1. Facilitated PCI & rescue PCI Dolly mathew

2. Primary PCI is the preferred reperfusion strategy in STEMI Most patients donot arrive at the PCI center within the 90mts of FMC If delay is expected, timely thrombolysis, followed by early transfer for PCI Combined reperfusion strategies include facilitated pci, pharmacoinvasive therapy,rescue pci

3. Facilitated PCI Strategy of thrombolysis immediately followed by PCI with a planned door to balloon time 90- 120 mts in pts with STEMI Reduction in ischemia time, earlier reperfusion,higher TIMI III flow in the occluded artery, with facilitation of guidewire or balloon passage, decreased clot burden, lower incidence of distal embolization Full / half dose thrombolysis, half dose thrombolysis with GPIIb/IIIa antagonists Addresses the value of pre treatment with thrombolytics in patients otherwise eligible for primary pci

4. Pharmacoinvasive therapy Giving T lysis at a non PCI center, transfer the pt to PCI center, performed within 2- 24 hrs within Tlytic therapy, regardless of whether Tlysis results in successful reperfusion Time to PCI is longer than facilitated PCI Routine early PCI after Tlysis in pts who are not eligible for primary PCI

5. Rescue PCI PCI performed urgently if Tlysis fails -Persistant hemodynamic or electrical instability -Persistant ischemic symptoms -Failure to achieve 50-70% ST resolution at 90mts after infusion started

7. Timing of PCI

8. Trials reviewed - facilitated PCI

9. GRACIA 2002 N500 30 day results Early post t lysis PCI Vs Routine drug treatment Early intervention supr to drug treatment CAPITAL AMI 2004 N 170 30 day results Combined angioplasty + pharmacologic treatment Vs thrombolysis Primary end point sig reduced in combination group FINESSE 2004 N 2452 90 day results Primary PCI Facilitated PCI with abciximab FPCI with reteplase or abciximab No significant difference in end points ASSENT- 4 PCI 838/829 Std PCI Tenecteplase + PCI Prematurely terminated BRAVE N 253 Half dose reteplase + abciximab / abciximab alone + PCI No diff in the post pci TIMI flow Major bleeding more in combination group

10. PCI immediately after thrombolysis-GRACIA 2002 (Group analysis of a/c IHD ) lancet 500 AMI pts, 23 centers in Spain and Portugal, the 30-day results - early interventional strategy within 24 hours of thrombolysis, followed by stent implantation - post thrombolysis classical drug-based treatment Early intervention may be superior to medical therapy in AMI Reduction in inhospital ischemia driven revascularisation- 2% vs 12% ( p<o.oo1) A combined therapy of stenting within 24 hours of thrombolysis results in shorter hospital stays and a lower risk of adverse events after discharge, compared with conventional drug therapy

11. Combined angioplasty & pharmacological intrvention vs thrombolysis in AMI - CAPITAL AMI ;jacc2004 trial 170 high-risk MI patients within 6 hrs of symptom onset thrombolysis alone with full-dose tenecteplase or thrombolysis with full-dose tenecteplase followed by immediate transfer for CAG and possible PCI (combination group) Pts with failed thrombolysis also referred for CAG &possible intervention The primary end point of the study was a composite of death/MI/stroke/recurrent ischemia at 30 days, which was significantly reduced in the combination group Major bleeding was not significantly different between the two groups

12. Major efficacy results in CAPITAL-AMI End pointThrombolysis alone Thrombolysis plus immediate transfer for angiography/ PCI Significant Death/MI/stroke/rec urrent ischemia (%) 21.49.3Yes (p=0.034) Death (%)3.62.3No MI (%)11.94.7No Stroke (%)1.2 No Recurrent ischemia (%) 17.97.0Yes (p=0.037) LeMay M. American College of Cardiology 2004 Scientific Sessions; Mar 7-10, 2004; New Orleans, LA.

13. GRACIA 2 trial 2003 212 pts,AMI <12hrs -Primary PCI with abciximab -tenecteplase + enoxaparin followed by CAG within 2-12 hrs & interventions if indicated No difference in the infarct size or LV function at 6 wks No difference in the major bleeding

14. BRAVE trial – Baverian Reperfusion Alternative Evaluation 253 pts, 12 hrs of symptom onset to facilitated PCI Half dose reteplase + abciximab or abciximab alone Primary endpoint – infarct size estimation by SPECT at 5-10 days after randomization Higher incidence of TIMI III flow in the infarct occluded artery in the reteplase plus abciximab group than in the abciximab group alone (40% vs 18%, p<0.001) No difference in the post PCI TIMI III flow (87.2% vs 86.7%, p 0.91) or infarct size (13% vs 11.5%) Major bleeding 5.6% (reteplase +abciximab) vs 1.6% (abciximab), p o.16 Within 6 months after randomization, the composite end point of death, recurrent MI, or stroke occurred in 6.4% pts vs 4.7%

15. Tirofiban given in the emergency room before angioplasty( TIGER- PA) pilot study- circulation 2003 100 acute MI pts, within 12 hrs of symptom onset Tirofiban in the emergency dept / cath lab Early administration asso with improvement in the initial TIMI flow grade Early administration of of tirofiban is feasible & safe, it improved the angiographic outcome in in pts with AMI undergoing PCI 30 day incidence of MACE suggested by early administration of tirofiban beneficial

16. Ongoing tirofiban in myocardial infarction evaluation trial( On- TIME) 507 pts with AMI, transferred to pci center, randomized to early prehospital initiation or late cath lab initiaition of tirofiban Primary end point, TIMI iii flow at initial angio did not differ significantly between the 2 groups ( 19 vs 15%, p0.22) Thrombus or fresh occlusion – 60%vs 73%, p0.002 30 day death 3.7% vs 0.8% 1yr mortality 4.5vs 3.7%, p 0.66 Despite lower prevalence of thrombus or fresh occlusion, early initiation of tiro was not asso with beneficial effects in the post pci angiographic or 1yr clinical outcome

17. Facilitated intervention with enhanced reperfusion to stop events FINESSE trial –Am heart j 2004 (-ve results) 2452 pts, 3 arm study, double blind, 6hrs of pain onset, estimated time to cathlab 1-4 hrs, door to balloon 132mts -Primary PCI - Facilitated PCI with abciximab alone - Facilitated PCI with reteplase/abciximab Primary endpoint: Composite at 90 days of all-cause mortality/re hospitalization for CCF, resuscitated VF more than 48 hours after randomization & cardiogenic shock Secondary endpoints: Complications of MI through 90 days – Re hospitalization for congestive heart failure – Resuscitated ventricular fibrillation – Cardiogenic shock

18. FINESSE Conclusions No significant improvement in the 1° endpoint in pts treated with either abciximab-facilitated PCI or reteplase/abciximab-facilitated PCI compared with primary PCI with administration of abciximab in the cath lab Reteplase/abciximab administered early was associated with an increase in pre-PCI TIMI 3 flow and > 70% ST-segment resolution at 60-90 minutes Post-PCI TIMI 3 flow and ST resolution at 180-240 minutes was similar in all 3 treatment groups

19. FINESSE Conclusions Significant increase in major and minor bleeding complications in the facilitated PCI groups No increase in total stroke rate An increase in the rate of intracranial hemorrhage in the reteplase / abciximab group Therefore, primary PCI with in-lab abciximab administration provides better benefit/risk profile than the 2 facilitated strategies in patients with STEMI who can undergo PCI within 4 hours of first medical contact

20. FINESSE before pci After pci

21. FINESSE subgroup analysis 60% pts entered in pci hospitals Analysis of pts with TIMI score ≥3, within 4hrs of symptom onset had a reduction in ischemic events with facilitated strategy Thus, for pts seen 2-3 hrs of symptom onset, immediate thrombolysis recommended, if PCI likely to be delayed

22. Assessment of safety & efficacy of a new treatment strategy for AMI -4 (ASSENT-4)trial lancet2006 (-ve results in facilitated PCI) Randomized trial, 6 hrs of symptom onset, who were scheduled to undergo pci after a delay of 1-3 hrs, who were assigned to std pci(n- 838), pci preceded by full dose tenecteplase(n 829) ; door- balloon- 110mts Premature termination – higher inhospital mortality in facilitated pci group 1° end point achieved in 19% in facilitated 13% in the std pci group(RR=1.39,95% CI:1.11-1.74;P.0045) Inhospital stroke 1.8 vs 0%,p <0.001 Higher incidence of re infarction(6 %vs 4% 0.0279), target vessel revascularization (7% vs 3% p.0041)

23. ASSENT-4 Strategy of facilitated pci consisting of full dose thrombolysis plus anti thrombotic co therapy & preceding pci by 1-3 hrs was associated with worse clinical outcome than primary pci alone & cannot be recommended - Absence of heparin infusion, clopidogrel loading, prohibition of routine use of GP IIbIIIa antagonists - Delay in thrombolytic therapy

24. Subgroup analysis -ASSENT 4 45% pts enrolled in the PCI hospitals with a minimal pci related delay time These pts had a worst outcome with facilitated strategy In contrast, pts who had a short time pain onset to thrombolysis(2-3hrs), who were given prehospital thrombolysis, had a trend towards better outcome with facilitated pci

25. Meta analysis by Keeley & coworkers, 17 trials, lancet 2006 Facilitated pci (n- 2237) was associated with significantly worse short term outcomes( upto 42 days) than primary pci (n- 2267)alone Death 5% vs 3% Nonfatal MI 3% vs 2% Urgent target vessel revas 4% vs 1% Major bleeding 7% vs 1% Total stroke 1.1% vs 0.3% Increased rates of adverse events observed mainly when thrombolytic therapy was used to facilitate pci

26. Pharmacoinvasive trials

27. CARESS IN AMI 297/300 Facilitated pci Vs Medical/ rescue Combined end point lower in facilitated pci WEST 304 Early fibrinolytics With or without Routine rescue/ early invasive vs primary pci Similar end points TRANSFER AMI 1059 TNK  immediate pci TNK  rescue pci Cardiovascular events lower in the pharmacoinvasive group compared with std care & rescue pci

28. The Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction (CARESS in AMI) pharmacoinvasive compared a strategy of early transfer of patients to a PCI center after thrombolysis vs medical treatment continued in the admitting hospital and transfer for rescue PCI only if there was evidence of lack of reperfusion Patients less than 12 hours from symptom onset and with STEMI were randomized to either -- Facilitated PCI (lytics and transfer to the nearest PCI center) -- Medical treatment/rescue (lytics and transfer for rescue PCI if persistent ST elevation)

29. 600 patients were randomized to facilitated PCI (n = 297) or to the medical/rescue (n = 300) arms of the study time from pain onset to reteplase treatment was 169-171 minutes time from reteplase administration to PCI was 136 mts in the facilitated arm vs 212 mts in the rescue arm The combined endpoint of death/reinfarction/refractory ischemia at 30 days was significantly lower in the facilitated arm compared with the medical/rescue-treated patients (4.1% vs 11.1%, respectively; P =.001)

30. Outcome Immediate PCI (%) Rescue PCI (%) p Death, re-MI, refractory ischemia at 30 days* 4.4 10.7 0.004 Major bleed 3.4 2.3 0.47 Stroke 0.7 1.3 0.50

31. The WEST (Which Early ST-Elevation Myocardial Infarction Therapy) trial 304 patients -- fibrinolytic therapy at the earliest contact (prehospital or in referral hospital, with clopidogrel and enoxaparin) with/without routine rescue or early invasive therapy -- primary PCI Tenecteplase and enoxaparin followed by routine early invasive therapy had similar death and MI rates to primary PCI This supports the need for further trials to assess the role of optimal early fibrinolytic therapy (including prehospital) and antithrombotic therapy versus primary PCI in settings where very rapid PCI is not available

32. Routine angioplasty after thrombolysis for AMI: TRANSFER-AMI –nejm2009 1059 pts with high risk STEMI, at non PCI center Full dose tenecteplase  immediate transfer for PCI tenecteplase  transfer for rescue PCI Median time for PCI 3.9 hrs(2-6hrs)

33. Inclusion Criteria –TRANSFER AMI Within 12 hrs of symptom onset ≥ 2 mm ST-segment elevation in 2 anterior leads OR ≥ 1 mm ST-segment elevation in 2 inferior leads and at least one of the following: – SBP < 100 – HR > 100 – Killip Class II-III – ≥ 2mm ST-segment depression in anterior leads – ≥ 1 mm ST-segment elevation in V 4 R

34. Selected Exclusion Criteria Cardiogenic Shock PCI within 1 month Previous CABG Primary PCI available with DTB < 60 minutes Use of Enoxaparin in last 12 hours in patient > 75 years of age Consent not obtained within 30 minutes of TNK

35. Procedures Cardiac Cath performed (%) Time- TNK to Cath (hrs) Time- TNK to Cath (hrs) PCI performed (%) Stent used (% of PCI cases) Stent used (% of PCI cases) Time- TNK to PCI (hrs) Time- TNK to PCI (hrs) PCI within 6 hrs of TNK (%) PCI within 6 hrs of TNK (%) PCI within 12 hrs of TNK (%) PCI within 12 hrs of TNK (%) GP IIb/IIIa inhibitor use (%) GP IIb/IIIa inhibitor use (%) Time- TNK to GP IIb/IIIa inhib. (hrs) Time- TNK to GP IIb/IIIa inhib. (hrs) IABP use (%) CABG performed (%) StandardTreatment(n=508)82 27 (4, 69) 6298 18 (4, 73) 384753 11 (4, 63) 68PharmacoinvasiveStrategy(n=522)97 3 (2, 4) 8498 4 (3, 5) 899773 76

36. 0 2 4 6 8 10 12 14 16 18 051015202530 10.6 16.6 Days from Randomization % of Patients Standard PCI > 24 hrs (n=496) Invasive < 6 hrs (n=508) n=496n=508422468415466415463414461 414460412457 Primary Endpoint: 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock OR=0.537 (0.368, 0.783); p=0.0013

37. Components of Primary Endpoint DeathReinfarction Recurrent Ischemia Death/MI/Ischemia New / worsening CHF Cardiogenic Shock StandardTreatment(n=498)3.66.02.211.75.22.6 PharmacoinvasiveStrategy(n=512)3.73.30.26.52.94.5P-Value0.940.0440.0190.0040.0690.11

38. Summary Compared with ‘Standard Treatment’, a ‘Pharmacoinvasive Strategy’ of routine early PCI within 6 hrs after thrombolysis is associated with a 6% absolute (46% relative) reduction in the composite of death, reinfarction, recurrent ischemia, heart failure and shock The pharmacoinvasive strategy is not associated with any increase in transfusions, severe bleeding or intracranial hemorrhage despite high use of GP IIb/IIIa inhibitors during PCI In contrast to older trials, routine early PCI after thrombolysis using stents and contemporary pharmacotherapy is safe and effective

39. Conclusions For high-risk STEMI patients receiving thrombolysis at non-PCI centres, urgent transfer and PCI within 6 hours is associated with significantly less ischemic complications and no excess in bleeding Transfers to PCI centres should be initiated immediately after thrombolysis without waiting to see whether reperfusion is successful

40. Rescue trials

41. trialcomparisonPatient group MERLIN 2004 N 153/154 30 day follow up CAG± rescue pci Vs Conserv mgt STEMI, failed tlysis REACT 2005 N 144/141 6months follow up Rescue pci Vs Rpt t lysis or Conserv mgt STEMI, failed reperfn, within 90mts after lytic treatment STOPAMI 2004 N 90/ 91 SI 7-10 days apart 1yr follow up Stenting Vs Balloon angioplasty STEMI,failed thrombolysis TIMI flow grade ≤2 at CAG

42. Middlesbrough early revascularization to limit infarction – MERLIN trial JACC 2004 307 patients Didn’t improve survival at 30 days Improved event free survival More strokes, more bleeding complications Didn’t result in preservation of LV systolic function at 30 days

43. MERLIN TRIAL – end points

44. Rescue angioplasty vs conservative treatment or repeat thrombolysis – REACT trial, nejm2005 427 patients Primary end points significantly reduced in rescue group

46. Coronary stenting vs balloon angioplasty as a rescue intervention after failed thrombolysis in pts with AMI – STOPAMI 4 trial JACC 2004 181 patients,after failed thrombolysis, within 24 hrs (TIMI flow ≤ 2during CAG ) Coronary stenting 90 patients Balloon angioplasty in 91 patients Salvage index ( proportion of initial perfusion defect salvaged by rescue intervention) obtained by paired scintigraphic studies performed 7-10 days apart was the primary end point

47. Myocardial salvage index was significantly greater in the stent group (.35 vs.25,p.005) than in angioplasty group No difference in the major bleeding 1yr mortality was 8% vs 12% Pts with AMI, failed thrombolysis benefit from rescue mechanical reperfusion in terms of myocardial salvage Stenting asso with greater myocardial salvage than balloon angioplasty group

48. Meta analysis of rescue PCI trials Reduction in heart failure, reinfarction & a trend towards lower mortality rate with rescue PCI Another meta analysis of 5 randomized trials- -36% reduction in risk of death, 28% reduction in the risk of heart failure, compared with the conservative group

49. Reperfusion strategy

50. For patients presenting with high risk STEMI, who cannot undergo timely primary PCI, best approach would be pre hospital thrombolysis, or local thrombolysis at non PCI hospitals, followed by transferring the patient for PCI