1. Emergent Transfer of Acute MI Patients for Facilitated Angioplasty Rationale and DHMC Experience Nathaniel Niles, MD Associate Professor of Medicine Dartmouth-Hitchcock Medical Center Androscoggin Valley Hospital October 7 th 2003

2. Presumed prognosis: very high risk of in-hospital death Treatment goal: prevent death by restoring coronary blood flow Fibrinolytic Therapy Primary/ Facilitated PCI Restore flow to epicardial vessel  Myocardial perfusion perfusion Current Management Goals for Treating Acute STEMI

3. Occlusion Penetration Slow Flow Normal Flow TIMI 0 TIMI 1 TIMI 2 TIMI 3 9.3% 6.1% 3.7% p<0.0001 vs TIMI 0/1 p<0.0001 vs TIMI 2 p<0.0001 vs TIMI 0/1 p<0.0001 vs TIMI 2 P=0.003 vs TIMI 0/1 Team 2 German GUSTO 1 TAM I 1-7 TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B CM Gibson 1998 in Acute Coronary Syndromes Sample Size of Pooled Analysis: 5,498 0 2 4 6 8 10 12 Epicardial Flow and Mortality Outcomes

4. GUSTO-I: 90’ TIMI Flow and Ventricular Function Preservation of Regional Wall Motion at 5-7 days % of Group p=0.007 p=0.001 N= 17163212284 The GUSTO Angiographic Investigators. N Engl J Med 1993; 329:1615-1622.

5. Paradigm for Mechanism of Benefit of Reperfusion Therapy for AMI Earlier Myocardial Reperfusion Earlier Myocardial Reperfusion Limitation of Infarct Size Limitation of Infarct Size Better LV Function Better LV Function Improved Survival Improved Survival

6. 60% 57% 63% 0% 20% 40% 60% 80% 100% tPArPAnPATNK ASSENT-2 Results TNKt-PA n 8,4628,488 Deaths 521524 6.16%6.17% ICH 7980 0.93%0.94% Mod Bleeds26.0%28.1% Transfusion4.3%5.5% 90-minute TIMI 3 Flow TIMI Flow & Mortality in Recent Lytic Trials— Ceiling of Reperfusion with Fibrinolytics

7. Rationale for Combination Therapy For Acute ST Elevation MI Gibson, Circulation 2001 GP IIb/IIIa Inhibitor + Reduced-Dose Lytic  Thrombus  % Stenosis  Luminal Diameter  Epicardial Perfusion  Myocardial Perfusion  ST Resolution Reduces Reinfarction Facilitates Early PCI

8. Full-Dose Lytic GP IIb/IIIa +½Lytic % TIMI 3 Flow (60-90 mins) IMPACT-AMI TIMI-14 SPEED INTRO-AMIINTEGRITY IMPACT-AMI TIMI-14 SPEED INTRO-AMIINTEGRITY Full-Dose t-PA + ½ t-PA + ½ r-PA + ½ t-PA +½ Dose TNK Eptifibatide Abciximab Abciximab EptifibatideEptifibatide Eptifibatide Abciximab Abciximab EptifibatideEptifibatide IMPACT-AMI TIMI-14 SPEED INTRO-AMIINTEGRITY IMPACT-AMI TIMI-14 SPEED INTRO-AMIINTEGRITY Full-Dose t-PA + ½ t-PA + ½ r-PA + ½ t-PA +½ Dose TNK Eptifibatide Abciximab Abciximab EptifibatideEptifibatide Eptifibatide Abciximab Abciximab EptifibatideEptifibatide Early TIMI 3 Flow with Combination Therapy

9. 0 20 40 60 80 100 0102030405060708090100 Corrected TIMI Frame Count 100% --- 103 40 50% 180/180 154 34 TNK Eptifibatide N Median CTFC % INTEGRITY Trial Corrected TIMI Frame Count

10. TIMI 14 Complete (>70%) ST-Segment Resolution % of Patients All Patients Patients with TIMI 3 flow at 90’ EHJ 2000;21:1944-53

11. ST , lytic eligible, < 6 h ASAASA No Abciximab 2 x 10 U bolus (30’) Reteplase Abciximab* Low Dose Heparin: 60 U/kg bolus followed by a 7 U/kg/h infusion 1º endpoint: mortality at 30 days 2º endpoint: clinical and safety events at 30 days 1º endpoint: mortality at 30 days 2º endpoint: clinical and safety events at 30 days 2 x 5 U bolus (30’) Reteplase Standard Heparin: 5,000 U bolus followed by either 800 U/hr (pts < 80 kg) or 1,000 U/hr (pts > 80 kg) infusion Lancet 2001; 357:1905-14 GUSTO V - Trial Schematic (n = 16,588)

12. Primary Endpoint: 30 Day Mortality Lancet. 2001;357:1905-1914. 0 % Mortality 4 6 2 Days 051015202530 P=0.43 for superiority Non-Inferiority RR 0.95 (95% CI, 0.84-1.08) 5.6% Abciximab +  Dose Reteplase (n = 8328) 5.9% Std. Dose Reteplase (n = 8260)

13. Death 30 Days Death 30 Days Re-MI 7 Days Re-MI 7 Days Urgent PCI 6 Hrs Urgent PCI 6 Hrs 0 0 3 3 6 6 9 9 % of Patients 5.9 5.6 3.5 2.3 8.6 5.6 Reteplase Abciximab + Reteplase OR = 0.95 p = 0.43 OR = 0.67 p < 0.0001 OR = 0.64 p < 0.0001 Lancet, 2001 GUSTO-V: Ischemic Endpoints

14. UFH IV bolus enoxaparin IV bolus Low Dose UFH IV bolus Wt adj TNK-tPA full-dose IV bolus abciximab IV bolus UFH IV infusion for up to 48 hours enoxaparin SC injections every 12 hours up to discharge or revascularization (max of 7 days) Wt adj TNK-tPA half-dose IV bolus abciximab IV infusion for 12 hours Low Dose UFH IV infusion for up to 48 hours randomization 1:1:1 ASSENT 3: Trial Design patients with ST-elevation AMI presenting within 6 hours of symptom onset

15. Days to Death or Reinfarction or Refractory Ischemia Probability (%) 0 2 4 6 8 10 14 12 16 18 20 51015202530 Log-rank test: P=0.0001 0UnfractionatedHeparin 15.4% Enoxaparin 11.4% Abciximab 11.1% ASSENT 3 Days to Death or Reinfarction or Refractory Ischemia

16. N= 8328 8260 2038 2017 2040 118 291 GUSTO V ASSENT III INTEGRITY ICH with ½Dose Lytics + GP 2b3a Inh. Risk compared with Full Dose Lytic

17. ICH Rates for Age > 75 yrs p=0.07p=0.07 p=0.26p=0.26 n lytic n lytic + Abciximab n lytic n lytic + Abciximab ICH with ½Dose Lytics + Abciximab Increased Risk in Elderly Patients

18. Mechanical Reperfusion for Acute MI Primary Percutaneous InterventionPrimary Percutaneous Intervention Meta-analysis →Better than lytics alone (  death,  ICH)Meta-analysis →Better than lytics alone (  death,  ICH) 10–20% patients unsuitable for PCI10–20% patients unsuitable for PCI Time to PCI important (delay   CHF,  death)Time to PCI important (delay   CHF,  death) Stents probably better than balloon angioplastyStents probably better than balloon angioplasty Facilitated Percutaneous Intervention (=treating the blockage pharmacologically before the procedure)Facilitated Percutaneous Intervention (=treating the blockage pharmacologically before the procedure) Faster reperfusion before mechanically treating culprit lesionFaster reperfusion before mechanically treating culprit lesion  TIMI 3 flow pre-PCI (  success,  EF,  death)  TIMI 3 flow pre-PCI (  success,  EF,  death) Extend window of “eligibility” for procedureExtend window of “eligibility” for procedure ? Optimal adjunctive antithrombotics? Optimal adjunctive antithrombotics

19. 30-Day1-Year p = 0.02 p < 0.001 p = 0.014 Weaver WD, JAMA 1997;278 p = 0.001 Primary PCI versus Lysis for ST  AMI

20. balloon" Primary angioplasty 10% spontaneous reperfusion 73% "Door-to- time 114 min 0 25 54% "Door-to- needle" time 30 min t-PA 39% 50 75 100 0306090120150 Time from presentation (min) Reperfusion Strategy and TIMI-3 Flow Rate (30 min angio) (60 min angio)(90 min angio) TIMI 3 Flow (%)

21. Influence of Ultimate TIMI Flow on mortality 0 2 4 6 8 10 0 20406080100 Ultimate TIMI 3 Flow (%) Mortality (%) 1 2 3 4 5 8 6 7 7 8 9 9 Thrombolysis 1.Occluded 2.SK/SQ heparin 3.SK/t-PA 4.SK/IV heparin 5.Acc. T-PA Primary PCI 6. GUSTO-2b 7. PAMI-1 8. PAMI Reg. 9. PAMI-2

22. Expanded Paradigm for Mechanism of Benefit of Reperfusion Therapy for AMI Earlier Pharmacologic Myocardial Reperfusion Earlier Pharmacologic Myocardial Reperfusion Limitation of Infarct Size Limitation of Infarct Size Better LV Function Better LV Function Improved Survival Improved Survival Later Mechanical Myocardial Reperfusion Later Mechanical Myocardial Reperfusion Open Infarct Artery Open Infarct Artery ↓Recurrent MI↓Recurrent MI Prevent LV Remodeling Prevent LV Remodeling Improve Electrical Stability Improve Electrical Stability Provide Source of Collaterals Provide Source of Collaterals Improved Survival Improved Survival

23. P=0.01P=0.0007P=0.0003P=NS 1.14 1.15 1.41 1.62 1.61 N=2,230 5,734 6,616 4,461 2,627 5,412 NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality Multivariate Adjusted Odds of Death

24. 14.6 6.1 N:64392/83200403 300 Random:NoNoYesYesYes PCI:PTCAPTCA StentPTCAStent P:0.060.040.03<0.05<0.05 26.1 4.5 9.7 3.6 9.2 2 11.2 5.8 0 10 20 30 Control Abciximab 30-d Mortality, MI, Urgent ReV Primary PCI with Adjunctive GP IIb/IIIa Percent TrialEPICGUSTO-IIINeumannRAPPORTADMIRAL Herrmann HC. Am J Cardiol. 2000;85:10C-16C.

25. % of patients Stone GW. CADILLAC trial. TCT XI: October 18-22, 2000. No P value given Death, re-MI, ischemic TVR, or disabling stroke 0 5 10 15 20 25 15.2 10.9 10.8 19.3 P=0.001 Stenting in AMI - Stenting in AMI - CADILLAC Trial Primary End Point—MACE Through 6 Months PTCA STENT No Abciximab Abciximab  44%  29%

26. balloon" Primary angioplasty 10% spontaneous reperfusion 73% "Door-to- time 114 min 0 25 54% "Door-to- needle" time 30 min t-PA 39% 50 75 100 0306090120150 Time from presentation (min) Reperfusion Strategy and TIMI-3 Flow Rate (30 min angio) (60 min angio)(90 min angio) TIMI 3 Flow (%) 17% with early Abciximab 95% Average “Door-to- stent” time 120 min Primary Stent with early Abciximab 65% t-PA + abciximab 77%

27. 0 25 50 75 100 0306090120150 Time from presentation (min) Reperfusion Strategy and TIMI-3 Flow Rate 65% t-PA + abciximab 77% (30 min angio) (60 min angio)(90 min angio) 17% with early Abciximab 95% Average “Door-to- stent” time 120 min Primary Stent with early Abciximab TIMI 3 Flow (%)

28. 3% 1% 2% 6% 4% 5% 9% 16% 0% 5% 10% 15% 20% DeathRe-MIUrgent Revasc Composite Early PCI No Early PCI Facilitated PCI in SPEED (All Lytic treated patients) p=1.0p=0.03 p < 0.001 Hermann H, JACC 2000 6-Month Mortality 4.4 2.8 0.5 0 1 2 3 4 5 TIMI 0-1TIMI 2TIMI 3 TIMI Flow Prior to Direct PCI: Pooled PAMI Trials (n=2327) Stone G, Circulation 2001 Potential Benefit with Facilitated PCI in AMI

29. Eptifibatide + 50% TNK Placebo Primary Endpoint: Death or New or Worsening Severe CHF at 30 days UFH LMWH UFH ST  AMI Sx  6 hours Lytic Eligible Planned Primary PCI (n = 5640) Primary PCI Eptifibatide + 50% TNK ADVANCE MI Study Design

30. How Should We Manage the Transfer Patient with AMI?

31. PRAGUE Study Design Death/Reinfarction/Stroke At 30 days (%) Results Eur Heart J 2000;21:823-831

32. 0 25 50 75 100 0306090120150 Reperfusion Strategy and TIMI-3 Flow Rate Time from presentation (min) (30 min angio) (60 min angio)(90 min angio) 210240 Primary angioplasty 12% spontaneous reperfusion 94% Average “Door- to-balloon” time for transfer patients in PRAGUE Study: ~100 min Streptokinase 31% (Transfer Patients in PRAGUE Study) TIMI 3 Flow (%)

33. High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs 5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs 5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs Lytic therapy Front-loaded tPA 100 mg (n=782) Lytic therapy Front-loaded tPA 100 mg (n=782) Death / MI / Stroke at 30 Days DANAMI-2: Study Design Primary PCI with transfer (n=567) Primary PCI with transfer (n=567) Primary PCI without transfer (n=223) Primary PCI without transfer (n=223) Stopped early by safety and efficacy committee

34. Pre-hospital Door-to-needle In-door-out-door Door-to- Balloon Door-to-Balloon Transportation DANAMI 2:Time From Onset of Symptoms to Treatment n=1572 Hospital Site PCI Thrombolysis www.danami-2.dk/Index.htm

35. Death / MI / Stroke (%) Lytic 1° PCI P=0.0003 Combined DANAMI-2: Primary Results RRR 45% P=0.002 Transfer Sites RRR 40% Lytic 1° PCI P=0.048 Non-Transfer Sites RRR 45% Lytic 1° PCI

36. 0 25 50 75 100 0306090120150 Reperfusion Strategy and TIMI-3 Flow Rate Time from presentation (min) (30 min angio) (60 min angio)(90 min angio) 210240 (Transfer Patients in DANAMI 2) TIMI 3 Flow (%) Primary angioplasty 10% spontaneous reperfusion 89% 54% "Door-to- needle" time 30 min t-PA 39% “Door-to-Balloon Time” in DANAMI 2 114 min

37. Transfer for PCI – Emerging Strategy? Mortality %

38. 54% t-PA 39% t-PA + abciximab 65% 77% 0 25 50 75 100 0306090120150 Reperfusion Strategy and TIMI-3 Flow Rate Time from presentation (min) (30 min angio) (60 min angio)(90 min angio) 180210 10% spontaneous reperfusion 95% “Door-to- balloon” time for transfer patients “Door-to- balloon” time for transfer patients ~ 211 min Streptokinase31% (AVH to DHMC Transfer Patients) TIMI 3 Flow (%) Primary angioplasty

39. DHMC AMI Database

40. DHMC Emergency Dept AMI diagnosed: >30 min of CP and/or ECG with 1mmST elevation or LBBB DHMC Emergency Dept AMI diagnosed: >30 min of CP and/or ECG with 1mmST elevation or LBBB Oxygen, ASA, heparin, beta blocker, nitrates, Morphine, 2 IV lines, treat pain, CHF, shock, arrhythmias Oxygen, ASA, heparin, beta blocker, nitrates, Morphine, 2 IV lines, treat pain, CHF, shock, arrhythmias Weekday hours Call 5-7783, Notify “charge-person” After hour or weekends (technician not on site) Page Cardiology fellow on call Administer abciximab unless contraindication or significant cautions Administer abciximab unless contraindication or significant cautions No Cath lab ready Cath lab ready Consent and transport to Catheterization Lab on Call 15 min 25 min 45 min 75 min 55 min 75 min 105 min Cath Lab time Door-to-balloon

41. Transport to DHMC for potential salvage PCI ASAP Transport to DHMC Cath Lab ASAP Oxygen, ASA, low dose heparin, beta blocker, nitrates, Morphine, 2 IV lines, treat pain, CHF, shock, arrhythmias Non-DHMC Emergency Dept AMI diagnosed >30 min of CP and/or ECG with 1mmST elevation or LBBB Primary or Possible Planned Rescue/Facilitated PCI Call DHMC Cardiology fellow - activate Catheterization Lab Primary Thrombolytic Therapy Expected transfer time to arrival at DHMC (Call-to-table time) >60 min Age <75yrs <60 min Primary PCI If en route at 30’ give second bolus of r-PA 5U IV Front-loaded t-PA or Double bolus r-PA or Single bolus TNK + enoxaparin Administer abciximab and r-PA 5U IVB Administer abciximab Contraindication or Significant Cautions for Thrombolytic therapy/ abciximab * For Age>75 increased risk of ICH, consider Primary PCI if Call-to-table time <60 min. or Primary thrombolytic therapy with TNK plus enoxaparin

42. AMI Database 1/01-1/03 (1 year backward and 1 year forward from program initiation)1/01-1/03 (1 year backward and 1 year forward from program initiation) CardioMac query of all patients cathed with hx of MI within 24 hrsCardioMac query of all patients cathed with hx of MI within 24 hrs

43. AMI Database - Case Report Form Emergency RoomEmergency Room Presentation (Hx/PE)Presentation (Hx/PE) ECGsECGs TreatmentTreatment Cath LabCath Lab TIMI FlowTIMI Flow Timing of reperfusionTiming of reperfusion InterventionIntervention Extent of CADExtent of CAD Follow-upFollow-up DeathDeath StrokeStroke Recurrent MIRecurrent MI CHFCHF

44. 325 charts reviewed 284 Confirmed caths after recent MI (<24 hours) 228 lytic eligible ECGs and emergent caths Presented to DHMC Emergency Room (n=54) Presented to APD or VA Emergency Room (n=15) Presented to Emergency Room Outside area (n=159) AMI Database

45. DHMC ER (54) APD or VA ER (15) Elsewhere (159) ER Treatment Full dose lytic 0162 Half dose lytic 2143 No lytic given 511245 Unknown 119 In-hospital Outcome Death (%) 8.711.9 Recurrent MI (%) 5.86.9 Stroke (%) 0.00.6 CHF (%) 10.116.4 Subseq. Revasc. (%) 7.25.0 Composite (%) 27.531.4 TIMI Major Bleeding (%) 2.93.8 AMI Database

46. 211 Patients in Specific Strategy Subgroups  63 Presenting to DHMC, APD, VA – Treated with Primary PCI, No lytic  60 Presenting elsewhere – Treated with Full dose Thrombolytic  43 Presenting elsewhere – Treated with Half dose Thrombolytic  45 Presenting elsewhere – Not Treated with Thrombolytic AMI Database

47. Group PPCIFD TTxHD TTxNo TTx N63604345 Mean Age (years)61.661.059.261.8 Glycoprotien 2b3a inhibitor in ER (%)3839336 ER Presentation to Cath Lab Time (min)100337178399 Shock on Arrival in Lab (%)9.716.97.018.6 PCI attempted at cath (%)98958898 Outcomes Death (%)7.910.02.324.4** Stroke (%)002.30 Composite* (%)28.633.318.6***40.0 TIMI Major Bleeding (%)3.23.34.72.2 *Any death, recurrent MI, stroke, clinical CHF, repeat revascularization **p<0.05 compared with any other group ***p<0.05 compared with group 2 and group 4 AMI Database

48. PPCI HD TTx (FPCI) p-value n6343 Mean Age (years)61.659.2ns Door-to-balloon time (minutes)100178<0.0001 Shock on arrival in cath lab (%)9.77.0ns Initial TIMI 2/3 flow (%)3973.001 PCI attempted at cath (%)9888.026 Outcomes Procedural success (%)97 ns Ejection fraction (%)4952ns Death (%)7.92.3ns Intracranial hemorrhage (%)02.3ns Composite* (%)28.618.6ns TIMI Major Bleeding (%)3.24.7ns *Any death, recurrent MI, intra-cranial hemorrhage, clinical congestive heart failure, repeat revascularization AMI Database

49. AMI Dtabase – Conclusions Outcomes are not as good as those in RCTsOutcomes are not as good as those in RCTs Higher risk patients?Higher risk patients? Quality of Care?Quality of Care? Compared with Primary PCI pts, pts treated with a strategy of facilitated PCI (initial HD lytics and GP IIb/IIIa inhibitor) had outcomes at least as favorable despite:Compared with Primary PCI pts, pts treated with a strategy of facilitated PCI (initial HD lytics and GP IIb/IIIa inhibitor) had outcomes at least as favorable despite: longer transfer timeslonger transfer times no increased bleeding problems.no increased bleeding problems. In pts with an initial strategy of FD thrombolytic followed by emergent PCI, outcomes were less favorable probably because of longer transfer times and greater morbidity by the time of cath lab arrival.In pts with an initial strategy of FD thrombolytic followed by emergent PCI, outcomes were less favorable probably because of longer transfer times and greater morbidity by the time of cath lab arrival. Patients arriving late relative to the start of their MI who are not initially treated with any thrombolytic tended to have the greatest morbidity by the time cath was initiated and did poorly following PCI.Patients arriving late relative to the start of their MI who are not initially treated with any thrombolytic tended to have the greatest morbidity by the time cath was initiated and did poorly following PCI. Next StepsNext Steps Broaden RegistryBroaden Registry

50. Questions?