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

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

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

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

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

Thrombosaurus Rex EXTINCTOPLASE ? Courtesy Bob Wilcox

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

Keeley et al, 2003 OR 0.70, 95% CI 0.59-083, P<0.0001

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

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

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 (0.59-0.83) <0.0001 PCI vs fibrin-specific lytic 5902 1.7% 0.77 (0.63-0.94) 0.009 PCI vs acc tPA 5314 1.6% 0.78 (0.64-0.96) 0.019 PCI vs acc tPA, excluding SHOCK 5012 1.2% 0.81 (0.64-1.02) 0.07

OR 0.81, 95% CI 0.64-1.02, P=0.07

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

Problem with primary PCI……

Reperfusion therapy Time is muscle is survival

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

Time delay from symptom onset to primary PCI: every minute counts 60 120 180 240 300 360 2 4 6 8 10 12 6 RCTs of primary PCI by the Zwolle group 1994-2001 (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 1.01-1.16, p<0.0001 Ischaemic time (mins) De Luca, Circulation 2004;109:1223

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=0.006. 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

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 1999-2002 Magid, JAMA 2005;294:803

Main cause of delay to treatment

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

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 0.83 95% CI 0.70-0.98 Morrison, JAMA 2000;283:2686

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

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

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

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

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

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 http://www.asancep.org.uk/thromb%20update%20August05.doc

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

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!

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

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!

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!

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

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

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

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 1.03-17.0, p=0.045 Steg, Circulation 2003;108:2851

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