1. Primary Angioplasty – The case is not proven: pre-hospital thrombolysis with mandated PCI may be equally effective Primary Angioplasty – The case is not proven: pre-hospital thrombolysis with mandated PCI may be equally effective Tony Gershlick University Hospitals of Leicester UK TCT 2005 Department Academic Cardiology

2. The debate is not about alternatives –but about resources, identifying real outcome differences between treatments, trying remain un-polarised, doing best for all patients with AMI i.e strategies applicable to different scenarios Does the data support the proposal ? What do Kevin and I agree on? Where are our differences? 1.In the real world what is important for the AMI patient ? 2.How good is the PPCI data 3.How good is real world PPCI (cf trial data) 4.How robust is the evidence for superiority of PPCI over thrombolysis (?) 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? The debate is not about alternatives –but about resources, identifying real outcome differences between treatments, trying remain un-polarised, doing best for all patients with AMI i.e strategies applicable to different scenarios Does the data support the proposal ? What do Kevin and I agree on? Where are our differences? 1.In the real world what is important for the AMI patient ? 2.How good is the PPCI data 3.How good is real world PPCI (cf trial data) 4.How robust is the evidence for superiority of PPCI over thrombolysis (?) 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? LYTIC MECHANICAL V PPCI

3. “To a man with a hammer, - all nails look as though they need pounding” Mark Twain “To a man with a hammer, - all nails look as though they need pounding” Mark Twain mission lesions stenting

4. Relationship of TIMI flow grade to survival 5 and 12 year follow up JACC 1999;34:(1) 62-69 P=0.04 5 5 0 10 20 30 40 50 90 100 TIMI 2TIMI 1/0 Survival percent 12 5 5 5 5 60 70 80 12 5 5 TIMI 3 What do we all agree on ?

5. 10 80 70 60 50 40 30 20 90 100 0 % TIMI Grade 3 patency @ 90 mins SK tPA Accel Reteplase TNKPA tPA Adjunctive LYSIS PPCI TIMI GRADE 3 FLOW

6. 1.In the real world what is important for the AMI patient ? TIMI flow/ 2.How good is the PPCI data 3.How good is real world PPCI (cf trial data) 4.How robust is the evidence for superiority of PPCI over thrombolysis 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? 1.In the real world what is important for the AMI patient ? TIMI flow/ 2.How good is the PPCI data 3.How good is real world PPCI (cf trial data) 4.How robust is the evidence for superiority of PPCI over thrombolysis 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? Clinical outcome

8. Quantitative review of 23 trials of primary angioplasty versus thrombolysis ( n=7739 ) Keeley, Lancet 2003;361:13 Short-term outcome 7.0% 3.0% 1.0% 0.1% 8.0% 9.0% 7.0% 2.0% 1.0% 14.0% 0.0% 5.0% 10.0% 15.0% DeathRe-MIStrokeHaem stroke Any event Primary angioplasty Thrombolysis 0.0002< 0.0001

9. short term death non-fatal AMI death, non fatal MI stroke

10. C-PORT - Primary Endpoint Through 6 months Primary PCI for AMI Intention to Treat JAMA 2002; 287:1943-51 7.1 10.6 4.0 6.2 5.3 2.2 19.9 12.4 0 5 10 15 20 25 p = 0.03 p = NS p = 0.04 p = NS Accel. t-PA (n=226)PCI (n=225) Combined*DeathReinfarctionDisabling Stroke *Primary Endpoint: Death, Reinfarction, or Stroke % of Patients Median Door to Needle Time = 46 min Median Door to Balloon Time = 102 min

11. Short-term clinical outcomes in individuals treated with primary PTCA or thrombolytic therapy, according to type of thrombolytic agent used

12. 2% absolute difference (p=0.0002) 1.6% cf fibrin specific (p=0.021) 1.2% exclude shock (p=0.08) Size trials (15 < 200 patients) Variable definition of end points eg re-infarction Double counting fatal strokes No blinded validation 2% absolute difference (p=0.0002) 1.6% cf fibrin specific (p=0.021) 1.2% exclude shock (p=0.08) Size trials (15 < 200 patients) Variable definition of end points eg re-infarction Double counting fatal strokes No blinded validation Issues related to Keeley’s m-a Mortality Other issues And in real life ? Is this evidence to introduce a new strategy ?

13. NRMI-2: Primary angioplasty versus thrombolysis Tiefenbrunn, JACC 1998;31:1240 Presentation to alteplase 42 min Presentation to balloon 111 min Presentation to alteplase 42 min Presentation to balloon 111 min P<0.0001 5.2% 2.5% 0.7% 5.4% 2.9% 1.6% 0.0% 5.0% 10.0% DeathRe-MIStroke Primary angioplasty (n=4939) Alteplase (n=24705)

14. USIC 2000, French Registry Data Hospital administered ‘lysis as good as PCI EURO-PCR Paris 2003

16. TRANSFER

17. DANAMI-2: transfer for primary PCI vs on-site Alteplase (n=1572) Anderson 2003;349:733 p=0.002 P<0.001 6.6% 1.6% 1.1% 8.0% 6.3% 2.0% 13.7% 0.0% 5.0% 10.0% 15.0% DeathRe-MIStrokeAny event Primary angioplasty Thrombolysis P=0.35 P=0.0003 7.8%

18. TIMI Risk Score N= 1134 Low 0-4 High >5 In-H Lysis 5.6% PPCI 8.0 In-H Lysis 36.2% PPCI 25.3% p=0.02

19. Transfer for primary PCI vs on-site lytic Quantitative review of 5 trials* Keeley, Lancet 2003;361:13 *LIMI, Prague I & II, Air PAMI, DANAMI-2 P=0.057P<0.0001 7.0% 1.8% 1.1% 8.2% 8.9% 6.7% 2.2% 15.0% 0.0% 5.0% 10.0% 15.0% Death Re-MI Stroke Any event Primary PCI (n=1466) Thrombolysis (n=1443) P<0.0001

20. DANAMI-2 Study 790 assigned to PCI –706 PCI attempted (36 technical problems, 31 normal coros, 3 died, 3 CTO, ) –By intention to treat analysis only 71% achieved TIMI 3 flow. 775 of the 782 assigned to ‘lysis received the treatment 99% 790 assigned to PCI –706 PCI attempted (36 technical problems, 31 normal coros, 3 died, 3 CTO, ) –By intention to treat analysis only 71% achieved TIMI 3 flow. 775 of the 782 assigned to ‘lysis received the treatment 99% NEJM 2003;349:733

21. DANAMI-2 Study The reduction in re-infarction occurred where only 2.5% of ‘lysed pts in the referring hospitals subsequently received PCI compared with 28% in invasive centres –i.e. Lysed patients were treated conservatively in the referring hospitals NEJM 2003;349:733 By 30days, 19% ‘lysed pts had PCI and 9% PCI group required repeat PCI –ie Primary PCI reduces the need but a significant number require repeat PCI

22. Prague-2: Transfer for PCI vs on-site thrombolysis in acute MI (n=850) Widimsky, Eur Heart J 2003;24:94 Mortality at 30 days Symptoms to balloon 277 min Symptom to lysis 195 min Planned 1200 patients Symptoms to balloon 277 min Symptom to lysis 195 min Planned 1200 patients 6.8% 7.3% 6.0% 10.0% 7.4% 15.3% 0% 5% 10% 15% 20% All patientsRx <3hrs of symptoms Rx >3hrs of symptoms Transfer for PCI Streptokinase p=0.12 p=0.02

23. 1.In the real world what is important for the AMI patient ? TIMI flow/CO 2.How good is the PPCI data NOT GREAT ! 3.How good is real world PPCI (cf trial data) Can the trial criteria be achieved 4.How robust is the evidence for superiority of PPCI over thrombolysis 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? 1.In the real world what is important for the AMI patient ? TIMI flow/CO 2.How good is the PPCI data NOT GREAT ! 3.How good is real world PPCI (cf trial data) Can the trial criteria be achieved 4.How robust is the evidence for superiority of PPCI over thrombolysis 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ?

24. 23 trials of PCI versus thrombolysis (n=7419) 0 0 -5 5 5 10 15 0 0 20 40 60 80 100 PCI-related time delay (mins) Absolute difference in 4-6 week mortality (%) Absolute difference in 4-6 week mortality (%) Nallamothu & Bates, Am J Cardiol 2003;92:824 Circles reflect trial sample size Blue line: weighted meta-regression Circles reflect trial sample size Blue line: weighted meta-regression Mean time delay 39.5 mins (SD 22.1, range 7- 104) 0.94% decrease in mortality benefit for every 10 min delay, p=0.006 No evidence of benefit if delay >62mins Mean time delay 39.5 mins (SD 22.1, range 7- 104) 0.94% decrease in mortality benefit for every 10 min delay, p=0.006 No evidence of benefit if delay >62mins

25. Time to angioplasty in 27080 patients with acute myocardial infarction Cannon, JAMA 2000;283:2941 Multivariate adjusted odds of in-hospital mortality (95% CI) * * * * * p<0.001 Median door to balloon time 116 mins 0 0 0.5 1 1 1.5 2 2 2.5 0-60 61-90 91-120 121-150 151-180 >180 Door to balloon time (min)

27. High failure rate with out-of-hours PCI even in high volume centre In 1702 cases –referral centre for 11 hospitals –48% presented between 1800hrs and 0800hrs –PCI failure rate 6.9% vs. 3.8% p<0.01 –30d mortality 4.2% vs. 1.9% p< 0.01 Zwolle Group JACC 2003;41:2138 In 1702 cases –referral centre for 11 hospitals –48% presented between 1800hrs and 0800hrs –PCI failure rate 6.9% vs. 3.8% p<0.01 –30d mortality 4.2% vs. 1.9% p< 0.01 Zwolle Group JACC 2003;41:2138

29. Nallamothu BK, Bates E R, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the US. National Registry of Myocardial Infarction (NRMI)-3/4 Analysis. Circulation 2005; 111:761-767 Thrombolysis (IH) can be given 30-60 mins after presentation - 60 min (lysis-PPCI) = 90-120 mins door> 80% lost incremental benefit 4278 transfer patients

30. MINAP Data UK 2004 -6 month 2005

33. 1.In the real world what is important for the AMI patient ? TIMI flow/CO 2.How good is the PPCI data NOT GREAT ! 3.How good is real world PPCI (cf trial data) Can the trial criteria be achieved 4. 5. 6.Are there any trials that can still be done ? 1.In the real world what is important for the AMI patient ? TIMI flow/CO 2.How good is the PPCI data NOT GREAT ! 3.How good is real world PPCI (cf trial data) Can the trial criteria be achieved 4. 5. 6.Are there any trials that can still be done ? re AMI

34. Primary PCI in the UK Resource Implications BCS Working Group on Cardiology Workforce Requirements –2 to 3 pmp additional interventionists for resident shift system or 1-2 pmp for non- resident shift system for Primary PCI – additional 150 interventionists for the UK – 381 SpR’s in UK We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts

35. 1.In the real world what is important for the AMI patient ? TIMI flow/CO 2.How good is the PPCI data NOT GREAT ! 3.How good is real world PPCI (cf trial data) Can the trial criteria be achieved 4.How robust is the evidence for superiority of PPCI over thrombolysis 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? 1.In the real world what is important for the AMI patient ? TIMI flow/CO 2.How good is the PPCI data NOT GREAT ! 3.How good is real world PPCI (cf trial data) Can the trial criteria be achieved 4.How robust is the evidence for superiority of PPCI over thrombolysis 5. How optimal is thrombolysis ? 6.Are there any trials that can still be done ? re AMI

36. Recurrent MI post Thrombolysis

37. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Boersma E, Maas AC, Deckers JW, Simoons ML. Lancet. 1996 Sep 21;348(9030):771-5. Difficult to achieve – can lysis be optimised ?

38. Pre-hospital thrombolysis: meta-analysis of 6 trials (n=6436) % mortality in-hospital thrombolysis % mortality in-hospital thrombolysis % mortality pre-hospital thrombolysis % mortality pre-hospital thrombolysis 2 2 4 4 6 6 8 8 10 12 14 0 0 2 2 0 0 4 4 6 6 8 8 10 12 14 Morrison JAMA 2000;283:2686 OR 0.83 95% CI 0.70-0.98 Time (SE) to thrombolysis: 104 (7) min for pre-hospital 162 (16) mins for in-hospital Time (SE) to thrombolysis: 104 (7) min for pre-hospital 162 (16) mins for in-hospital

39. 50 mins 42 mins arrival to needle 34 mins 11 mins 8 mins EAST MIDLANDS AMBULANCE SERVICE UK

40. PAIN CALL NEEDLE ?~ 60 mins ~ 20 mins PCI ~ 60 mins FMC ~ 30 mins DOOR ~ 60 mins Door to PCI time to compete is 11 mins 50 mins ?~ 60 mins 40 mins FMC PAIN CALL ~ 80- 90 mins

41. Can we improve the outcome of patients receiving pre-hospital lysis ?

42. Primary Endpoint: Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P=0.00000036P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrelbetter Placebobetter n=1752n=1739 36% Odds Reduction 36% Odds Reduction

43. Hierarchical Analysis at 6 Months Re-Lysis Conservative Rescue -PCI The REACT trial in press Gershlick et al C Death 10.6 9.9 5.6 Re AMI 10.6 8.5 2.1 CVA (ich)0.7 0.7 2.1 Severe HF7.07.8 4.9 C Death 10.6 9.9 5.6 Re AMI 10.6 8.5 2.1 CVA (ich)0.7 0.7 2.1 Severe HF7.07.8 4.9

44. Chest Pain Paramedic  AMI PH Lysis 90 min ECG MANDATED RESCUE PCI (REACT) Pre-discharge angio (GRACIA) REACT-2 PPCI 600 mg clopidogrel 600 mg clopidogrel 300 mg clopidogrel 300 mg clopidogrel

45. Primary PCI in the UK Resource Implications BCS Working Group on Cardiology Workforce Requirements –2 to 3 pmp additional interventionists for resident shift system or 1-2 pmp for non- resident shift system for Primary PCI – additional 150 interventionists for the UK – 381 SpR’s in UK We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts

46. Advantages of Integrated approach Combines the best of 2 complementary treatments From the start treatment can be individualised Lives and myocardium being saved from the start Emergency PCI required less often (>50% have TIMI 3 flow) PCI done more safely –more stable patients, patent IRA, better visualisation etc etc Combines the best of 2 complementary treatments From the start treatment can be individualised Lives and myocardium being saved from the start Emergency PCI required less often (>50% have TIMI 3 flow) PCI done more safely –more stable patients, patent IRA, better visualisation etc etc

47. Summary & Conclusions o Case versus Non PPCI is unproven o PPCI only approach is blinkered  Primary PCI may have some advantages if it can be undertaken extremely quickly and within the time frames of the RCT earlier if to compete with PHL !  PHL with mandated rescue has added advantages of earlier treatment, but must have mandated rescue and pre-hospital discharge assessment built in  ONLY when the appropriate trial has been done can PPCI be considered the optimal treatment of choice considering the changes in logistics required for a whole country – even then there is evidence of failure to meet time lines and serious resource implications  Can we afford to implement a strategy that cannot be delivered and may be no better than a model that suits all PHL + Mandated R-PCI ? o Case versus Non PPCI is unproven o PPCI only approach is blinkered  Primary PCI may have some advantages if it can be undertaken extremely quickly and within the time frames of the RCT earlier if to compete with PHL !  PHL with mandated rescue has added advantages of earlier treatment, but must have mandated rescue and pre-hospital discharge assessment built in  ONLY when the appropriate trial has been done can PPCI be considered the optimal treatment of choice considering the changes in logistics required for a whole country – even then there is evidence of failure to meet time lines and serious resource implications  Can we afford to implement a strategy that cannot be delivered and may be no better than a model that suits all PHL + Mandated R-PCI ?

48. The problems with the catch-all unselective approach The “Kevins” of the world “The clinical scientist”