- Primary PCI is the preferred reperfusion strategy for STEMI when it can be performed at an experienced center within 120 minutes of first medical contact. Fibrinolysis is an alternative if PCI cannot be performed within this time window. - Clopidogrel in combination with aspirin results in significant improvements in outcomes for STEMI patients over aspirin alone based on the CLARITY-TIMI 28 and COMMIT trials. - Enoxaparin is superior to unfractionated heparin as an anticoagulant to support reperfusion therapy for STEMI based on the ExTRACT-TIMI 25 trial.

1. STEMI – My Approach 2010 Dr S A Merchant Interventional Cardiologist DM MD DNB FSCAI Lilavati, CritiCare, BSES, Breach Candy Hospitals

2. Clinical manifestations of arterial thrombosis UA/NQMI:Partially-occlusive thrombus (primarily platelets) ST  MI:occlusive thrombus (platelets, red blood cells, and fibrin) Intra-plaque thrombus (platelet dominated) Plaque core Intra-plaque thrombus (platelet dominated) Plaque core SUDDEN DEATH Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46. Dr S A Merchant

3. Initial Diagnosis of STEMI Dr S A Merchant

4. 68% 60 40 20 18% 14% 0 <50% 50%–70% >70% % Stenosis Small, vulnerable plaques are responsible for causing MI MI Patients (%) Falk et al: Circulation 1995;92:657–671 Dr S A Merchant

5. MANAGEMENT OF Acute Myocardial Infarction THE IMPACT OF MEDICAL THERAPY % Mortality Defibrillation, Hemodynamic monitoring Beta Blockade Thrombolysis/adjuct therapy PTCA, Stent Dr S A Merchant

7. Consider prehospital fibrinolytic if capable and EMS–to–needle within 30 minOnset of symptoms of STEMI 9-1-1 EMS dispatch EMS triage plan PCI capable GOALS 5 min 8 min EMS transport Patient EMS Prehospital fibrinolysis EMS–to–needle ≤ 30 min EMS transport EMS–to–balloon ≤ 90 min Patient self-transport Hospital door–to–balloon ≤ 90 min Dispatch 1 min Total ischemic time: within 120 min “Golden Hour” = 1st 60 min Transport of Patients With STEMI and Initial Reperfusion Treatment J Am CollCardiol. 2004;44:671; Circulation. 2004;110:588.

8. Thrombolysis Versus Primary PCI - Time Dependancy Absolute 35 day mortality reduction v treatment delay N=50246 Primary PCI Boersma et al, Lancet 1996 348:771 Dr S A Merchant

9. Primary PCI angioplasty vsthrombolysis Dr S A Merchant

10. PerCutaneous Interventions following AMI : A variety !! Dr S A Merchant

11. Primary PCI POBA vs Stent Dr S A Merchant

12. primary PTCA vs stent 6-month outcomes stent PTCA OR (95% CI) 3.3% 1.7% 4.9% 8.3% 13.7% 3.8% 3.0% 6.8% 18% 25.9% death reMI death/ reMI TVR death/reMI/TVR 0.85 (0.57-1.27) 0.58 (0.35-0.96) 0.72 (0.52-0.98) 0.41 (0.32-0.52) 0.45 (0.37-0.55) 0 0.5 1.5 1 2 stentbetter PTCA better Dr S A Merchant

13. Real world situation: Door to balloon times in USA N=365 N Engl J Med 2006;355 Dr S A Merchant

14. Conclusion : Every minute delay in P’PCI affects 1 year mortality. Therefore, all efforts should be made to shorten Ischemia time not only for thrombolysis but also for P’PCI.

16. Assessment of time is the key point in the choice of reperfusion strategyDr S A Merchant

17. USIC 2000, French Registry Data Hospital administered ‘lysis as good as PCI Pre hospital lysis EURO-PCR Paris 2003 Dr S A Merchant

18. French USIC 2000 survey: real world USIC. Circulation 2004;110:1909-1915 Dr S A Merchant

19. Fibrinolysis vs Transfer for PCI Pre HospPrimaryIn HospLysisPCILysisCAPTIM CAPTIM DANAMI 2 DANAMI 2 Death (%) 3.8 4.8 6.6 7.6 1yr 5.4 7.3 Reinfarction (%) 3.7 1.7 1.6 6.3 Disabling CVA (%) 1.0 0.0 1.1 2.0 Any of Above (%) 8.2 6.2 8.0 13.7*(* P < 0.003) VahanianESC, 2002 Dr S A Merchant

20. Pre Hospital thrombolysisCAPTIM 1 Year Results (TNK) Sx < 2 hours Death P=0.057 Pre Hospital Lysis Primary PCI GW Symposium, AHA 2002 Dr S A Merchant

21. Blush Score : 30 D, M in AMI receiving fibrinolysis regardless of TIMI Grade flow in Epicardial Artery, Myocardial perfusion by blush score predicts mortality Failed flows Gibson : Circulation 2000; 101-125 Improved flows

22. PTCA vsFibrinolysis:Short Term Clinical Outcomes (23 RCTs) PTCA P<0.0001 Fibrinolysis P<0.0001 Frequency (%) P=0.0002 P=0.0003 P<0.0001 P=0.032 P=0.0004 P<0.0001 Death Death, no SHOCKdata ReMI Rec. Isch Total Stroke Hem. Stroke Major Bleed DeathMICVA N = 7739 Keeley E. et al., Lancet 2003; 361:13-20.

23. Is timing an issue even for Primary PCI? Dr S A Merchant

24. Survival Benefit by Time to Treatment with Lytics Dr S A Merchant

25. Dr S A Merchant

26. NRMI-2 : 27080 consecutive patients 24% % of patients 21% 20% 20 17% 15 10% 10 8% 5 0 min <60 60-90 120-150 90-120 150-180 >180 C.P. CANNON. JAMA 2000;283:2941-7 door-to-balloon times in primary PCI Dr S A Merchant

27. Mortality by time to reperfusion with Primary PCINRMI-2 Registry (27,080) C.P. CANNON. JAMA 2000;283:2941-7 Dr S A Merchant

30. Why is Primary PCI less time dependent than Lysis? Lysis is less effective at restoring infarct artery patency as the clot ages Myocardial salvage and infarct size after lytics are very sensitive to time to reperfusion Cardiac rupture is more likely to occur as the time to lysis increases Dr S A Merchant

32. PCI for AMI: door-to-balloon time < 2hrs (time window up to 12 hours accepted)* operator: 75 PCI (any type) / year; center: 36 Primary PCI / year Dr S A Merchant

33. After 12 hours??? BRAVE-2 Rationale: While thrombolysis has been shown to produce no benefit after 12 hours, no similar studies have looked at primary PCI in this group. Study: 365 patients randomized to in an invasive arm or a conservative arm. The invasive group underwent angiography and then PCI if necessary, while the conservative group was treated with conventional medical therapy. The primary end point was infarct size determined by SPECT at five to 10 days. Results: Infarct size (%LV) was significantly reduced in the invasive arm (8.0 vs 13%; p=0.002). No clinical differences. Kastrati ACC 2005 Dr S A Merchant

36. transfer, rescue and facilitated PCI

37. the challengeshow to achieve optimal reperfusion what to do with the occluded IRA replacing the function of death cells Dr S A Merchant

38. Dr S A Merchant

40. Exception: in case of cardiogenic shock, systematic intervention in multiple vessels may be required to optimize reperfusion of the heart. Dr S A Merchant

41. Role of GP 2b/3a inhibitors Dr S A Merchant

43. GP IIb/IIIa Inhibitors For Primary PCI—30-Day Death, (re)MI or Urgent Revascularization 30% Placebo GP IIb/IIIa 26.1% 20% 14.6% 11.2% 9.7% 10% 6.8% 6.0% 5.8% 4.5% 4.5% 2.0% p = 0.06 p = 0.01 p = 0.03 p = 0.03 p = 0.02 0% CADILLAC EPIC RAPPORT Neumann ADMIRAL N: 64 483 200 300 2082

46. Types of Thrombolytics A. Clot Selective / Clot-Binding / fibrin Specific B. Non clot Selective/ Non–Clot-Binding / Non Fibrin Specific Dr S A Merchant

47. Clinical Relevance of Fibrin Affinity Action of Non–Clot-Binding Agents Action of Clot-Binding Agents (Urokinase, Streptokinase) (Alteplase, Tenecteplase) Clot-BindingPlasminogenActivators Clot Blood Vessel Non–Clot-BindingPlasminogenActivators Clot Blood Vessel Dr S A Merchant

49. Streptokinase

50. AnisoylatedPlasminogen Streptokinase Activator Complex

51. Fibrin-Specific

52. Recombinant tissue plasminogen activator (rt-PA)

53. Mutants and Variants of Tissue-type Plasminogen Activator

54. TNK-rt-PA

55. Reteplase

56. Lanetoplase

57. Single-chain Urokinase-type Plasminogen Activator

58. Recombinant pro-urokinase (saruplase)

59. StaphylokinaseDr S A Merchant

60. Overview of Thrombolytics

61. Overview of Thrombolytics

62. Comparison with Streptokinase Dr S A Merchant

63. Dr S A Merchant

64. Dr S A Merchant

65. Dr S A Merchant

66. total 528 6.7% 11.5% 0.55 (0.30-1.01) p=0.052 rescue PCI short termoutcome: death odds ratio (95% CI) n PCI cons. 0.13 (0.01-1.40) Belenkie RESCUE PRAGUE Vermeer 28 151 200 149 6.3% 5.1% 7% 8.7% 33.3% 9.6% 14.0% 6.7% 0.51 (0.12-2.06) 0.46 (0.16-1.30) 1.24 (0.31-4.49) 0 0.5 1.5 1 2.0 Dr S A Merchant

67. Incidence of Shock P=0.09 Pre Hospital Lysis Primary PCI CAPTIM – PrehospitaltPAvs 1°PCI1 Year Results Death at 1 Year P=0.27 Primary PCI Pre Hospital Lysis Bonnefoy Lancet 2002 Dr S A Merchant

69. "Streptokinase is not very cath-lab friendly, so patients were more prone to getting bleeding complications when they went to the cath lab.

70. Those previous trials were also done before we knew the benefits of preloading patients with clopidogrel and using antithrombotic therapies like GP IIb/IIIa inhibitors during the angioplasty."Dr S A Merchant

71. Dr S A Merchant

76. ExTRACT TIMI 25Net Clinical Benefit at 30 Days UFH (%) Enox (%) RRR (%) Death / Nonfatal MI / Nonfatal Disabling Stroke 10.1 18 12.3 Death / Nonfatal MI / Nonfatal Major Bleed 11.0 14 12.8 Death / Nonfatal MI / Nonfatal ICH 10.1 17 12.2 Enox Better UFH Better RR Dr S A Merchant

82. CLARITY–TIMI 281° Endpoint:Occluded Artery (or D/MI Thru Angio/HD) 36% odds reduction Odds ratio 0.64 (95% CI, 0.53 – 0.76) P < 0.001 Occluded artery or death/MI (%) n = 1,752 n = 1,739 | | | | | | 0.4 0.6 0.8 1.0 1.2 1.6 Clopidogrel Placebo LD 300 mg MD 75 mg Clopidogrel Placebo better better Sabatine MS, N Engl J Med. 2005;352:1179-1189. Dr S A Merchant

83. 10 9 8 7 6 5 4 3 2 1 0 0 7 14 21 28 COMMIT: Effect of Clopidogrel on Death Inhospital Placebo + ASA: 1,845 deaths (8.1%) Clopidogrel + ASA: 1,726 deaths (7.5%) Proportion dead before first discharge (%) 0.6% ARD7% RRR P = 0.03 N = 45,852 No age limit; 26% age ≥ 70 years Lytic Rx 50% No LD given Time since randomization (days) Chen ZM, et al. Lancet. 2005;366:1607-1621. Dr S A Merchant

85. Reasonable options for hospitals without onsite PCI capability

86. Fibrinolytic Therapy (goal : door to needle time ≤ 30 minutes)

87. Transfer for Primary PCI (goal: door to balloon time ≤ 90 minutes)

88. Transfer for Rescue PCI if reperfusion with lytic fails

89. Facilitated PCI : no clinical benefit seen to date

90. Clopidogrel in combination with aspirin results in significant further improvements in outcomes of patients with STEMI (CLARITY-TIMI 28/COMMIT)Dr S A Merchant

92. Enoxaparin is superior to current standard of UFH as the antithrombin to support fibrinolysis (ExTARCT TIMI 25)

93. Enoxaparin has a beneficial effect in patients undergoing elective PCI,with no increase in bleeding (PCI - ExTARCT TIMI 25)

94. Fondaparinux is beneficial in STEMI without increasing the risk of bleeding or stroke (OASIS 6), but some subsets do not benefit (eg primary PCI)

95. Fondaparinux was not superior to UFH is Stratum 2 of OASIS 6 for STEMI

96. Long term treatment involves aggressive multifactorial lifestyle modification & both antithrombotic & anti ischemic therapiesDr S A Merchant

97. PCI p lytic Pharmacoinvasive approach Partial flow Complete obstruction Partial success with pharmacologic reperfusion Rethrombosis: Prevented by antiplatelet and anticoagulant Rx Full flow Ideal goal of pharmacologic reperfusion Dr S A Merchant

100. When patients present to a primary unit withoutinterventional capabilities:Therapeutic options a) lytics b) “transfer” to a facility with acardiaccath lab (with or without adjunctive therapy – “facilitated PCI”). Any such “transfer” needs to be effected rapidly to take advantage of the early benefits of revascularization. Dr S A Merchant

101. ‘Best of both worlds’ : Local rapidThrombolysisto majority & PCI Routinely Dr S A Merchant

104. TRANSFER-AMI:30-Day Primary End Point and Components Dr S A Merchant

106. This suggests that transfer to PCI centers should be initiated immediately after fibrinolysis without waiting to see whether reperfusion is successful or not. Dr S A Merchant

107. TRANSFER-AMI:30-Day Bleeding End Points Dr S A Merchant

108. direct stenting in acute MI 26.9% 11.7% angioendpoint slow flow (TIMI 3  2) 12.5% 2.9% direct stenting n 102 pre- dilatation n 104 p=0.01 p=0.02 26.9% 12.5% 7.6% 6.7% 3.8% 3.8% 6.7% 11.7% 2.9% 4.9% 3.9% 0.9% 2.9% 8.8% angioendpoint slowflow (TIMI 3  2) no-flow (TIMI 0-1) distal embolization clinicaloutcomes (6-m F/U) death re-MI TVR C. LOUBEYRE et al. JACC 2002;39:15-21

109. cooling n 21 control n 21 10% % LV % pts 10 10 8% 5 5 2% 0% 0 0 median infarct size MACE endovascularcooling COOL-MI n 400 pts SR DIXON. JACC 2002;40:1928-34

110. X-SIZER• ANGIOJET EXPORT CATHETER PERCU-SURGE FILTER-WIRE thrombectomy distal protection device mechanism new cathether-based techniques X-AMINE AIMI EMERALD CRTs in AMI N 200 N 500 PROMISE N 200 Dr S A Merchant

111. RECOMMENDATION Task Force ESC 2005 guideline Routine Coronary Angio & PCI, if applicable, in successful Thrombolysis: 1 A LYSE NOW, STENT LATER !! Dr S A Merchant

112. Despite the clinical superiority of PAMI, thrombolytic therapy is the default treatment in many countries due to the practical limitations of PAMI Dr S A Merchant

114. PCI is superior as per data but not practical and feasible, not only in India but also all over worldDr S A Merchant

116. New emerging post fibrinolysis PCI has emerged as an alternative method of treatment that appears to be safer &better as compared to PAMIDr S A Merchant

119. ELAXIM INDIAN REGISTRY Dr S A Merchant

120. ELAXIM INDIAN REGISTRY * ICH = Intracranial hemorrhage Dr S A Merchant

122. CAPTIM – PrehospitaltPAvs 1°PCI1 Year Results Incidence of Shock P=0.09 Pre Hospital Lysis Primary PCI Death at 1 Year P=0.27 Pre Hospital Lysis Primary PCI Bonnefoy Lancet 2002 Dr S A Merchant

123. OPEN ARTERY THEORY: Better flow in the infarct artery improves survival Mortality at 42 Days TIMI 0 Complete occlusion TIMI 1 Penetration of obstruction by contrast but no distal perfusion TIMI 2 Perfusion of entire artery but delayed flow TIMI 3 Full perfusion, normal flow P < 0.005 TIMI 1 Chesebro JH et al. Circulation 1987;76:142-54

124. Full-Dose TNK 3-12h Before PCI: GRACIA-2 Characteristic TNK+PCI PCI No. patients 103 102 TIMI flow grade 3 59%* 43% Complete STRes (6h) 61%* 43% Death, MI, RI-UR 9% 12% Major bleeding 2% 3% No differences in infarct size, LV function *p < 0.05 Aviles ESC 2003 Dr S A Merchant

125. n 3200 patients occluded IRA (TIMI 0,1) randomization PCI (3-28 days after MI) + risk factor modification no PCI ASA -blockers ACE inhibitors Occluded Artery Trial (OAT) multicenter, randomized, controled 1º endpoint: death/reMI/rehosp. CHF (NYA class IV) over 3 years

126. Apoptotic Rate in Occluedvs Open IRA Abbate A et al. Circulation 2002

128. arrhythmogenic potential of implanted cells

129. economic issues

130. the capacity of the stem cells to find their optimal myocardial ‘niche’

131. long-term fate of transplanted cells in the recipient heart

132. optimal timing for transplantationDr S A Merchant

134. Endovascular cooling: Aspirin, loading dose clopidogril/prasugrel, InjEnoxyparin, GpIIb/IIIa Inhibitor, nitrates, Ace-Inhibitors, beta blocker, diltiazem, high dose statins, trimatazione, sedationDr S A Merchant

136. Thrombectomy: Suction by Export Cath, AngioJet

137. Direct stenting

138. Intracoro NTG/NicorandilThis makes sense to everyone – patient, relations, family doctor, consultant physician, interventional cardiologist. Also, both short term & long term clinical trials show excellent result with pharmacoinvasive approach in terms of reduce mortality, re-infarction & overall preservation of LV function Dr S A Merchant

139. Rescue PCI, Cardiogenic shock PCI, Facilitated PCI, Elective PCI are special subsets where clinician discretion is required Dr S A Merchant LONG DIFFUSE STENOSIS

140. HOW FAST SHOULD WE GO ? QUICKER IS BETTER THANK YOU