1. To Transfer or Not to Transfer? The debate between transfer for PCI versus local thrombolysis. Todd Ring, BSc., MD, CCFP March 11, 2004 University of Calgary Emergency Medicine Grand Rounds

2. An Area of Controversy…

3. Overview Is PCI better than thrombolysis? Evidence behind transfer for PCI Is transfer safe? Is timing everything? Issues closer to home

4. Rationale Minority of patients with AMI present directly to PCI center –Reality most present to EMS or local hospital (non PCI center) Results from prior trials comparing PCI to local thrombolysis difficult to extrapolate to non PCI center –Treatment bias –Center and operator experience –Effect of treatment delay unknown

5. Is PCI Better?

6. Primary Angioplasty Versus Intravenous Thrombolytic Therapy for AMI: A Quantitative Review of 23 Randomized Trials. The Lancet 36. 2003 Meta-analysis of 23 RCT 7739 TL eligible patients –3872 PCI –3867 TL (67% TPA) Short (4 – 6 week) and long term (6 – 18 month) outcomes

7. p =.003 (excluding SHOCK) p <.0001

8. Similar results short and long term favouring PCI Major bleed only sig. negative result for PCI

9. Problems with Evidence Favoring PCI If SHOCK data is excluded and look at subgroup receiving aTPA –Mortality: 5.5 PCI vs 6.7 TL p =.08 Definition of re-infarction –Majority of cases of re-infarction in TL group occurs in 1 st hour –At this time patients many patients still in cath lab demonstrating low flow, spasm, dissection, distal embolization Only 2 large trials >1000 pts; 15 trials < 200 pts No weighting of outcome data

10. Conclusions Regarding PCI Evidence favours PCI over all forms of thrombolysis ? Evidence is not as convincing at it may appear –Bias from pro-lytic and pro-interventionalists TL has higher complications of stroke and re- infarction and PCI higher bleeding risks Both groups agree that even despite the large number of trials confirmation in a large trial comparing mortality for PCI vs. modern quick infusion TL is needed

11. What is the Evidence Supporting Transfer for PCI?

12. PRAGUE: Multicenter RCT comparing PCI vs. TL vs. combined strategy for patients with AMI presenting to a community hospital. EHJ 21. 2000 1 st randomized study to compare transfer for PCI vs. thrombolysis; June ’97 – March ’99 17 community referral centers; 4 PCI centers Patients randomized into one of three groups –Group A: TL at local hospital; remained at local hospital –Group B: TL en route; angiography  angioplasty if necessary –Group C: transfer for PCI

13. PRAGUE 1588 pts with STEMI/new LBBB; 300 randomized Within 6h Sx onset Endpoints: combined end point (CEP); death/re-infarction/stroke Transport distance 5 – 75 km

14. Re-infarction rate only sig. result

17. PRAGUE: Discussion/Limitations Trial only enrolled 300/1588 eligible patients < 6h from Sx onset Transport time <60min; distance <75km CEP; largely driven by re-infarct Support data regarding experienced labs/operators No evidence to support facilitated PCI

18. PRAGUE-2: Long distance transport for PCI vs. immediate thrombolysis for AMI. EHJ 24. 2003 Based on results of PRAGUE and LIMI (Vermeer); larger, nationwide, 30 d mortality as primary endpoint Sept ’99 – Jan ’02 41 community hospitals and 7 PCI centers 4853 patients with MI; 850 randomized (target sample 1200) 2 groups –TL: streptokinase (remain in first hospital) –PCI: transport to tertiary center; PCI

19. PRAGUE-2 Based on safety concerns regarding treatment delay subgroup analysis –< 3 h and 3 – 12 h after Sx onset Transport distance 5 – 120 km Study prematurely stopped –2.5 fold excess mortality in TL group treated >3h

20. Trend p.12 No difference p <.02

21. PRAGUE 2: Discussion/Limitations No difference in < 3 h group Distance < 120 km Streptokinase TL agent TL patients remained at local hospital Physician at local hospital could elect to send patients directly for PCI –One reason trial stopped early –? Source of bias

22. DANAMI: A comparison of coronary angioplasty with fibrinolytic therapy in AMI. NEJM 349 (8). 2003 Danish trial; Dec’97 – Oct ‘01 24 referral centers; 5 PCI centers –62% Danish population 2 groups –TL: remained at local hospital –PCI CEP (death, re-infarct, stroke) at 30 days Distance 3 – 150 km (mean 50 km)

23. DANAMI 2 concurrent study groups –Referral hospital –Invasive 1527 pts  1129 from 24 referral hospitals  443 from 5 invasive centers

24. NNT = 17 NNT = 18 CEP driven by 75 % reduction in re-infarction, BUT 30 day mortality 24 % (re-infarct) vs. 6.5 %

26. DANAMI: Repeat Revascularization 26 of 782 patients (3.3 %) in TL group underwent repeat TL within 12 h; 15 (1.9%) rescue angioplasty Over 30 days of follow up 148 (18.9%) of patients in TL vs. 72 (9.1%) of PCI underwent mechanical revascularization (p<.001)

27. DANAMI: Discussion/Limitations Primary endpoint CEP Excluded high risk patients –? Benefit most Short transport distance Only 2/5 PCI centers performed PCI prior to study –? Greater benefit than reported Sickest patients not transported

28. CAPTIM: Primary angioplasty vs. prehospital fibrinolysis in AMI: a randomised study. The Lancet 360. 2002 Randomized, multi-center trial based in France; June ’97 – Sept ’01 840 patients (1200 planned—lack of funding) 27 hospitals and associated EMS Presented within 6 h Two groups –Pre-hospital fibrinolysis (419); alteplase –PCI (421) Primary endpoint: CEP (death, re-infarct, stroke) at 30 d

29. Mortality benefit favouring TL group (trend) CEP favouring PCI group (trend)

30. Mortality rates significantly lower than other trials Trend (p =.61) Trend (p =.29)

31. CAPTIM: Discussion Low mortality rate in TL group –Early TL, transfer to invasive center, liberal rescue angioplasty (25% patients rescue angioplasties), low risk patients Benefit of early TL –Mortality reduction if treated < 2 h (57%) –2.2 TL vs. 5.7 % PCI (p.04) Well equipped ambulance –ACLS crew/physician on board

32. Limitations to Generalizations… 26 % of patients need rescue angioplasty Only 4% of ambulance calls for CP are STEMI eligible for TL ½ of patients with STEMI drive themselves to hospital Physician in ambulance

33. Transfer for Primary Angioplasty Versus Immediate Thrombolysis in Acute Myocardial Infarction: A Meta-Analysis. Circulation 108. 2003 6 RCT’s identified from Jan ’85 – Sept ’02 3 significantly favour transfer for PCI and 3 non-significant or no trend 2 limited by sample size, 1 a feasibility study, 1 hampered by recruitment Primary endpoint: CEP Excluded trials or arms of facilitated PCI

35. NNT = 30NS (with CAPTIM) RR =.76 p=.03 (Exclude CAPTIM)

36. NNT = 33NNT = 86

37. Conclusion: Effectiveness of Transport for PCI Overall PCI probably the best option –BUT not always achievable TL effective in early MI; > 6h largely ineffective; ? Very early TL as effective as PCI With TL significant number of patients will need to go on to further angiography/plasty Need to consider other issues surrounding transport –Safety –Timing/Distance –Availability

38. Safety and Quality of Transport

39. # of Patients Transported Failed to be Transported Deaths en Route Deaths within 1 h Adverse Events Maastricht 14640n/a2 VF, 2 brady- arrhythmias Prague 201n/a0 2 VF; 2 worsening CHF Prague-2 4254 (3 deaths, 1 worsening CHF) 2n/a3 VF arrest (resuscitated) Danami 5598018 VF; 13 advanced AV block Air- PANAMI 7100n/a0 Total 140216 (1.1%)2 (0.1%)1 (0.07%)32 (2.3%) 3.6 %

40. Quality of PCI Impact of Routine Duty Hours vs. Off Hours JACC 41(12). 2003 –1,702 consecutive patients at one center –Failure rate: 3.8% (routine) vs. 6.9 % (off) p <.01 –Mortality rate (30d): 1.9 % vs. 4.2 % p <.01 Relationship between volume and mortality JAMA 284(24). 2000 –NRMI database –Mortality rate PCI vs. TL: high volume 3.4 vs 5.4 % p<.001; intermediate 4.5 vs. 5.9 p <.001; low volume 6.2 vs. 5.9 % –More experienced operators; shorter door-balloon times

41. Conclusions Regarding Safety/Quality Transport appears to be safe Quick and dirty vs. slow and clean –Quick and dirty: fast but only basic equipment –Slow and clean: fully equiped; slow deployment times All studies to date some form of slow and clean No studies look at safety of long transports –PRAGUE2 longest transports but highest death and adverse events Impact of off hours and cath lab volumes likely to affect quality

42. Is Timing Everything?

43. Relationship of Symptom Onset to Balloon Time and Door to Balloon Time with Mortality in Patients Undergoing Angioplasty for AMI. JAMA 83(22). 2000 Prospective observational study of data collected in the Second National Registry of MI 27,080 consecutive patients with STEMI/ new LBBB Only 2230 (8% of patients) underwent PCI within 60 min of presentation –In-hospital mortality rate 4.2 % –> 3 h mortality rate 8.5 % mortality

44. Relationship of Symptom Onset to Balloon Time and Door to Balloon Time with Mortality in Patients Undergoing Angioplasty for AMI. JAMA 83(22). 2000 Performed logistic regression to adjust for baseline differences –Door to balloon time greater than 2h 41 – 62 % increased risk of death Confounding was serious concern in door to balloon times in this study –Shorter time: men, younger, non-DM –Propensity analysis: door to balloon time longer than 2h still increased risk of death (28 % vs. 41 – 62 %) Did not find an increased mortality associated with prolonged Sx onset to balloon time

45. Percutaneous Coronary InterventionVersus Fibrinolytic Therapy in AMI: Is Timing (Almost) Everything? AJC 92. 2003 Meta-regression analysis of the Grines meta- analysis comparing PCI and TL –Assess the impact of time delay –Endpoints were 4-6 week incidence of death and CEP of death, re-infarction and stroke As PCI related time delay increased, mortality reduction favouring PCI decreased –.94% reduction for every 10 minute delay –2 strategies equal after PCI delay of 62 min CEP equivalence occurred at 93 min

46. PraguePrague 2DANAMI Randomization to Treatment (time) PCI958290 TL221220 Difference7370 Symptom Onset to Treatment (time) PCI215277224 TL132185169 Difference839255

47. Clinical Characteristics and Outcome of Patients with Early, Intermediate and Late Presentation Treated by PCI and TL for AMI. EHJ 23. 2002 2635 patients in 10 RCT’s Presentation delay associated with older age, female, DM, increased HR CEP (death, re-infarction, stroke) at 30d for PCI vs. TL –Early (<2h) group: 5.8 vs. 12.5 % –Int. (2-4h) group: 8.6 vs. 14.2 % –Late (>4h) group: 7.7 vs. 19.4 % With increase in time to presentation adverse events increase in TL group (p.4)

48. Conclusions Regarding Timing PCI superior at all time points AHA goal TL door-needle time 6h ineffective AHA goal PCI door-balloon time 90 min +/- 30 min Evidence from transport trials supports feasibility with respect to timing With increasing delay (60 – 90 min) for transport for PCI mortality benefit may be lost ? Most beneficial group late presenters (>3 – 6h)

49. Issues Closer to Home… Limited availability of tertiary care centers in Canada (< 10 % of all hospitals) Large geographic area Substantial disparities in the quality of ambulance and pre-hospital services Tertiary care center variability Cost Effectiveness –$ 10,711 PCI vs. $13,664 TL

50. Questions to Ask? 1.What is the time from Sx onset to medical contact? 2.What is the risk associated with this MI? 3.What are the risks of TL? 4.What are the risks of transport? 5.What is the time to PCI?

51. Conclusions Regardless of strategy early reperfusion paramount –In early presenters TL should not be delayed for PCI especially in those patients at low risk for TL complications Each center must decide which strategy is best Transport appears safe but adverse events during transport can occur and need to be considered Time delays need to be minimized –Door to needle < 30min; door to balloon < 90min