Primary angioplasty

EXPERTS WORKSHOP ON EARLY TREATMENT STRATEGIES FOR ACUTE MYOCARDIAL INFARCTION FOR THE MIDDLE EAST COUNTRIES FEBRUARY 26 TH -28 TH 2005 / DUBAI, UAE SPONSORED BY BOEHRINGER INGELHEIM SUNDAY, 27 th FEBRUARY – SESSION 2 A rationale for pre-hospital thrombolytic therapy Patrick Goldstein

Fire !

Your house is on fire...

The Fire Spreads Quickly

Every second is crucial, the damage is getting worse

Transportation !?

You are watching the firemen loading the burning stuff...

To Extinguish the Fire !

” Time is muscle and life!”

“ Time is Muscle” Cross-sections of left ventricle after experimental coronary artery occlusion (Reimer KA, et al. Circulation. 1977;56:786-794). Duration of occlusion 3 h Area supplied by occluded artery x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x XXXX Necrosis Ischemic but viable Non-ischemic 24 h 40 min

Acute MI again? Why?

 It is serious

 It’s desperately urgent

 We must act efficiently, in order to significantly reduce mortality before arrival at the hospital

 The diagnosis is clinical

 The strategy and the therapeutic management are in constant movement

“ Time is muscle” MITI 4.9 11.2 14 12 10 8 6 4 2 0 Infarct Size (%) < 70 min 70-180 min

Estimated benefit (lives saved at 35 days) per 1000 patients Time from onset (hours) Mortality Reduction Depends on the Delay “Onset of Pain - Thrombolytic Treatment” Eric Boersma’s meta-analysis (22 trials from 83 to 93 - 50 246 patients) BOERSMA, E. et al Early thrombolytic in acute myocardial treatment infarction : reappraisal of the golden hour - Lancet 1996 ; 771 - 775 0 12 18 24 6 0 20 40 60 80 11% 30 to 50 lives saved for 1000 patients 1 to 3 hours 60 to 80 lives saved for 1000 patients 30 to 60 min 1- month benefit Delay

Morrison’s Meta-analysis

OBJECTIVE

To realize a meta-analysis of randomized trials exploring mortality in pre-hospital vs in-hospital thrombolysed AMI

INCLUDED STUDIES

6 studies (n = 6 434)

RESULTS

Delay pain to treatment : Pre-hospital thrombolysis = 104 min In-hospital thrombolysis = 162 min (diff = 58 min) (p=0.007)

Significant reduction of the in-hospital death rate (all causes) with pre-hospital thrombolysis : (- 17%) (OR 0.83; 95% CI, 0.70-0.98).

JAMA, May 2000 - Vol 283 - N ° 20 - 2686-92

Delay pain – treatment French experience 1.60 1.59 2.10 2.10 2.35 3.03 3.03 2.50 3.03 2002 2001 1997 2001 2002 2001 2000 1995 1990 ESTIM Nord ESTIM IdF STIM SAMU CAPTIM A3+ A3 A2 G3 GI

Material and Drugs of the SMUR

Diagnostics:

ECG

Mini laboratory

Therapeutics:

fibrinolytic

heparin

anti GP IIb/IIIa

aspirin

nitroglycerine

morphine

defibrillator

electric syringe

oxygen

and more

Monitoring :

Scope Sao2

ASSENT-3 Plus (Pre-hospital Treatment) Early treatment (ambulance-car) of AMI patients <6 hrs ASA RANDOMIZATION 1:1 TNK-tPA full dose 0.53 mg/kg bolus Unfractionated heparin 60 IU/kg bolus (max. 4000 IU) 12 IU/kg/hr infusion (max 1000 IU/ hr) target aPTT 50-70 sec Patients’ outcome will be compared with matched pairs extracted from the corresponding arm of the ASSENT-3 main study. The same exploratory endpoints (single and composite) as in the ASSENT-3 main study will be evaluated; the influence of time to treatment will be analyzed. (500) TNK-tPA full dose 0.53 mg/kg bolus Enoxaparin 30 mg i.v. bolus 1 mg/kg s.c. twice a day (500)

Hours to treatment (median) 3+ 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 ENOX UFH TNK TNK Symptom - call Call - arrival Arrival - Rand. Rand. - first drug First drug - ER ASSENT-3 In-hospital Symptom – TNK 45 min

Thrombolysis or PTCA still a debate ?

CAPTIM

C omparison of

A ngioplasty and

P re-hospital

T hrombolysis

I n acute

M yocardial infarction

ESC 2001

M I C U - SMUR

CAPTIM Design ST segment  onset of pain < 6 h All received ASA + Heparin Central randomisation In-hospital Pre-hospital PCI thrombolysis Diagnosis positive in 95%

Primary

Composite (30 day)  all-cause mortality

 recurrent MI

 disabling stroke

Secondary

Cardiovascular death

New onset of angina

Urgent angioplasty

Cardiogenic shock

Hemorrhagic stoke

Severe hemorrhage

CAPTIM - Clinical Endpoints

Primary endpoint %

Death (%)

Reinfarction (%)

Disabling stroke (%)

CAPTIM - Results primary endpoint Pre-hospital thrombolysis n = 419 Primary PCI n = 421 P Value 8.2 RR = 0.76 3.8 3.7 1.0 6.2 RR = 0.76 4.8 1.7 0.0 0.29 0.60 0.13 0.12

Cardiovascular death (%)

New onset of angina (%)

Urgent angioplasty (%)

Cardiogenic shock (%)

Hemorrhagic stoke (%)

Severe hemorrhage (%)

CAPTIM - secondary endpoints Pre-hospital thrombolysis n = 419 Primary PCI n = 421 P Value 3.8 7.2 33.0 2.5 0.5 0.5 4.3 4.0 4.0 4.9 0.0 2.0 0.86 0.09 < 0.01 0.09 0.49 0.06

DANAMI-2 DENMARK 5.4 mill. inhabitants 5 PCI centers 24 referral hospitals 62% of Danish population Transport distance up to 95 US miles (mean 35 miles) 100 US miles

DANAMI II ACC 2002

5 PCI centers + 22 referring hospitals

distance average = 56 km

1129 patients 443 patients

referring hospitals PCI centers

no transfer ambulance PCI fibrinolysis

transfer on site

fibrinolysis

Very high risk patients: ST > 4 mm

Comparaison CAPTIM / DANAMI II

Thrombolysis PCI p

CAPTIM 8.2 % 6.2 % 0.29

DANAMI II combined 13.7 % 8.0 % 0.003

DANAMI II referring 14.2 % 8.5 %

DANAMI II invasive 12.3 % 6.7 % 0.048

Combined Death, ReMI and stroke

CAPTIM DANAMI II combined

PHT PCI thrombolysis PCI

Death 3.8 % 4.8 % 7.6 % 6.6 %

Disabling 1.0 % 0.0 % 2.0 % 1.1 % stroke

Reinfarction 3.7 % 1.7 % 6.3 % 1.6 %

Look at the single endpoints: 30 days

Preventing Reinfarction : IIb/IIIa Inhibitors, Enoxaparin, or Primary PCI PRAGUE-2 30-day deaths 6.8 v 10.0 % , p = 0.12 * 6-month data in press, Simes AHU 2002 ** Pre-hospital administration p < 0.05 reMI, death (PCAT only) ; stroke (PCAT only) CAPTIM 840 PCI t - PA** DANAMI - 2 1.572 PCI t - PA C - PORT* 451 PCI t - PA PCAT* 2.725 PCI lytic Death 4.6% 3.7% 6.6% 7.6% 6.2% 7.1% 6.2% 8.2% ReMI 1.7% 3.7% 1.6% 6.3% 5.3% 10.6% 4.8% 9.8% Stoke 0 1.0% 1.1% 2.0% 2.2% 4.0% 0.7% 1.9%

DANAMI-2 vs CAPTIM vs ASSENT-3 Mortality at 30 days % (TNK + ENOX) ESSAI TOTAL 6.6 4.8 7.6 3.8 5.4 5.8 0 2 4 6 8 DANAMI-2 CAPTIM ASSENT-3 ASSENT3+ PCI TT

CAPTIM 1-Year Results Pre-Hospital Lysis Primary PCI Death GW Symposium, AHA 2002 Death Pre-Hospital Lysis Primary PCI Sx < 2 hours Sx > 2 hours P=0.057 P=0.47 2.2% 5.7% 0% 5% 5.9% 3.7% 0% 10%

CAPTIM 1 Year Results Pre-Hospital Lysis Primary PCI P=0.032 Shock Randomization to DC GW Symposium, AHA 2002 P=0.0007 Shock Randomization to Adm Pre-Hospital Lysis Primary PCI Sx < 2 hours Sx < 2 hours 1.3% 5.3% 0% 5% 0.0% 3.6% 0%

All presented periods are median Beginning of pain 65 min Emergency call at SAMU 19 min PEC SMUR Beginning of thrombolysis 35 min 66 min Arrival at hospital 84 min Puncture According to ATLS: 32 min 120 min 185 min E-MUST Comparable periods

The Lille Experience 4h55 3h 3h 1h49 1h42 0 1 2 3 4 5 6 Thr. pre-hosp. Thr. pre-hosp. + angioplasty Thr. hosp. Thr. hosp.+ angioplasty Angioplasty

USIC 2000

French nationwide survey designed as a multicenter, prospective longitudinal study over one month

Aim: to assess current practices and clinical outcome in patients admitted to an ICU for AMI in France

Organisation :

in-hospital outcome

one-year follow-up

One-month Mortality in Patients with Reperfusion Therapy: USIC 2000 n = 428 370 108 47 % 41 % 12 % 7.9 7.8 4.6 0 1 2 3 4 5 6 7 8 9 Primary PTCA IV lysis Lysis + PTCA

USIC 2000: One-month Mortality in Patients with Reperfusion Therapy n = 370 108 428 41% 12% 47% 7.1 9.6 3.0 5.8 3.6 7.9 0 2 4 6 8 10 12 Hosp. lysis no PCI Pre-hosp. lysis no PCI Hosp. lysis + PCI Pre-hosp. lysis + PCI Primary PCI

Combined Strategy of reperfusion

The Combined Strategies of Reperfusion J.M. Julliard : A matched comparison of the combination of prehospital thrombolysis and stand bye rescue angioplasty with primary angioplasty. Am.J. Cardiol. 1999 ; 83 - 305-310. 170 patients in Paris city Pre-hospital Thrombolysis Angiography at 80 min TIMI 3 108 (64%) TIMI 2 12 (7%) TIMI 0 50 (29%) angioplasty TIMI 3 91% TIMI 2 7%

Which Delays for This Technique of Combined Reperfusion

PHT Admission = 58  20 min

Admission Angiography = 59  19 min

Then

2 h after PHT only 2% of patients are TIMI O or 1

Outcome after Combined Reperfusion Therapy for AMI, Combining Pre-hospital Thrombolysis with Immediate PTCA and Stent

1995-1999 1010 patients with AMI (Paris Sud Cardiovascular Institute) 148 patients with pre-hospital full-dose thrombolytic therapy 131 patients included (median time = 2 h after onset of pain ) C. Loubeyre and all. Eur. Heart J. 2001 ; 22 : 1128-1135

131 patients Angiography 95 min after TT 64 (49%) TIMI 3 54 (84%) PTCA 65 (50%) TIMI 0 - 2 PTCA 119 (91%) PTCA 114 stent 120/131 TIMI 3 (92%) 9/131 TIMI 2 2 TIMI 0-1 no emergency surgery From C. Loubeyre

Long-term follow-up

2  1 year

mortality rate : 6% (8 patients)

non-fatal re MI : 2 patients

survival + no RI rate

= 90%

94 patients (70%) symptom free

- no re-hospitalization

- no revascularization

C. Loubeyre. Eur. Heart J. 2001 ; 22 : 1128-1135

Early PCI versus Guided PCI after Lytics in the Modern Era Death Relative risk, fixed model Bilateral CI, 95% for trials, 95% for MA SIAM III 0.44 [0.14;1.37] GRACIA-1 0.57 [0.26;1.26] CAPITAL-AMI 0.67 [0.11;3.89] Total 0.54 [0.29;0.99] 0.047 Cochran Q het. p=0.91 Rel. Risk 0 1 2 3 4 0.538, p=0.047 RR CI p

Rescue PCI after Lytics RESCUE 0.53 [0.16;1.75] REACT 0.51 [0.24;1.10] MERLIN 1.14 [0.59;2.20] LIMI 0.84 [0.27;2.65] Belenkie et al 0.19 [0.02;1.47] Total 0.73 [0.48;1.11] 0.138 Cochran Q het. P=0.33 Death 6 weeks Relative risk, fixed model Bilateral CI, 95% for trials, 95% for MA Rel. Risk 0.4 1.0 1.6 2.2 RR CI p

Conclusion