1. A modern thrombolysis service is superior to primary angioplasty
Rob Henderson
Consultant Cardiologist
Trent Cardiac Centre
Nottingham

3. Responses to a request to defend thrombolysis at BCIS Autumn meeting
Thanks…..but NO!

4. Responses to a request to defend thrombolysis at BCIS Autumn meeting
Yes……but can I take the other side?

6. Fibrinolytic Therapy Triallists 35 Day Outcome in 58 600 patients
16 per 1000 lives saved
Lancet 1994:343;311

7. Thrombolysis equivalence trials ‘ceiling’ of benefit?
30 d mortality

8. Thrombosaurus Rex
EXTINCTOPLASE ?
Courtesy Bob Wilcox

9. Patency of infarct-related artery
NEJM 1993;335:1313
% Patients
PCI

10. Keeley et al, 2003
OR 0.70, 95% CI , P<0.0001

11. Short-term clinical outcomes
Quantitative review of 23 trials of primary angioplasty versus thrombolysis (n=7739)
Short-term clinical outcomes
Keeley, Lancet 2003;361:13

12. Keeley meta-analysis of 23 trials Some limitations…
Suboptimal lytic strategies
symptom onset to drug ≈ 3 hrs
streptokinase in 8 trials
Inclusion of SHOCK trial (only 63% lysis)
End-points not defined, no blinded validation
Most trials (15) had fewer than 200 patients
Double counting of fatal stroke
2% excess major bleeding in PPCI group

13. Keeley meta-analysis: proof of concept?
Patient group N
Absolute mortality difference OR
95%CI
P value
All 23 trials
7739
2.3%
0.70
( )
<0.0001
PCI vs fibrin-specific lytic
5902
1.7%
0.77
( )
0.009
PCI vs acc tPA
5314
1.6%
0.78
( )
0.019
PCI vs acc tPA, excluding SHOCK
5012
1.2%
0.81
( )
0.07

14. OR 0.81, 95% CI , P=0.07

15. NRMI-2: Primary angioplasty versus thrombolysis Real life registry
Median presentation to alteplase time 42 min
Median presentation to balloon time 111 min
Mortality no different because delay to PCI?
Presentation to alteplase 42 min
Presentation to balloon 111 min
Tiefenbrunn, JACC 1998;31:1240

16. Problem with primary PCI……

17. Reperfusion therapy
Time
is muscle
is survival

18. Thrombolysis: the ‘golden hour’
Absolute reduction in 35 day mortality per 1000 patients treated 20 40 60 80 3 6 9 12 15 18 21 24
Lives saved per 1000 treated patients
Treatment delay (h)
FTT data - closed circles
Smaller trials - open circles
Boersma, Lancet 1996;348:771

19. Time delay from symptom onset to primary PCI: every minute counts60
120
180
240
300
360 2 4 6 8 10 12
6 RCTs of primary PCI by the Zwolle group
(1791 STEMI patients)
One year mortality (%)
Risk of one year mortality increases by 7.5% for each 30 min delay
RR 1.08 for every 30 min delay
95% CI , p<0.0001
Ischaemic time (mins)
De Luca, Circulation 2004;109:1223

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

21. Relationship between time of day and time to reperfusion
67.9% lysis and 54.2% PPCI were treated off hours
STEMI with diagnostic ECG within 6hrs of admission
Regular hours = weekdays 7am to 5pm
67.9% lysis and 54.2% PPCI were treated off hours
NRMI registry
Magid, JAMA 2005;294:803

22. Main cause of delay to treatment

23. Delays to treatment in AMI
TIME
Patient education
Pre-hospital intervention
(lytics, IIbIIIa etc)
Logistics
Interhospital transfer

24. Meta-analysis of 6 trials of pre-hospital thrombolysis (n=6436)
% mortality in-hospital
thrombolysis
% mortality pre-hospital 2 4 6 8 10 12 14
Time from symptoms (SE) to
thrombolysis:
104 (7) min for pre-hospital
162 (16) mins for in-hospital
(Urokinase, anistreplase, t-PA)
For all cause in-hospital mortality
OR % CI
Morrison, JAMA 2000;283:2686

25. Comparison of primary PCI and prehospital thrombolysis in acute MI (CAPTIM n=840)
Events at 30 days
Differences not significant
26% of pre-hospital lysis group underwent PCI
P=0.61
P=0.29
Planned 1200 patients
Symptoms to lysis 130 min
Symptoms to balloon 190 min
Bonnefoy, Lancet 2002;360:825

26. Pre-hospital thrombolysis vs primary PCI French Nationwide USIC 2000 registry (n=1922)
Age-adjusted survival (%)
100
Pre-hospital lysis 94% 95
In-hospital lysis 89% 90
Primary PCI 89% % 85 80
No reperfusion 79%
P<0.0001 75
180
360 days
Danchin et al, Circulation 2004;110:1909

27. Grampion region early anistreplase trial
Delaying thrombolysis by 1 hour results in 43 additional deaths per 1000 lives over 5 years
Years 1 2 3 4 5 60 70 80 90
100
% Survival
Prehospital lysis 75%
In-hospital lysis 64%
Rawles, J Am Coll Cardiol 1997;30:1181

28. Time from symptom onset to treatment in recent trials
Time from symptom onset to treatment (mins)

29. Onset of pain to needle time East Midlands Ambulance Service
Median symptom onset to needle 93 minutes
N=117
EMAS PHT audit 04/05

30. Pre-hospital thrombolysis in the UK (27 of 31 ambulance services participating)
2877 patients treated
Ambulance Service Association and
Joint Royal Colleges Ambulance Liaison committee

31. Dr Curzen liaises with Hampshire Ambulance Service Trust
At July 05 HAST had treated 8 patients with pre-hospital lysis

32. Primary PCI - providing a UK service?
In 2004 there were 3447 STEMI interventions
This morning Peter Ludman estimated number of STEMIs requiring reperfusion at 30000
Provision of nationwide PPCI service is not feasible in the short term!

33. What would you want…? You develop central chest pain….
The paramedic arrives and does an ECG….
The ECG is faxed to the local CCU who confirm evolving anterior myocardial infarction

34. What would you want…?
The local DGH is 30 mins away.…and the door to balloon time is 30 mins
The local PCI unit is 45 mins away…. and the door to balloon time is 90 mins
The paramedic is clutching a syringe of lytic...
The choice is yours!

35. Conclusions
For foreseeable future thrombolysis will remain the default reperfusion strategy in most UK hospitals
Pre-hospital thrombolysis saves lives and is only practical strategy for timely delivery of reperfusion therapy
The NHS should fully implement a national programme of pre-hospital thrombolysis (with rescue PCI as necessary) targeting symptom-onset to drug times less than 120 minutes
Primary PCI programmes are costly, potentially delay treatment, and disturb our sleep!

36. My opponent has a tendency to overestimate size! (and treatment effect)

38. National Infarct Angioplasty Pilot (NIAP)
3 of 6 pilot sites are not running 24/7
At 1 centre median door to balloon times were >90 mins for 5 consecutive months

39. Introduction of Primary PCI at a NIAP centre
…..careful case selection?

40. Comparison of angioplasty and prehospital thrombolysis in acute MI (CAPTIM n=840)
Mortality at 30 days
Time from symptoms to treatment
Cardiogenic shock occurred in 1.3% of patients treated <2hrs and 5.3% of patients treated >2hrs
N=460
N=374
Interaction test HR 4.19, 95%CI , p=0.045
Steg, Circulation 2003;108:2851

41. Meta-analysis in cardiology Hypothesis-generating or definitive research?
Rx for STEMI
Meta-analysis
Definitive trial
iv magnesium
+ve
ISIS-4
iv nitrate
GISSI-3
GIK ?
Primary PCI