1. 1 An Evidence-Based Approach to STEMI: The Emergency Department Perspective Charles V Pollack, Jr, MA, MD, FACEP, FAAEM Professor and Chairman, Emergency Medicine Pennsylvania Hospital University of Pennsylvania Health System Philadelphia, Pennsylvania

2. 2 + + Ischemic Discomfort at Rest No ST-segment Elevation Non-Q-wave MI Unstable Angina Q-wave MI ST-segment Elevation + + (+ : positive cardiac biomarker) Emergency Department In-hospital 6-24 h Presentation Spectrum of Acute Coronary Syndromes NSTEMI

3. 3 Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST- elevation myocardial infarction. Full text at www.acc.org; also in Circulation. 2004;110:e82-e293.www.acc.org Pollack CV, Diercks DB, Roe MT, Peterson ED. 2004 ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med. 2005;45:363-376. New studies of interest since the Guidelines Evidence-Based Therapy 2006: STEMI Antman EM, et al. Circulation. 2004;110:e82-e293. Pollack CV, et al. Ann Emerg Med. 2005;45:363-376.

4. 4 Importance of Early Reperfusion Therapy in STEMI Outcomes Dependent Upon: Time to treatment: TIME IS STILL MUSCLE Early and full restoration of coronary blood flow Sustained restoration of flow

5. 5 Time Delays and 30-Day Outcome Collins R, et al. N Engl J Med. 1997;336:847-860. 45,000 patients in placebo-controlled lytic trials 0 20 30 6121824 40 0 10 Hours From Onset of Symptoms to Randomization 3000 Loss of benefit per hour of delay: 1.6 ± 0.6 lives per 1000 patients Lives Saved/1000 Patients 14,000 12,000 9000 7000

6. 6 1.14 1.15 1.41 1.62 1.61 0.2 0.6 1 1.4 1.8 2.2 0-6061-9091-120121-150151-180> 180 Door-to-Balloon Time, min Multivariate Adjusted Odds of Death P <.001 P =.01 P <.001 n = 223057346616446126275412 NRMI, National Registry of Myocardial Infarction; PCI, percutaneous coronary intervention. Cannon CP, et al. JAMA. 2000;283:2941-2947. Time Delays and 30-Day Outcome

7. 7 Patients Transported by EMS After Calling 911 EMS Triage Plan Interhospital Transfer Hospital Fibrinolysis: Door- to-needle within 30 min EMS transport: EMS to balloon within 90 min Patient self-transport: Hospital door-to-balloon within 90 min EMS transport EMS on scene Within 8 min Dispatch 1 min Patient 5 min after Sx onset GOALS: Total ischemic time: Within 120 min* PPCI: Door-to-balloon within 90 min * Golden hour = first 60 minutes. Antman EM, et al. Circulation. 2004;110:e82-e293. Onset of STEMI Symptoms 911 EMS Dispatch EMS on scene Encourage 12-lead ECGs Consider prehospital fibrinolytic if capable and EMS-to-needle within 30 min Not a PCI- Capable Hospital PCI- Capable Hospital Call 911—Call Fast

8. 8 Hospital Care: STEMI Oxygen if pulmonary congestion Oxygen to all STEMI patients during first 6 h NTG for ongoing ischemic discomfort or for management of pulmonary congestion No NTG if SBP < 90 or if evidence of RV infarction No NTG if patient has received sildenafil < 24 h MS is analgesic of choice for STEMI pain IIIaIIbIII NTG, nitroglycerin; MS, morphine sulfate; SBP, systolic blood pressure; RV, right ventricular. Antman EM, et al. Circulation. 2004;110:e82-e293. Basic Therapy B B C C C C

9. 9 Hospital Care: STEMI Immediate aspirin (ASA) ASA dose is 162-325 mg Substitute clopidogrel or ticlopidine if true ASA allergy is present IV→oral  -blocker therapy given promptly unless contraindicated, regardless of management strategy IIIaIIbIII Antman EM, et al. Circulation. 2004;110:e82-e293. Basic Therapy A C C A B

10. 10 Reperfusion Therapy for STEMI If expert primary PCI is not available within 90 min of first medical contact, lysis unless contraindicated In absence of absolute contraindications, lysis for symptoms of STEMI and: ST  > 0.1 mV in ≥ 2 contiguous leads New or presumably new LBBB ECG findings of true posterior AMI No lytic therapy for: Asx patients with symptoms > 24 h ago Only ST  unless true posterior MI is suspected IIIaIIbIII Antman EM, et al. Circulation. 2004;110:e82-e293. A A A C C

11. 11 Contraindications to Lytic Therapy Class I –Any history of ICH –Significant CHI past 3 months –Ischemic CVA past 3 months –Uncontrolled hypertension Class IIA –TIA or ischemic CVA past 3 to 6 months –History of dementia “It is preferable to treat STEMI patients at substantial (≥ 4%) ICH risk with PCI rather than with fibrinolytic therapy” ICH, intracranial hemorrhage; CHI, closed head injury; CVA, cerebrovascular accident; TIA, transient ischemic attack. Antman EM, et al. Circulation. 2004;110:e82-e293.

12. 12 Hospitals with angioplasty facilities with on-site cardiac surgical support: 10% Hospitals with angioplasty facilities that lack on-site cardiac surgical support: 10% Hospitals without angioplasty facilities: 80% 10% 10% 80% Angioplasty Facilities in the US Antman EM, et al. Circulation. 2004;110:e82-e293.

13. 13 Implications for the ED “Time is Muscle” In most US hospitals, expert intervention for STEMI is not available within 90 minutes; even in fully interventional centers, a lytic protocol should be in place

14. 14 STEMI Reperfusion Options Reperfusion should be “early, complete, and sustained” in both the coronaries and the microcirculation PCILytics

15. 15 “Golden Window” of Salvage Symptoms < 3 h –Goal = myocardial salvage –Lytics and PCI have similar benefit Symptoms > 3 h –Goal = Open the infarct- related artery –PCI more beneficial Problem  95 min (mean) Sx onset to hospital arrival Gersch BJ, et al. JAMA. 2005;293:979-986. 04812162024 100 80 60 40 20 0 Mortality Reduction, % Extent of Myocardial Salvage D C B A Shifts in Potential Outcomes With Different Treatment Strategies A to BNo Benefit A to CBenefit B to CBenefit D to BHarm D to CHarm Time From Symptom Onset to Reperfusion Therapy, h Time-Independent Period Goal: Open Infarct-Related Artery Critical Time-Dependent Period Goal: Myocardial Salvage

16. 16 Sx  2 h 0.0 Sx  2 h 5.0 7.5 2.5 Prehospital LysisPrimary PCI 2.2 5.7 Death P =.058 0.0 7.5 10.0 2.5 Prehospital LysisPrimary PCI 5.9 3.7 5.0 Percent Death P =.47 STEMI Within 6 h; N = 840 (419 PHL, 421 PPCI) CAPTIM: 1-Year Results: Sx to Treatment Analysis Steg PG, et al. Circulation. 2003;108:2851-2856. Percent

17. 17 DANAMI-2: Results Anderson HR, et al. N Engl J Med. 2003;349:733-742. Death/MI/Stroke, % Lytic Primary PCI P =.35 Death 0 2 6 4 7.8 6.6 Lytic Primary PCI P <.001 Recurrent MI 0 2 6 8 4 6.3 1.6 Lytic Primary PCI P =.15 Stroke 0 2 6 8 4 1.1 2.0 8 STEMI < 12 h; N = 1572 Only 2% of patients randomized to lysis required rescue PCI... and 96% of transfer patients had DTB < 2h!

18. 18 15.3 6.0 0.0 5.0 10.0 15.0 20.0 LysisPrimary PCI 7.4 7.3 0.0 5.0 10.0 15.0 20.0 LysisPrimary PCI Sx  3 h (n = 551)Sx  3 h (n = 299) Death P = NS Death P ≤.02 Mortality, % Widimsky P, et al. Eur Heart J. 2003;24:94-104. STEMI < 12 h; N = 850 PRAGUE-2: 30-Day Mortality

19. 19 Skilled PCI laboratory available with surgical backup –Medical contact-to-balloon time is < 90 min –Door-to-balloon minus door-to-needle time is < 60 min High risk from STEMI –Cardiogenic shock –Killip class ≥ 3 Contraindications to fibrinolysis, including increased risk of bleeding and ICH Late presentation –Symptom onset was > 3 h ago Diagnosis of STEMI is in doubt Fibrinolytic Versus Interventional Management Fibrinolysis is generally preferred if: Very early presentation (3 h or less from symptom onset and delay to invasive strategy) Invasive strategy is not an option –Cath lab occupied/not available –Vascular access difficulties –Lack of access to a skilled PCI lab: Operator experience > 75 PPCI cases per year AND team experience > 36 PPCI cases per year Delay to invasive strategy –Prolonged transport –Door-to-balloon minus door-to- needle time is > 60 min –Medical contact-to-balloon time is > 90 min An invasive strategy is generally preferred if:

20. 20 Mortality Rates With Primary PCI as a Function of PCI-Related Time Delay Nallamothu BK, Bates ER. Am J Cardiol. 2003;92:824-826. P =.006 62 min Benefit Favors PCI Harm Favors Lysis For every 10-min delay to PCI: 1% reduction in mortality difference towards lytics 5 10 15 0 Absolute Risk Difference in Death, % –5 0 20 40 6080 100 PCI-Related Time Delay (door-to-balloon—door-to-needle) Circle sizes = sample size of the study Solid line = weighted meta-regression

21. 21 Mortality Rates With Primary PCI as a Function of PCI-Related Time Delay If door-to-balloon time is 62 min longer than door- to-needle time, the lytic approach should be strongly considered.

22. Post-2004 Guidelines Data

23. 23 CLARITY-TIMI 28 Trial: Study Design Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg QD Coronary Angiogram (2-8 days) Primary Endpoint: Occluded artery (TIMI flow grade 0/1) or death/MI by time of angio R A N D O M I Z E D Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, aged 18-75 y, with STEMI < 12 h Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

24. 24 CLARITY-TIMI 28 Trial: Primary Endpoint Occluded Artery or Death/MI (Before Angio/HD) PlaceboClopidogrel P <.001 Odds Ratio: 0.64 (95% CI, 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrel Better Placebo Better n = 1752n = 1739 36% Odds Reduction 15.0 21.7 Occluded Artery or Death/MI, % 0 5 10 15 20 25 HD, hospital discharge. Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

25. 25 Sabatine MS, et al. Circulation. 2005;112:3846-3854. CLARITY-TIMI 28: LMWH Versus UFH—30-Day Outcomes No. (%) Outcome LMWH (n = 1429) UFH (n = 1431) Adjusted OR (95% CI)P Value CV death or recurrent MI98 (6.9)165 (11.5)0.68 (0.48-0.96).03 CV death, recurrent MI, or stroke 109 (7.6)180 (12.6)0.66 (0.47-0.93).017 CV death44 (3.1)68 (4.8)0.83 (0.42-1.64).584 Recurrent MI54 (3.8)101 (7.6)0.62 (0.42-0.92).017 Stroke18 (1.3)22 (1.5)0.74 (0.26-2.12).58

26. 26 STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) Double-blind, double-dummy ASA Day 30 1° Efficacy End Point: Death or Nonfatal MI 1° Safety End Point: TIMI Major Hemorrhage ExTRACT-TIMI 25: Protocol Design UFH (N = 10,223) 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion ExTRACT = Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Antman EM et al. N Engl J Med. 2006;354:1477-1488. Adapted with permission from http://www.clinicaltrialresults.com. ENOXAPARIN (N=10,256) < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h ENOXAPARIN (N=10,256) < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h

27. 27 ExTRACT-TIMI 25: Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%) Enoxaparin UFH Relative Risk 0.83 (95% CI, 0.77 to 0.90) P<.001 Days after Randomization 9.9% 12.0% Lost to follow-up = 3 17% RRR Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

28. 28 ExTRACT-TIMI 25: Death or Nonfatal MI Day 30 Major Subgroups > Median < Median Fibrin-specific Streptokinase Prior MI No Prior MI DM No DM Other Anterior 0.512 Prior MI OVERALL Diabetes Fibrinolytic Infarct Location ENOX BetterUFH Better Relative Risk Time to Rx 20,479 11 23 17 21 17 20 13 18 23 12 17 Reduction In Risk (%) > 75 y < 75 y Age (y) 20 6 Female Male Sex 18 16 All Interaction Tests P = NS P <.001 Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354.

29. 29 ExTRACT-TIMI 25: Bleeding End Points (TIMI) at 30 Days UFH Enoxaparin % Events Major Bleed (fatal + nonfatal) ICH ARD = 0.7% RR = 1.53 P <.001 ARD = 0.1% RR = 1.27 P =.14 Nonfatal Major Bleed ARD = 0.4% RR = 1.39 P =.014 Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

30. 30 ExTRACT-TIMI 25: For Every 1000 Patients Treated With Enoxaparin Events / 1000 Pts Nonfatal reMI Urgent Revasc. Death Nonfatal TIMI Major Bleed (No increase in nonfatal ICH) Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

31. 31 ExTRACT PCI Cohort: Efficacy Results Nonfatal Recurrent MI by 30 Days Primary Endpoint: Death or Nonfatal MI by 30 Days UFH Enoxaparin 0 5 10 15 051015202530 Nonfatal MI (%) 7.8% 10.9% Days After Randomization Relative Risk 0.72 P<0.001 Enoxaparin Days After Randomization 13.8% 0 5 10 15 051015202530 Death or MI (%) UFH 10.7% Relative Risk 0.77 P=0.001 Gibson CM et al. Presented at: ESC/WCC; September 4, 2006; Barcelona, Spain. Presentation 708001. Available at http://www.escardio.org/knowledge/congresses/CongressReports/hotlinesandctus/708001_Gibson.htm. Accessed September 14, 2006. 23% RRR 28% RRR

32. 32 OASIS-6 Trial: Study Design 12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial) Randomized, Blinded, Factorial. 28% female, mean age, 62 years, mean follow-up, 3-6 months Fondaparinux N=2,823 2.5 mg/day for up to 8 days or hospital discharge Placebo N=2,835 Fondaparinux N=3,213 2.5 mg/day for up to 8 days or hospital discharge UFH N=3,221  Primary end point: Composite of death or reinfarction at 30 days  Secondary end point: Composite of death or reinfarction at 9 days and at final follow-up Stratum 1 (No UFH) N=5,658 Stratum 2 (UFH) N=6,434 Yusuf S, et al. JAMA. 2006;295:1519-1530. Adapted with permission from www.clinicaltrialresults.org.

33. 33 OASIS-6 Trial: Results 15% Primary End Point: Death/Reinfarction (%) P=.008 P=.003P=.008 Frequency 12% 9% 6% 3% 0% 9.7% 11.2% 7.4% 8.9% 13.4% 14.8% 30 days9 days3-6 months Fondaparinux (n=6036 ) Control (n=6056) 14% Reduction in Death/MI at 30 days: Stratum 1 (No UFH indicated) P<.05 Reduction in Death/MI: Stratum 2 (UFH Indicated) P=NS p=0. 97 12% 10% 8% 6% 4% 2% 0% 11.2% 14% FondaparinuxPlacebo 14% 12% 10% 8% 6% 4% 2% 0% FondaparinuxUFH 8.3% 8.7% Yusuf S, et al. JAMA. 2006;295:1519-1530. Adapted with permission from www.clinicaltrialresults.org

34. 34 OASIS-6: Severe Bleeding at 9 Days FondaparinuxPlacebo/UFHHRP All cases1.0%1.3%0.77.13 Stratum 1 vs placebo 1.0%1.6%0.63.06 Stratum 2 vs UFH 1.1% 0.95.82 Yusuf S, et al. JAMA. 2006;295:1519-1530.

35. 35 OASIS-6 Trial: PCI Substudy at 30 Days  There was no difference in the primary endpoint for patients who were managed with primary PCI (6.1% vs 5.1%, P=.19)  Guiding catheter thrombosis in the primary PCI cohort occurred more often with fondaparinux compared with control (n=22 vs n=0, P <.001) Primary Endpoint of Death or MI in PCI Cohort (%) P =.19 Yusuf S, et al. JAMA. 2006;295:1519-1530. Adapted with permission from www.clinicaltrialresults.org

36. 36 OASIS-6 Trial: PCI Substudy (cont.)  Coronary complications occurred in more patients treated with fondaparinux compared to control (n=270 vs n=225, P=.04)  Coronary complications include abrupt closure, no reflow, dissection, new angiographic thrombus, perforation, or catheter thrombus Coronary Complications P=.04 Yusuf S, et al. JAMA. 2006;295:1519-1530. Adapted with permission from www.clinicaltrialresults.org

37. 37 OASIS-6 Trial: Clinical Implications In patients with STEMI, particularly those not undergoing primary PCI, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes compared with placebo/UFH Benefits of fondaparinux were observed in Stratum 1 where placebo or no antithrombin was administered Fondaparinux trended to produce less severe bleeding Fondaparinux was associated with a hazard in those patients who underwent primary PCI, including the development of guiding catheter thrombosis

38. 38 New data from the Vienna STEMI registry reinforces benefit—mostly seen in Europe—of prehospital lysis Reducing time to treatment requires close collaboration among prehospital, ED, and cardiology resources Kalla K et al, Circulation 2006;113:2398-2405

39. 39 Conclusions: STEMI Optimal medical care of STEMI begins in the prehospital setting, continues in the ED, and culminates in a prompt and informed decision about reperfusion strategy. Optimal outcomes in STEMI can be achieved only with a multidisciplinary approach. The ACC/AHA Guidelines invest initial decision making authority in the emergency physician.

40. 40 Conclusions: STEMI Even though direct PCI is preferable when available, lysis remains a viable option in selected patients, even in “cathing centers” when delays to PCI intervene. New research indicates that lytic outcomes can be improved with new adjunctive agents. Prehospital lysis, not often used in the US, may further improve outcomes.