Pre-hospital thrombolysis with mandated PCI for AMI

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  • Late follow up of streptokinase trials in 84-86 from Harvey White group in New Zealand
  • Median presentation to alteplase time 42 min Median presentation to balloon time 111 min Mortality no different because delay to PCI?
  • STEMI within 12 hours of symptoms. Excluded diabetics on warfarin
  • Patients STEMI within 12 hrs of symptom onset 299 patients within 3hrs, 551 patients after 3hrs D/reMI/CVA in 15.2% after lysis and 8.4% after transfer for PCI Planned 1200 recruitment – terminated early because excess mortality in lysis group 3-12 hrs
  • PCI-time delay is difference between door-to-balloon and door-to-needle times Analysis assumes linear association between time delay and outcome Time delay may be a marker for PCI quality and hence benefit Only 2 studies with time delay >60mins
  • Symptom onset to balloon time did not show relationship with in-hospital mortality Adjustment for institutional volume did not alter model
  • Pre-hospital thrombolysis with mandated PCI for AMI

    1. 1. 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 Department Academic Cardiology
    2. 2. <ul><li>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 </li></ul><ul><li>Does the data support the proposal ? </li></ul><ul><li>What do Kevin and I agree on? Where are our differences? </li></ul><ul><li>In the real world what is important for the AMI patient ? </li></ul><ul><li>How good is the PPCI data </li></ul><ul><li>How good is real world PPCI (cf trial data) </li></ul><ul><li>How robust is the evidence for superiority of PPCI over thrombolysis (?) </li></ul><ul><li>How optimal is thrombolysis ? </li></ul><ul><li>Are there any trials that can still be done ? </li></ul>PPCI LYTIC MECHANICAL V
    3. 3. <ul><li>“ To a man with a hammer, </li></ul><ul><li>- all nails look as though they need pounding” </li></ul><ul><li>Mark Twain </li></ul>mission lesions stenting
    4. 4. Relationship of TIMI flow grade to survival 5 and 12 year follow up JACC 1999;34:(1) 62-69 P=0.04 5 0 10 20 30 40 50 90 100 TIMI 2 TIMI 1/0 Survival percent 12 5 5 60 70 80 12 12 5 TIMI 3 What do we all agree on ?
    5. 5. 100 0 % TIMI Grade 3 patency @ 90 mins SK tPA Accel Reteplase TNKPA tPA Adjunctive LYSIS PPCI TIMI GRADE 3 FLOW 10 80 70 60 50 40 30 20 90
    6. 6. <ul><li>In the real world what is important for the AMI patient ? TIMI flow/ </li></ul><ul><li>How good is the PPCI data </li></ul><ul><li>How good is real world PPCI (cf trial data) </li></ul><ul><li>How robust is the evidence for superiority of PPCI over thrombolysis </li></ul><ul><li>How optimal is thrombolysis ? </li></ul><ul><li>Are there any trials that can still be done ? </li></ul>Clinical outcome
    7. 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% Death Re-MI Stroke Haem stroke Any event 0.0002 < 0.0001 Primary angioplasty Thrombolysis
    8. 9. short term death non-fatal AMI death, non fatal MI stroke
    9. 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* Death Reinfarction Disabling Stroke *Primary Endpoint: Death, Reinfarction, or Stroke % of Patients Median Door to Needle Time = 46 min Median Door to Balloon Time = 102 min
    10. 11. Short-term clinical outcomes in individuals treated with primary PTCA or thrombolytic therapy, according to type of thrombolytic agent used
    11. 12. <ul><li>2% absolute difference (p=0.0002) </li></ul><ul><li>1.6% cf fibrin specific (p=0.021) </li></ul><ul><li>1.2% exclude shock (p=0.08) </li></ul><ul><li>Size trials (15 < 200 patients) </li></ul><ul><li>Variable definition of end points eg re-infarction </li></ul><ul><li>Double counting fatal strokes </li></ul><ul><li>No blinded validation </li></ul>Issues related to Keeley’s m-a Mortality Other issues And in real life ? Is this evidence to introduce a new strategy ?
    12. 13. NRMI-2: Primary angioplasty versus thrombolysis Tiefenbrunn, JACC 1998;31:1240 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% Death Re-MI Stroke Primary angioplasty (n=4939) Alteplase (n=24705)
    13. 14. USIC 2000, French Registry Data Hospital administered ‘lysis as good as PCI EURO-PCR Paris 2003
    14. 16. TRANSFER
    15. 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% Death Re-MI Stroke Any event Primary angioplasty Thrombolysis P=0.35 P=0.0003 7.8%
    16. 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
    17. 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=0.057 P<0.0001 P<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)
    18. 20. DANAMI-2 Study <ul><li>790 assigned to PCI </li></ul><ul><ul><li>706 PCI attempted (36 technical problems, 31 normal coros, 3 died, 3 CTO, ) </li></ul></ul><ul><ul><li>By intention to treat analysis only 71% achieved TIMI 3 flow. </li></ul></ul><ul><li>775 of the 782 assigned to ‘lysis received the treatment 99% </li></ul>NEJM 2003;349:733
    19. 21. DANAMI-2 Study <ul><li>The reduction in re-infarction occurred where </li></ul><ul><li>only 2.5% of ‘lysed pts in the referring hospitals subsequently received PCI compared with 28% in invasive centres </li></ul><ul><ul><li>i.e. Lysed patients were treated conservatively in the referring hospitals </li></ul></ul>NEJM 2003;349:733 <ul><li>By 30days, 19% ‘lysed pts had PCI and 9% PCI group required repeat PCI </li></ul><ul><ul><li>ie Primary PCI reduces the need but a significant number require repeat PCI </li></ul></ul>
    20. 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 p=0.12 p=0.02 6.8% 7.3% 6.0% 10.0% 7.4% 15.3% 0% 5% 10% 15% 20% All patients Rx <3hrs of symptoms Rx >3hrs of symptoms Transfer for PCI Streptokinase
    21. 23. <ul><li>In the real world what is important for the AMI patient ? TIMI flow/CO </li></ul><ul><li>How good is the PPCI data NOT GREAT ! </li></ul><ul><li>How good is real world PPCI (cf trial data) Can the trial criteria be achieved </li></ul><ul><li>How robust is the evidence for superiority of PPCI over thrombolysis </li></ul><ul><li>How optimal is thrombolysis ? </li></ul><ul><li>Are there any trials that can still be done ? </li></ul>
    22. 24. 23 trials of PCI versus thrombolysis (n=7419) PCI-related time delay (mins) 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 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 0 -5 5 10 15 0 20 40 60 80 100
    23. 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 0.5 1 1.5 2 2.5 0-60 61-90 91-120 121-150 151-180 >180 Door to balloon time (min)
    24. 27. High failure rate with out-of-hours PCI even in high volume centre <ul><li>In 1702 cases </li></ul><ul><ul><li>referral centre for 11 hospitals </li></ul></ul><ul><ul><li>48% presented between 1800hrs and 0800hrs </li></ul></ul><ul><ul><li>PCI failure rate 6.9% vs. 3.8% p<0.01 </li></ul></ul><ul><ul><li>30d mortality 4.2% vs. 1.9% p< 0.01 </li></ul></ul><ul><ul><ul><ul><ul><li>Zwolle Group JACC 2003;41:2138 </li></ul></ul></ul></ul></ul>
    25. 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
    26. 30. MINAP Data UK 2004 -6 month 2005
    27. 33. <ul><li>In the real world what is important for the AMI patient ? TIMI flow/CO </li></ul><ul><li>How good is the PPCI data NOT GREAT ! </li></ul><ul><li>How good is real world PPCI (cf trial data) Can the trial criteria be achieved </li></ul><ul><li>Are there any trials that can still be done ? </li></ul>re AMI X
    28. 34. Primary PCI in the UK Resource Implications <ul><li>BCS Working Group on Cardiology Workforce Requirements </li></ul><ul><ul><li>2 to 3 pmp additional interventionists for resident shift system or 1-2 pmp for non-resident shift system for Primary PCI </li></ul></ul><ul><ul><li>additional 150 interventionists for the UK </li></ul></ul><ul><ul><li>381 SpR’s in UK </li></ul></ul><ul><ul><li>We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts </li></ul></ul>
    29. 35. <ul><li>In the real world what is important for the AMI patient ? TIMI flow/CO </li></ul><ul><li>How good is the PPCI data NOT GREAT ! </li></ul><ul><li>How good is real world PPCI (cf trial data) Can the trial criteria be achieved </li></ul><ul><li>How robust is the evidence for superiority of PPCI over thrombolysis </li></ul><ul><li>How optimal is thrombolysis ? </li></ul><ul><li>Are there any trials that can still be done ? </li></ul>re AMI X
    30. 36. Recurrent MI post Thrombolysis
    31. 37. Difficult to achieve – can lysis be optimised ? 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.
    32. 38. Pre-hospital thrombolysis: meta-analysis of 6 trials (n=6436) % mortality in-hospital thrombolysis % mortality pre-hospital thrombolysis 2 4 6 8 10 12 14 0 2 0 4 6 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
    33. 39. 50 mins 42 mins arrival to needle 34 mins 11 mins 8 mins EAST MIDLANDS AMBULANCE SERVICE UK
    34. 40. PAIN CALL NEEDLE ?~ 60 mins ~ 20 mins FMC ~ 30 mins DOOR ~ 60 mins Door to PCI time to compete is 11 mins 50 mins PCI ~ 60 mins ?~ 60 mins 40 mins FMC PAIN CALL ~ 80- 90 mins
    35. 41. Can we improve the outcome of patients receiving pre-hospital lysis ?
    36. 42. Primary Endpoint: Occluded Artery (or D/MI thru Angio/HD) Placebo Clopidogrel P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel better Placebo better n=1752 n=1739 36% Odds Reduction
    37. 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 HF 7.0 7.8 4.9
    38. 44. Chest Pain Paramedic  AMI 90 min ECG 300 mg clopidogrel PH Lysis MANDATED RESCUE PCI (REACT) Pre-discharge angio (GRACIA) REACT-2 PPCI 600 mg clopidogrel
    39. 45. Primary PCI in the UK Resource Implications <ul><li>BCS Working Group on Cardiology Workforce Requirements </li></ul><ul><ul><li>2 to 3 pmp additional interventionists for resident shift system or 1-2 pmp for non-resident shift system for Primary PCI </li></ul></ul><ul><ul><li>additional 150 interventionists for the UK </li></ul></ul><ul><ul><li>381 SpR’s in UK </li></ul></ul><ul><ul><li>We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts </li></ul></ul>
    40. 46. Advantages of Integrated approach <ul><li>Combines the best of 2 complementary treatments </li></ul><ul><li>From the start treatment can be individualised </li></ul><ul><li>Lives and myocardium being saved from the start </li></ul><ul><li>Emergency PCI required less often (>50% have TIMI 3 flow) </li></ul><ul><li>PCI done more safely –more stable patients, patent IRA , better visualisation etc etc </li></ul>
    41. 47. Summary & Conclusions <ul><li>Case versus Non PPCI is unproven </li></ul><ul><li>PPCI only approach is blinkered </li></ul><ul><li>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 ! </li></ul><ul><li>PHL with mandated rescue has added advantages of earlier treatment, but must have mandated rescue and pre-hospital discharge assessment built in </li></ul><ul><li>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 </li></ul><ul><li>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 ? </li></ul>
    42. 48. The problems with the catch-all unselective approach The “Kevins” of the world “ The clinical scientist”

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