of randomisation

54. Total major bleeding NS 0 K-M estimated rate (% per year) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13 TIMI major bleeding Red cell transfusion * PLATO life- threatening/ fatal bleeding Fatal bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; * Proportion of patients (%); NS = not significant 11.6 11.2 7.9 7.7 8.9 5.8 0.3 Ticagrelor Clopidogrel 54

55. Therapeutic Consideration per 1000 patients treated PLATO Ticag vs. Clo CURRENT Stan vs. High Clopid TRITON Prasu vs. Clo Death 14 Fewer No changeNo Change MI 11 Fewer 6 Fewer 23 Fewer Stent Thrombosis 11 Fewer 7 Fewer 13 Fewer BleedingNo Penalty 3 Additional 6 Additional 55

56. Collagen TXA 2 ADP TXA 2 ADP PDE (Fibrinogenreceptor) GP IIb/IIIa Activation COX Ticlopidine Clopidogrel Prasugrel Tocagrelor Cangrelor PRT060128 ASA Dipyridamole ↑cAMP Targets for antiplatelet therapies Thrombin PAR-1 SCH 530348 Abciximab Eptifibatide Tirofiban Courtesy of BM Scirica, MD. Adapted from Schafer AI. Am J Med. 1996;101:199-209. cAMP = cyclic adenosine monophosphate, COX = cyclooxygenase, PAR = protease-activated receptor, PDE = phosphodiesterase 56

57. 9803mo01, 57 57 New antithrombotic drugs in Phase II trials Tissue Factor Plasma Clotting Cascade Prothrombin Thrombin FibrinogenFibrin Thrombus Platelet Aggregation Conformational Activation of GPIIb/IIIa Collagen Thromboxane A 2 ADP AT Dabigatran AZD 0837 Factor Xa Idraparinux Otamixaban (SEPIA) Apixaban (APPRAISE II) Rivaroxaban(ATLAS II) TAK-442 (AXION-ACS ) YM-150 (RUBY-1) LY-517717 (lilly) Betrixaban (Portolla) SCH 530348 (TRACER)

58. A Modern cardiac Intensive care Unit : Impella Experience and Bleeding and Blood transfusion 58

59. 59

60. Impella 2.5 unloads the LV & Increases Cardiac Output M.Valgimigli et al Catherterization & Card Intervention 2005 60

61. St. Pauls Hospital pVAD Experience Started in 2007 N= 30 (8pts with 2.5l/min) 15 prior IABP during admission Ischeia/MIIDCMMyocardiitisPost cardiotomy VT/VF 127542 EF (%)CI L/mim/m2 PCWPCVP Pre pVAD191.82414 Post pVAD322.81612 61

62. St.Paul’s Hospital pVAD Experience Median duration of pVAD 3.9  0.7 days Median CCU stay 9 days Median Hospital stay 14 days Worsening of Aortic regurgitation No death Blood loss minimal no cases of hemolysis Structural Integrity of the heart maintained 62

63. Benefit-to-Risk Ratio of Antithrombotics in UA/NSTEMI in the Last Decade: Increased Efficacy at the Price of Increased Bleeding 16-20% 12-15% 8-12% 6-10% 4-8% Death / MI Bleeding 1988 ASA 1992 ASA+ Heparin 1998 ASA+ Heparin+ Anti- GPIIb/IIIa 2003 ASA+ LMWH + Clopidogrel + Intervention 63

64. Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS Patients Moscucci et al. Eur Heart J 2003;24:1815-23 GRACE Registry in 24,045 ACS patients 40 *After adjustment for comorbidities, clinical presentation and hospital therapies **p<0.001 for differences in unadjusted death rates OR (95% CI) 1.64 (1.18 to 2.28*) 0 Overall ACS UA NSTEMISTEMI 10 20 30 ** 5.1 18.6 3.0 16.1 5.3 15.3 7.0 22.8 In-hospital death (%) In hospital major bleeding Yes No 64

65. St. Paul’s Hospital Audit Results CCU Admissions 975 CCU Admissions 975 17 patients excluded Anemia N=123 Transfused N=73 64 patient excluded 59 56 65

66. Baseline Characteristics 66

67. Medication on Admission Percent of Patients * * p < 0.05 67

68. Non Transfused (n=59) Transfused (n=56) p-value Femoral angio (%)31 (52.5)34 (60.7)0.38 Radial angio (%)1 (1.7)3 (5.4)0.28 PCI (%)14 (23.7)20 (35.7)0.16 IABP (%)7 (11.7)18 (32.1)<0.01 Swan (%)8 (13.6)18 (32.1)0.02 CVL (%)29 (49.2)32 (57.1)0.39 TVPM (%)6 (10.2)6 (10.7)0.92 PPM_ICD (%)8 (13.6)4 (7.1)0.26 PROCEDURES 68

69. NADIR HEMOGLOBIN Hb g/L Number of Patients 69

70. Hemoglobin Thresholds ► The median drop in hemoglobin from admission was 15g/L in the non-transfused cohort ► The mean nadir Hb in the non-transfused cohort was 95 g/L (SD 8) ► The median drop in hemoglobin from admission was 24 g/L in the transfused cohort ► The mean Hb triggering transfusion was 82 g/L (SD 9) 70

71. Bleeding Sites ► GI Bleed (11) ► Retroperitoneum (2) ► Femoral Hematoma (4) ► IJ Hematoma (1) ► Hemothorax (1) ► Pulmonary Hemorrhage (1) ► Tamponade (2) ► Hematuria (1) 71

72. Rates of Medication Discontinuation Percentage of Patients * p< 0.05 * 72

73. Outcomes Non transfused n= 59 Transfused n= 56 p- value Median Length of Hospital Admission (days) 8 (IQR 6-11)14 (IQR 8-21)0.01 In-Hospital Mortality (%)8 (13%)13 (23%)0.18 73

74. Age of Blood at Time of Transfusion ► 192 units of blood were transfused ► Expiration data was available for 151 (79%) of the units transfused ► Average Age of Blood: 31 days (SD 9 days IQ 26, 38 days) 74

75. 75

76. 76 VANCOUVER HYPERTENSION September 26-30, 2010 VANCOUVER HYPERTENSION 2010 September 26-30 2010 Global Cardiovascular Risk Reduction www.vancouverhypertension2010.com