Prehospital Thrombolysis

1
Prehospital Thrombolysis

• Professor P J Fletcher
• Director, Cardiovascular Department
• John Hunter Hospital, Newcastle

2
Prehospital thrombolysis

• Review of evidence relating time of reperfusion
  treatment to outcome
• Review of evidence with prehospital thrombolysis
• Progress with pre-hospital thrombolysis in Hunter
  New England
• Recent publications on prehospital thrombolysis
• Outcome from very early prehospital thrombolysis
• Role of prehospital thrombolysis vs primary PCI
  in patients seen within 2 hours of pain onset

3
Time dependence of benefit of reperfusion therapy

• Hypothetical construct of the relationship
  between the duration of symptoms of acute MI
  before reperfusion therapy, mortality reduction
  and extent of myocardial salvage

Kiernan Gersh. Thrombolysis in acute myocardial
infarction current status. Medical Clinics of
North America 2007
4
Benefit of thrombolytic therapyFTT
Collaborative Group meta-analysis
Fibrinolytic Therapy Triallists (FTT)
Collaborative Group Indications for fibrinolytic
therapy in suspected acute myocardial infarction
collaborative overview of early mortality and
major morbidity results from all randomised
trials of more than 1000 patients. Lancet 1994
343311-322
5
Fibrinolysis and adjunctive therapy

• Antiplatelet therapy
• Glycoprotein IIb/IIIa antagonists
• Aspirin
• Clopidogrel
• Anti-thrombins
• Unfractionated heparin
• Low Molecular weight heparin
• Hirudin etc

6
Antiplatelet therapy aspirin clopidogrel

• Aspirin In ISIS-2, aspirin reduced vascular
  deaths, non-fatal reinfarction and non-fatal
  stroke, and was not associated with any
  significant increase in bleeding
• Clopidogrel
• CLARITY TIMI 28 COMMIT

Chen, Jiang, Chen. COMMIT (Clopidogrel and
Metoprolol in Myocardial Infarction Trial)
collaborative group, et al. Addition of
Clopidogrel to aspirin in 45852 patients with
acute myocardial infarction randomised placebo
controlled trial. Lancet 2005 366 1607
Sabatine, Cannon Gibson et al. Clarity TIMI 28
Investigators. Addition of clopidogrel to aspirin
and thrombolytic therapy for myocardial
infarction with ST segment elevation. N Eng J Med
2005 3521179
7
Pre-hospital fibrinolysis

• Theoretical advantages of earlier reperfusion

Boersma, Maas, Deckers Simoons. Early
thrombolytic treatment in acute myocardial
infarction reappraisal of the golden hour.
Lancet 1996 348771
FTT Collaborative Group
Surprisingly little actual data, mostly from the
1990s
8
Pre-hospital fibrinolysisMorrison, Verbeek,
Richard et al. Mortality and prehospital
thrombolysis for acute myocardial infarction A
meta-analysis. JAMA 2000 2832686

• Conclusion
• Our meta-analysis suggests that prehospital
  thrombolysis for AMI significantly decreases the
  time to thrombolysis and all-cause hospital
  mortality

9
Pre-hospital fibrinolysisThe European
Myocardial Infarction Project Group. Prehospital
Thrombolytic therapy in patients with suspected
acute myocardial infarction. N Eng J Med 1993
329383

• Conclusions Prehospital thrombolytic therapy for
  patients with suspected myocardial infarction is
  both feasible and safe when administered by
  well-equipped, well-trained mobile emergency
  medical staff

10
Pre-hospital fibrinolysisRawles. Magnitude of
benefit from earlier thrombolytic treatment in
acute myocardial infarction new evidence from
Grampian region early anistreplase trial (GREAT).
BMJ 1996 312212

• Conclusions
• Substantial mortality benefit maintained out to
  4-5 years
• The magnitude of the benefit is such that giving
  thrombolysis at the first opportunity is a matter
  of the utmost clinical importance

11
Pre-hospital fibrinolysisKalla, Christ, Karnik
et al. Implementation of Guidelines improves the
standard of care The Viennese Registry on
reperfusion strategies in ST-elevation myocardial
infarction (Vienna STEMI Registry). Circulation
2006 1132398

• Figure 3 Influence of time to treatment on
  in-hospital mortality. Tendency for lower
  mortality with TT compared with PPCI.

Need to move assessment and triage into the
ambulance setting. Reinforced by accompanying
editorial
12
Prehospital Thrombolysis Project

• Partnership between NSW Ambulance and NSW Health
• Conductged in remote area of Hunter New England
• Ambulances equipped with ECG capable equipment
• Training of paramedics in ECG and thrombolysis
• 12-lead ECG assessment performed
• Transmitted to Medtronic website via Next-G
  network.
• Sent to email address of cardiologist equipped
  with computer or internet-enabled PDA
• Text message to alert cardiologist sent at same
  time
• Cardiologist calls mobile and discusses
  interpretation with paramedics
• If lt 30min from hospital, delay thrombolysis till
  hospital
• If gt 30min from hospital, administer thrombolysis
  in ambulance
• STEMI transported to physician-manned hospital

13
Prehospital thrombolysis project scope map
14
Prehospital thrombolysis project Test ECG
transmission
15
Prehospital Thrombolysis ProjectAcute
inferolateral infarct
16
Prehospital thrombolysis projectprogress report
July08-09

• Total ECG transmissions 461
• Transmission failures 26
• Number of STEMIs 21
• Prehospital thrombolysis 9
• Symptom to thrombolysis 80 (43-110) min

17
Prehospital thrombolysis projectparticipants

• NSW Ambulance
• P Stewart
• A Loudfoot
• Dr S Gallagher
• Dr P Middleton
• NSW Health
• J Dunn
• N Rickwood

• Hunter New Eng Health
• L Savage
• M DiRienzo
• Prof P Fletcher
• Dr B Bastian
• Dr S Turner
• Dr N Collins
• Dr S Mylabathula

18
Prehospital thrombolysis process

• Castle NR, Owen RC, Hann M Emergency Medicine
  Journal 24843-5, 2007. Is there still a place
  for emergency department thrombolysis following
  the introduction of the amended Joint Royal
  Colleges Ambulancve Liaison Committee criteria
  for thrombolysis?
• Conclusions The amended JRCALC guidelines for
  (2006) for paramedic initiated thrombolysis have
  successfully increased the proportion of patients
  suitable for prehospital thrombolysis by
  approximately 10. The ED retains an important
  role in the provision of prompt thrombolysis
  treatment for a proportion of patients
• Hanson TC, Williamson D Emergency Medicine
  Journal 23650-3, 2006. Identifying barriers to
  prehospital thrombolysis in the treatment of
  acute myocardial infarction
• Conclusions To increase the number of patients
  who are eligible for PHT the guidelines (for
  inclusion and exclusion criteria) need to be
  revised further in line with inhospital criteria
  for thrombolysis
• Keeling P, Hughes D, Price L et al. BMJ 3272728,
  2003. Safety and feasibility of prehospital
  thrombolysis carried out by paramedics
• Conclusions Paramedics can record and interpret
  12 lead electrocardiograms and safely administer
  thrombolysis in the community. Time saved 48
  minutes. Physician assisted model unreliable.

19
Prehospital Thrombolysis process

• Pedley DK, Bissett K, Connolly, EM et al. BMJ
  32722-26, 2003. Prospective observational cohort
  study of time saved by prehospital thrombolysis
  for ST elevation myocardial infarction delivered
  by paramedics
• Median time saving of 71 minutes with prehospital
  thrombolysis
• Conclusions Thrombolysis delivered by paramedics
  with support from the base hospital can meet the
  national targets for early thrombolysis. The
  system has been shown to work well and can be
  introduced without delay.
• Bongard V, Puel J, Savary D et al. Heart
  95799-806, 2009. Predictors of infarct artery
  patency after prehospital thrombolysis the
  multicentre prospective observational OPTIMAL
  study.
• Conclusions This study provides quantitative
  data for predicting success of prehospital
  thrombolysis. The nomogram is a simple tool for
  predicting likelihood of coronary patency based
  on clinical and electrocardiographic data. It may
  help to identify patients who require emergency
  angiography and rescue percutaneous coronary
  intervention.

20
Prehospital Thrombolysis Aborted MI

• Lamfers EJP, Hooghoudt THE, Hertzberger DP et al.
  Heart 89496-501, 2003. Abortion of acute ST
  segment elevation myocardial infarction after
  reperfusion incidence, patients characteristics
  and prognosis.
• Conclusion Prehospital thrombolysis is
  associated with a fourfold increase of aborted
  myocardial infarction compared with in-hospital
  treatment. A shorter time to treatment, a lower
  ST elevation and a higher incidence of
  preinfarction angina were predictors of aborted
  myocardial infarction.
• Lamfers EJP, Schut A, Hertzberger DP et al. Am
  Heart J 147509-15, 2004. Prehospital versus
  hospital fibrinolysis therapy using automated
  versus cardiologist electrocardiographic
  diagnosis of myocardial infarction Abortion of
  myocardial infarction and unjustified
  fibrinolytic therapy
• Conclusions Abortion of myocardial infarction is
  associated with prehospital thrombolysis.
  Unjustified fibrinolysis occurs in prehospital
  fibrinolysis as frequently as in the inhospital
  setting. The use of different electrocardiographic
  methods for diagnosing acute myocardial
  infarction does not appear to make any
  difference.
• Jackson L, Kendall J Castle N Emergency Medical
  Journal. 26206-9, 2009. Does prehospital
  thrombolysis increase the proportion of patients
  who have an aborted myocardial infarction?
• Conclusion Prehospital thrombolysis improved
  pain to needle time and a shorter pain to needle
  time increased the incidence of aborted
  infarction. However prehospital thrombolysis was
  not associated with an increase in the proportion
  of aborted myocardial infarctions

21
Prehospital thrombolysis general

• Lamfers EJP, Schut A, Hooghoudt THE et al. Am
  Heart J 146479-83, 2003. Prehospital
  thrombolysis with reteplase the
  Nijmegan/Rotterdam study
• Conclusions In prehosptial thrombolysis, double
  bolus reteplase is associated with a shorter time
  to treatment than bolus anistreplase or infusion
  of streptokinase.
• Wallentin L, Goldstein P, Armstrong PW et al.
  Circulation 108135-142, 2003. Efficacy and
  safety of tenecteplase in combination with the
  low molecular weight heparin enoxaparin or
  unfractionated heparin in the prehospital
  setting.
• Results Median time (symptom TNK) 115min
  (55-272)
• Conclusions Prehospital fibrinolysis allows 53
  of patients to receive reperfusion treatment
  within 2 hours after symptom onset. The
  combination of tenecteplase and enoxaparin
  reduces early ischemic events.

22
Prehospital thrombolysis outcome

• Danchin N, Blanchard D, Steg PG et al
  Circulation 110 1909-15, 2004
• Impact of Prehospital thrombolysis for acute
  myocardial infarction on 1-year outcome.

• Conclusion The 1-year outcome of patients
  treated with PHT compares favorably with that of
  patients treated with other modes of reperfusion
  therapy this favorable trend persists after
  multivariate adjustment. Patients with PHT
  admitted very early have a very high 1-year
  survival rate.

23
Prehospital Thrombolysis Outcome

• Steg PG, Bonnefoy E, Chabaud S et al. Circulation
  1082851-2856, 2003.
• Impact of time to treatment on mortality after
  prehospital fibrinolysis of primary angiogplasty.
• Findings Patients randomised within lt2hrs after
  symptom onset had a strong trend towards lower
  30day mortality with prehospital thrombolysis
  than with primary PCI (2.2 vs 5.7, P0.058)
  whereas mortality was similar in patients
  randomised gt 2hours. Among patients randomised lt
  2 hrs cardiogenic shock was less frequent with
  lytic therapy than with primary PCI (1.3 vs 5,
  P0.032) whereas the rates were similar in
  patients randomised later.
• Conclusions Time from symtom onset should be
  considered when one selects reperfusion therapy
  in STEMI. Prehospital thrombolysis may be
  preferable to primary PCI for patients treated
  within the first 2 hours after symptom onset.

24
Steg PG, Bonnefoy E, Chabaud S et al. Circulation
1082851-2856, 2003.Impact of time to treatment
on mortality after prehospital fibrinolysis of
primary angiogplasty.

• Log
• Rank
• Analysis
• of
• Mortality

25
Prehospital Thrombolysis Outcome

• Stenestrand U, Lindback J, Wallentin L et al.
  JAMA 2961749-756, 2006
• Long-term outcome of primary percutaneous
  coronary intervention vs prehospital and
  in-hospital thrombolysis for patients with
  ST-elevation myocardial infarction

• Unadjusted cumulative mortality during the first
  year after the index event admission

Conclusions In unselected patients with STEMI,
primary PCI, which compared favorably with IHT
and PHT, was associated with reduced duration of
hospital stay, reduced admission, reinfarction
and mortality
26
Pre-hospital Thrombolysis outcome

• Bonnefoy, Lapostolle, Leizorovicz et al. Primary
  angioplasty versus prehospital fibrinolysis in
  acute myocardial infarction a randomised study.
  Comparison of angioplasty and prehospital
  thrombolysis in acute myocardial infarction study
  group (CAPTIM) study group. Lancet 2002
  360825-29
• Study 841 pts Lyon recruited 1997-2000,
  randomised 419 PHF, 421 PCI
• Results no differences in death 30 days
  (p0.61) or composite EP (p0.29)

• Kaplan-Meier curves for deaths and cumulative
  rate of composite endpoint of death, reinfarction
  and diabling stroke in the study patients within
  the 30 days after randomisation according to
  treatment group

Conclusions A strategy of primary angioplasty
was not better than a strategy of prehospital
fibrinolysis (with transfer to an interventional
facility for possible rescue angioplasty) in
patients presenting with early myocardial
infarction
27
Primary angioplasty vs fibrinolysis

• General consensus that primary percutaneous
  coronary intervention is the preferred approach
  to reperfusion when delivered in expert centres
  in a timely fashion

Keeley, Boura Grines. Primary angioplasty
versus intravenous thrombolytic therapy for acute
myocardial infarction a quantitative review of
23 randomised trials. Lancet 2003 36112
28
1ry PCI vs fibrinolysis time dependence of
benefit

• Meta-analysis of 23 trials of 1ry PCI vs
  fibrinolysis relating 4-6 week death difference
  to PCI-related time delay.
• Mortality benefit of 1ry PCI may be lost if
  door-to-balloon time is delayed by gt60 min
  compared with door-to-needle time

Nallamothu Bates. Percutaneous coronary
intervention versus fibrinolytic therapy in acute
myocardial infarction Is timing (almost)
everything? Am J Cardiol 2003 92824
29
ETAMI Early Triage in Acute Myocardial
Infarction
30
ETAMI resultsCarstensen, Nelson, Hansen et al.
Field triage to primary angioplasty combined with
emergency department bypass reduces treatment
delays and is associated with impoved outcome.
Eur Heart J 2007 282313

• Field triage (n108) vs ED triage (n193)
• Symptom balloon times 154 vs 249 min (Plt0.001)
• Mortality 1.1 in Field Triage vs 8.2 ED Triage
  (P0.025)
• Field triage and ED bypass are feasible means of
  reducing treatment delay

31
Pre-hospital fibrinolysis

• Widimsky Budesinsky, Vorac et al. Long distance
  transport for primary angioplasty cs immediate
  thrombolysis in acute myocardial infarciton.
  Final results of the randomized national
  multicentre trial PRAGUE-2. Eur Heart J 2003
  2494
• Conclusions Transport to tertiary PCI centre is
  safe. For patients presenting gt 3 hrs, transport
  to tertiary PCI centre markedly decreases
  mortality compared with thrombolysis. For
  patients presenting within 3 hours of symptom
  onset, thrombolytic therapy results are similar
  to results from long distance transport for PCI
• Bonnefoy, Lapostolle, Leizorovicz et al.
  Comparison of angioplasty and prehospital
  thrombolysis in acute myocardial infarction study
  group (CAPTIM) study group. Primary angioplasty
  versus prehospital fibrinolysis in acute
  myocardial infarction a randomised study. Lancet
  2002 360825
• Conclusions A strategy of primary angioplasty
  was not better than a strategy of prehospital
  fibrinolysis (with transfer to an interventional
  facility for possible rescue angioplasty) in
  patients presenting with early myocardial
  infarction

32
PCI Door-to-Balloon times

• Rathore SS, Curtis JP, Chen J et al. BMJ
  338b1807 (pp1-7), 2009
• Association of door-to-balloon time and mortality
  in patients admitted to hospital with ST
  elevation myocardial infarction national cohort
  study.
• Conclusions Any delay in PCI after a patient
  arrives at hospital is associated with higher
  mortality in hospital in those admitted with ST
  elevation myocardial infarction

33
Prehospital Thrombolysis outcome

• Kent DM, Ruthazer R, Griffith JL et al. Am J
  Cardiol 991384-8, 2007
• Comparison of mortality benefit of immediate
  thrombolytic therapy versus delayed primary
  angioplasty for acute myocardial infarction
• Conclusions Mortality benefits of PPCI and
  hazard of PPCI related delay depend on baseline
  risk. Previous meta-regressions appear to have
  underestimated the PPCI related delay that would
  nullify the incremental benefits of PPCI

34
Risk modifiers of mortality following
fibrinolysis or PCI

• 3,006 patients from controlled PCI vs. lysis
  published trials patients divided into 5
  quantiles of risk (based upon ECG score, age,
  gender, BP, time to Rx, etc)

15.2
16
n2,780
14
Lysis
PCI
12
10
8.0
60
8
Mortality (30 days)
6
5.1
4
3.1
2.5
2.4
1.7
2
1.4
0
0
0
Q1
Q2
Q3
Q4
Q5
Risk quantile by score
Each quantile 556 patients

• Kent D et al, AJC May 2007.

35
Authors summary

• Mortality in the lower three fifths of risk
  categories is not reduced by PCI compared with
  lysis (but may be increased if the PCI delay is
  long)
• Higher risk patients (2/5) benefit from PCI if
  ECG-to-balloon time is 90 min or less but that
  advantage is lost at a mean ECG-to-balloon time
  of 100 min. (longer than that, lysis may be
  preferred)

• Kent, D et al. AJC 2007

36
Time and Mortality Primary PCI vs Thrombolysis
Huber et al. Eur Heart J 2005 26 1063-1074
Huber K et al. Eur Heart J 20052620632074.
37
Acute myocardial infarction Overviews

• Gersh 2006 MCNA
• The results to date of prehospital thrombolysis
  for acute MI are indeed encouraging but the
  implementation of corresponding clinical policies
  is subject to the logistic constraints of
  different health care systems and geographic
  regions throughout the world.
• White HD Chew DP. Lancet 372 570-584, 2008
• Seminar Acute Myocardial Infarction
• The earlier that fibrinolysis is begun, the
  greater the benefit with respect to preservation
  of left ventricular function and reduction in
  mortality which suggests an important role for
  prehospital fibrinolysis.
• In a study of prehospital fibrinolysis with a 26
  rate of rescue PCI, fewer patients randomised
  with 2 hr of symptom onset had cardiogenic shock
  and more survived to 30 days compared with
  primary PCI, although this finding was not
  statistically significant.
• The development of clinical networks designed to
  enable prehospital fibrinolysis could provide
  further mortality benefits to a broader
  population of patients presenting with STEMI.