Primary Angioplasty – The case is not proven: pre-hospital thrombolysis with mandated PCI may be equally effective Primary Angioplasty – The case is not

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  • 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

  • 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 scenariosDoes the data support the proposal ? What do Kevin and I agree on? Where are our differences? In the real world what is important for the AMI patient ?How good is the PPCI dataHow good is real world PPCI (cf trial data)How robust is the evidence for superiority of PPCI over thrombolysis (?) How optimal is thrombolysis ? Are there any trials that can still be done ? PPCI

  • To a man with a hammer, - all nails look as though they need pounding Mark Twain

  • Relationship of TIMI flow grade to survival5 and 12 year follow upJACC 1999;34:(1) 62-69P=0.0450102030405090100TIMI 2TIMI 1/0Survival percent125560708012125TIMI 3What do we all agree on ?

  • 100 0% TIMI Grade 3 patency @ 90 mins SK tPA Accel Reteplase TNKPA tPA Adjunctive

    LYSIS PPCITIMI GRADE 3 FLOW

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

  • Quantitative review of 23 trials of primary angioplasty versus thrombolysis ( n=7739 )Keeley, Lancet 2003;361:13Short-term outcome7.0%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-MIStrokeHaemstrokeAny event0.0002< 0.0001

  • short term death non-fatal AMI death, non fatal MI stroke

  • C-PORT - Primary Endpoint Through 6 monthsPrimary PCI for AMIIntention to TreatJAMA 2002; 287:1943-517.110.64.06.25.32.219.912.40510152025p = 0.03p = NSp = 0.04p = NSAccel. t-PA (n=226)PCI (n=225)Combined*DeathReinfarctionDisablingStroke*Primary Endpoint: Death, Reinfarction, or Stroke% of PatientsMedian Door to Needle Time = 46 minMedian Door to Balloon Time = 102 min

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

  • 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 strokesNo blinded validation

    Issues related to Keeleys m-aMortality Other issues And in real life ?

  • NRMI-2: Primary angioplasty versus thrombolysisTiefenbrunn, JACC 1998;31:1240Presentation to alteplase 42 minPresentation to balloon 111 minP
  • USIC 2000, French Registry Data Hospital administered lysis as good as PCIEURO-PCR Paris 2003

  • TRANSFER

  • DANAMI-2: transfer for primary PCIvs on-site Alteplase (n=1572)Anderson 2003;349:733p=0.002P
  • 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

  • Transfer for primary PCI vs on-site lyticQuantitative review of 5 trials*Keeley, Lancet 2003;361:13*LIMI, Prague I & II, Air PAMI, DANAMI-2P=0.057P
  • DANAMI-2 Study

    790 assigned to PCI706 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

  • DANAMI-2 StudyThe 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

  • Prague-2: Transfer for PCI vson-site thrombolysis in acute MI (n=850)Widimsky, Eur Heart J 2003;24:94Mortality at 30 daysSymptoms to balloon 277 minSymptom to lysis 195 minPlanned 1200 patientsp=0.12p=0.02

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

  • 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;92:824Circles reflect trial sample sizeBlue line: weighted meta-regressionMean time delay 39.5 mins (SD 22.1, range 7-104)0.94% decrease in mortality benefit for every 10 min delay, p=0.006No evidence of benefit if delay >62mins

  • Time to angioplasty in 27080 patients with acute myocardial infarctionCannon, JAMA 2000;283:2941Multivariate adjusted odds of in-hospital mortality (95% CI) *** p
  • High failure rate with out-of-hours PCI even in high volume centreIn 1702 cases referral centre for 11 hospitals48% presented between 1800hrs and 0800hrs

    PCI failure rate 6.9% vs. 3.8% p

  • 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

  • MINAP Data UK 2004 -6 month 2005

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

  • 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 SpRs in UK

    We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts

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

  • Recurrent MI post Thrombolysis

  • Difficult to achieve can lysis be optimised ?

  • Pre-hospital thrombolysis:meta-analysis of 6 trials (n=6436)% mortality in-hospitalthrombolysis% mortality pre-hospital thrombolysis2468101214020468101214Morrison JAMA 2000;283:2686OR 0.83 95% CI 0.70-0.98Time (SE) to thrombolysis:104 (7) min for pre-hospital162 (16) mins for in-hospital

  • 50 mins 42 mins arrival to needle 34 mins11 mins 8 mins EAST MIDLANDS AMBULANCE SERVICE UK

  • PAINCALLNEEDLE ?~ 60 mins ~ 20 mins FMC~ 30 mins DOOR~ 60 mins Door to PCI time to compete is 11 mins 50 mins

  • Primary Endpoint:Occluded Artery (or D/MI thru Angio/HD)PlaceboClopidogrelP=0.00000036Odds Ratio 0.64 (95% CI 0.53-0.76)1.00.40.60.81.21.6ClopidogrelbetterPlacebobettern=1752n=173936%Odds Reduction

  • 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

  • Chest Pain Paramedic D AMI 90 min ECG300 mg clopidogrel

  • 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 SpRs in UK

    We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts

  • Advantages of Integrated approachCombines the best of 2 complementary treatmentsFrom the start treatment can be individualisedLives and myocardium being saved from the startEmergency PCI required less often (>50% have TIMI 3 flow)PCI done more safely more stable patients, patent IRA , better visualisation etc etc

  • Summary & Conclusions Case versus Non PPCI is unproven 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