EXPERTS WORKSHOP ON EARLY TREATMENT STRATEGIES FOR ACUTE MYOCARDIAL INFARCTION FOR THE MIDDLE EAST COUNTRIES FEBRUARY 26 TH -28 TH 2005 / DUBAI, UAE SPONSORED.
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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
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