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  • Current goals for the management of patients with STEMI include early risk stratification and restoration of epicardial blood flow, with fibrinolytic therapy or primary/facilitated percutaneous coronary intervention (PCI), to reduce the incidence of mortality. More recently, research has demonstrated the added benefit of improving downstream microvascular coronary blood flow to further reduce long-term adverse ischemic events, including mortality.
  • Lecture Notes As a result of data collected in phase II angiographic trials, much of the benefit of combination therapy was predicted to be derived from improvements in epicardial and microvascular coronary blood flow. Arteries were opened earlier, and with better blood flow than with thrombolytic monotherapy. An underappreciated benefit of combination therapy may, however, lie in the ability of combination therapies to reduce thrombus burden and thereby reduce reinfarction rates. References 1. Gibson et al. Circulation. 2001;103:2550-2554. 2. Gibson et al. J Am Coll Cardiol. 1995;25:582-589.
  • This figure looks at the time course of TIMI 3 flow rates with these two different reperfusion strategies studied in GUSTO IIb
  • This figure looks at the time course of TIMI 3 flow rates with these two different reperfusion strategies studied in GUSTO IIb

Transcript

  • 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. Current Management Goals for Treating Acute STEMI 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
  • 3. Epicardial Flow and Mortality Outcomes 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=0.003 vs TIMI 0/1 Team 2 Team 2 Team 2 German German German GUSTO 1 GUSTO 1 GUSTO 1 TAM I 1-7 TAM I 1-7 TAM I 1-7 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
  • 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= 171 63 212 284 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 Limitation of Infarct Size Better LV Function Improved Survival
  • 6. TIMI Flow & Mortality in Recent Lytic Trials— Ceiling of Reperfusion with Fibrinolytics 60% 60% 57% 63% 0% 20% 40% 60% 80% 100% tPA rPA nPA TNK ASSENT-2 Results TNK t-PA n 8,462 8,488 Deaths 521 524 6.16% 6.17% ICH 79 80 0.93% 0.94% Mod Bleeds 26.0% 28.1% Transfusion 4.3% 5.5% 90-minute TIMI 3 Flow
  • 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. Early TIMI 3 Flow with Combination Therapy Full-Dose Lytic GP IIb/IIIa + ½ Lytic % TIMI 3 Flow (60-90 mins) IMPACT-AMI TIMI-14 SPEED INTRO-AMI INTEGRITY Full-Dose t-PA + ½ t-PA + ½ r-PA + ½ t-PA + ½ Dose TNK Eptifibatide Abciximab Abciximab Eptifibatide Eptifibatide
  • 9. INTEGRITY Trial Corrected TIMI Frame Count 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 90 100 Corrected TIMI Frame Count 100% --- 103 40 50% 180/180 154 34 TNK Eptifibatide N Median CTFC %
  • 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. GUSTO V - Trial Schematic (n = 16,588) ST  , lytic eligible, < 6 h ASA 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 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
  • 12. Primary Endpoint: 30 Day Mortality Lancet. 2001;357:1905-1914. 0 % Mortality 4 6 2 Days 0 5 10 15 20 25 30 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. GUSTO-V: Ischemic Endpoints 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 % of Patients 5.9 5.9 5.6 5.6 3.5 3.5 2.3 2.3 8.6 8.6 5.6 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
  • 14. UFH IV bolus enoxaparin IV bolus Low Dose UFH IV bolus Wt adj TNK-tPA full-dose 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 Log-rank test: P =0.0001 0 ASSENT 3 Days to Death or Reinfarction or Refractory Ischemia 5 10 15 20 25 30 Unfractionated Heparin 15.4% Enoxaparin 11.4% Abciximab 11.1%
  • 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 with ½Dose Lytics + Abciximab Increased Risk in Elderly Patients ICH Rates for Age > 75 yrs p=0.07 p=0.26  lytic  lytic + Abciximab
  • 18. Mechanical Reperfusion for Acute MI
    • Primary Percutaneous Intervention
      • Meta-analysis ->Better than lytics alone (  death,  ICH)
      • 10–20% patients unsuitable for PCI
      • Time to PCI important (delay   CHF,  death)
      • Stents probably better than balloon angioplasty
    • Facilitated Percutaneous Intervention (=treating the blockage pharmacologically before the procedure)
      • Faster reperfusion before mechanically treating culprit lesion
      •  TIMI 3 flow pre-PCI (  success,  EF,  death)
      • Extend window of “eligibility” for procedure
      • ? Optimal adjunctive antithrombotics
  • 19. Primary PCI versus Lysis for ST  AMI 30-Day 1-Year p = 0.02 p < 0.001 p = 0.014 Weaver WD, JAMA 1997;278 p = 0.001
  • 20. 0 25 50 75 100 0 30 60 90 120 150 Time from presentation (min) Reperfusion Strategy and TIMI-3 Flow Rate (30 min angio) (60 min angio) (90 min angio) TIMI 3 Flow (%) balloon&quot; Primary angioplasty 10% spontaneous reperfusion 73% &quot;Door-to- time 114 min 54% &quot;Door-to- needle&quot; time 30 min t-PA 39%
  • 21. Influence of Ultimate TIMI Flow on mortality 0 2 4 6 8 10 0 20 40 60 80 100 Ultimate TIMI 3 Flow (%) Mortality (%) Thrombolysis
    • Occluded
    • SK/SQ heparin
    • SK/t-PA
    • SK/IV heparin
    • Acc. T-PA
    1 2 3 4 5 8 6 7 7 8 9 9 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 Limitation of Infarct Size Better LV Function Improved Survival Later Mechanical Myocardial Reperfusion Open Infarct Artery • ↓ Recurrent MI • Prevent LV Remodeling • Improve Electrical Stability • Provide Source of Collaterals Improved Survival
  • 23. P=0.01 P=0.0007 P=0.0003 P=NS P=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. 6.1 N: 64 392/83 200 403 300 Random: No No Yes Yes Yes PCI: PTCA PTCA Stent PTCA Stent P : 0.06 0.04 0.03 <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 Trial EPIC GUSTO-III Neumann RAPPORT ADMIRAL Herrmann HC. Am J Cardiol. 2000;85:10C-16C. 14.6
  • 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 15.2 10.9 10.8 19.3 P =0.001 Stenting in AMI - CADILLAC Trial Primary End Point—MACE Through 6 Months PTCA PTCA STENT STENT No Abciximab Abciximab  44%  29% 0 5 10 15 20 25
  • 26. 0 25 50 75 100 0 30 60 90 120 150 Time from presentation (min) Reperfusion Strategy and TIMI-3 Flow Rate (30 min angio) (60 min angio) (90 min angio) TIMI 3 Flow (%) balloon&quot; Primary angioplasty 10% spontaneous reperfusion 73% &quot;Door-to- time 114 min 54% &quot;Door-to- needle&quot; time 30 min t-PA 39% 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 0 30 60 90 120 150 Time from presentation (min) Reperfusion Strategy and TIMI-3 Flow Rate (30 min angio) (60 min angio) (90 min angio) TIMI 3 Flow (%) 65% t-PA + abciximab 77% 17% with early Abciximab 95% Average “Door-to-stent” time 120 min Primary Stent with early Abciximab
  • 28. Potential Benefit with Facilitated PCI in AMI 3% 1% 2% 6% 4% 5% 9% 16% 0% 5% 10% 15% 20% Death Re-MI Urgent Revasc Composite Early PCI No Early PCI Facilitated PCI in SPEED (All Lytic treated patients) p=1.0 p=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 0-1 TIMI 2 TIMI 3 TIMI Flow Prior to Direct PCI: Pooled PAMI Trials (n=2327) Stone G, Circulation 2001
  • 29. Eptifibatide + 50% TNK Placebo Primary Endpoint: Death or New or Worsening Severe CHF at 30 days UFH LMWH 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 Eur Heart J 2000;21:823-831 AMI ST  or LBBB <6 hrs from onset One femoral pulse (n=300) Randomized to: GROUP A ASA+ 1.5 MU SK GROUP B ASA + 1.5 MU SK Transport For cath and possible PCI GROUP C ASA+Heparin Transport for primary PCI Design Death/Reinfarction/Stroke At 30 days (%) Results
  • 32. 0 25 50 75 100 0 30 60 90 120 150 Reperfusion Strategy and TIMI-3 Flow Rate Time from presentation (min) (30 min angio) (60 min angio) (90 min angio) 210 240 94% Average “Door-to-balloon” time for transfer patients in PRAGUE Study: ~100 min Streptokinase 31% (Transfer Patients in PRAGUE Study) TIMI 3 Flow (%) Primary angioplasty 12% spontaneous reperfusion
  • 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 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 without transfer (n=223) Stopped early by safety and efficacy committee
  • 34. DANAMI 2:Time From Onset of Symptoms to Treatment n=1572 Pre-hospital Pre-hospital Pre-hospital Pre-hospital Door-to-needle Door-to-needle In-door-out-door Door-to- Balloon Door-to-Balloon Transportation 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 0 30 60 90 120 150 Reperfusion Strategy and TIMI-3 Flow Rate Time from presentation (min) (30 min angio) (60 min angio) (90 min angio) 210 240 (Transfer Patients in DANAMI 2) TIMI 3 Flow (%) Primary angioplasty 10% spontaneous reperfusion 89% “ Door-to- Balloon Time” in DANAMI 2 114 min 54% &quot;Door-to- needle&quot; time 30 min t-PA 39%
  • 37. Transfer for PCI – Emerging Strategy? Mortality %
  • 38. 0 25 50 75 100 0 30 60 90 120 150 Reperfusion Strategy and TIMI-3 Flow Rate Time from presentation (min) (30 min angio) (60 min angio) (90 min angio) 180 210 95% “ Door-to-balloon” time for transfer patients ~ 211 min (AVH to DHMC Transfer Patients) TIMI 3 Flow (%) 54% t-PA 39% t-PA + abciximab 65% 77% 10% spontaneous reperfusion Streptokinase 31% Primary angioplasty
  • 39. DHMC AMI Database
  • 40. 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 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)
    • CardioMac query of all patients cathed with hx of MI within 24 hrs
  • 43. AMI Database - Case Report Form
    • Emergency Room
      • Presentation (Hx/PE)
      • ECGs
      • Treatment
    • Cath Lab
      • TIMI Flow
      • Timing of reperfusion
      • Intervention
      • Extent of CAD
    • Follow-up
      • Death
      • Stroke
      • Recurrent MI
      • CHF
  • 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. AMI Database 3.8 2.9 TIMI Major Bleeding (%) 31.4 27.5 Composite (%) 5.0 7.2 Subseq. Revasc. (%) 16.4 10.1 CHF (%) 0.6 0.0 Stroke (%) 6.9 5.8 Recurrent MI (%) 11.9 8.7 Death (%) In-hospital Outcome 9 1 1 Unknown 45 12 51 No lytic given 43 1 2 Half dose lytic 62 1 0 Full dose lytic ER Treatment Elsewhere (159) APD or VA ER (15) DHMC ER (54)
  • 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. AMI Database *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 2.2 4.7 3.3 3.2 TIMI Major Bleeding (%) 40.0 18.6*** 33.3 28.6 Composite* (%) 0 2.3 0 0 Stroke (%) 24.4** 2.3 10.0 7.9 Death (%) Outcomes 98 88 95 98 PCI attempted at cath (%) 18.6 7.0 16.9 9.7 Shock on Arrival in Lab (%) 399 178 337 100 ER Presentation to Cath Lab Time (min) 36 93 3 38 Glycoprotien 2b3a inhibitor in ER (%) 61.8 59.2 61.0 61.6 Mean Age (years) 45 43 60 63 N No TTx HD TTx FD TTx PPCI Group
  • 48. AMI Database *Any death, recurrent MI, intra-cranial hemorrhage, clinical congestive heart failure, repeat revascularization ns 4.7 3.2   TIMI Major Bleeding (%) ns 18.6 28.6   Composite* (%) ns 2.3 0    Intracranial hemorrhage (%) ns 2.3 7.9   Death (%) ns 52 49    Ejection fraction (%) ns 97 97   Procedural success (%)       Outcomes .026 88 98 PCI attempted at cath (%) .001 73 39 Initial TIMI 2/3 flow (%) ns 7.0 9.7 Shock on arrival in cath lab (%) <0.0001 178 100 Door-to-balloon time (minutes) ns 59.2 61.6 Mean Age (years)   43 63 n p-value HD TTx (FPCI) PPCI  
  • 49. AMI Dtabase – Conclusions
    • Outcomes are not as good as those in RCTs
      • Higher risk patients?
      • 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:
      • longer transfer times
      • 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.
    • 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 Steps
      • Broaden Registry
  • 50.
    • Questions?