EXPERTS WORKSHOP ON EARLY TREATMENT STRATEGIES FOR ACUTE MYOCARDIAL INFARCTIONFOR THE MIDDLE EAST COUNTRIES

FEBRUARY 26TH -28TH 2005 / DUBAI, UAESPONSORED BY BOEHRINGER INGELHEIM

SUNDAY, 27th 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!”

Cross-sections of left ventricle after experimentalcoronary artery occlusion

(Reimer KA, et al. Circulation. 1977;56:786-794).

“Time is Muscle”

Duration of occlusion 3 h

Area supplied byoccluded artery

xx

xx

xx

xxx

xx

xx

x xx

x

xx

x

XXXX

Necrosis

Ischemic but viable

Non-ischemic

24 h40

min

x xx

x

xx

x

xxx

xx xx

x

xxxx

xxx

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 70-180min

Estim

ated

ben

efit

(live

s sa

ved

at 3

5 da

ys) p

er 1

000

patie

nts

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 2460

20

40

60

80

11%

Delay 1-month benefit30 to 60 min 60 to 80 lives saved

for 1000 patients

1 to 3 hours 30 to 50 lives saved for 1000 patients

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

GI G3 A2 A3 A3+ CAPTIM STIMSAMU

ESTIM IdF

ESTIMNord

1990 1995 2000 2001 2002 2001 1997 2001 2002

3.03 2.50 3.03 3.03 2.35 2.10 2.10 1.59 1.60

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 dose0.53 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+

Symptom - call Call - arrival Arrival - Rand.Rand. - first drug First drug - ER

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

EN

OX

UF

H

ASSENT-3

In-hospital

Symptom – TNK

TNK

TNK

45 min

Thrombolysis or PTCAstill a debate ?

CAPTIM

Comparison of

Angioplasty and

Pre-hospital

Thrombolysis

In acute

Myocardial 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-hospitalthrombolysis

n = 419

PrimaryPCI

n = 421

8.2RR = 0.76

3.8

3.7

1.0

6.2RR = 0.76

4.8

1.7

0.0

P Value

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-hospitalthrombolysis

n = 419

PrimaryPCI

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 distanceup to 95 US miles

(mean 35 miles)100 US miles

DANAMI IIACC 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-3Mortality at 30 days

%

(TNK + ENOX)

ESSAI TOTAL

6.6

4.8

7.6

3.8

5.45.8

0

2

4

6

8

DANAMI-2 CAPTIM ASSENT-3 ASSENT3+

PCI

TT

Pre-HospitalLysis

PrimaryPCI

DeathDeath

CAPTIM 1-Year Results

GW Symposium, AHA 2002

DeathDeath

Pre-HospitalLysis

PrimaryPCI

Sx < 2 hours Sx > 2 hours

P=0.057P=0.057 P=0.47P=0.47

2.2%

5.7%

0%

5% 5.9%

3.7%

0%

10%

Pre-HospitalLysis

PrimaryPCI

P=0.032

Shock Randomization to DC

CAPTIM 1 Year Results

GW Symposium, AHA 2002

P=0.0007

Shock Randomization to Adm

Pre-HospitalLysis

PrimaryPCI

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 PECSMUR

Beginning ofthrombolysis

35 min

66 min Arrival at hospital

84 min

PunctureAccording to ATLS:

32 min

120 min

185 min

E-MUSTComparable 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. lysisno PCI

Pre-hosp.lysis no

PCI

Hosp. lysis+ PCI

Pre-hosp.lysis + PCI

PrimaryPCI

Combined Strategy ofreperfusion

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 cityPre-hospital Thrombolysis

Angiography at 80 min

TIMI 3108 (64%)

TIMI 212 (7%)

TIMI 050 (29%)

angioplasty

TIMI 391%

TIMI 27%

Which Delays for This Technique of Combined Reperfusion

PHT Admission = 58 20 min

Admission Angiography = 59 19 min

Then

2 h after PHTonly 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 minafter TT

64 (49%)TIMI 3

54 (84%)PTCA

65 (50%)TIMI 0 - 2

PTCA

119 (91%) PTCA114 stent

120/131 TIMI 3 (92%)9/131 TIMI 2

2 TIMI 0-1no 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

DeathRelative 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 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

Rescue PCI after Lytics

Death 6 weeksRelative 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

• Pre-hospital thrombolysis is still the gold standard

• Very high risk patients MUST have a PCI with a minimum delay

• Transfer is not an additional risk

Pre-hospital thrombolysis + Angioplasty

Pre-hospital thrombolysis

+ immediate angioplasty

+ stent implantation

is safe and effective

EP. Mc Fadden. Eur. Heart J. 2001 ; 22 : 1067-69