ICH in Major AMI Trials

1
ICH in Major AMI Trials
1.5
p 0.004
p NS
p NS
1.12
of Patients
0.94
0.93
0.91
1
0.87
p NS
0.64
0.62
0.59
0.5
Abx ? r-PA
t-PA
r-PA
t-PA
TNK
r-PA
n-PA
t-PA
0
GUSTO III
ASSENT II
GUSTO V
InTIME II
2
GUSTO V - ICH
Odds ratio (95CI) of combo therapy on risk of
ICH based on logistic regression model
6- 5- 4- 3- 2- 1- - 0-
Higher risk with combo
Lower risk with combo
30 40 50 60
70 80 90 yrs
Courtesy of Savonitto on behalf of GUSTO V
Invest., ESC Berlin 2002
3
Age/treatment interaction on ICH in the GUSTO V
logistic regression model
Odds ratio and 95 CI
4- 3- 2- 1- 0-
P0.03 for interaction
Higher risk with combo
P0.26
P0.06
Lower risk with combo
Age gt75 yr rPA 12/1088 combo 24/1149
Age lt75 yr rPA 37/7172 combo 28/7179
Courtesy of Savonitto on behalf of GUSTO V
Invest., ESC Berlin 2002
4
Calculating 95 confidence intervals for one
proportion
P 1.96 x V P x 1-P N
1.27
ICH in patients gt75 yrs combotherapy in GUSTO V
0.021 1.96 x V 0.021 x 0.979 1149
2.1 0.83
2.93
0.1
ICH in pazientsgt75 yrs enoxaparin in ASSENT III
0.017 1.96 x V 0.017 x 0.983 263
1.7 1.6
3.3
Courtesy of Savonitto on behalf of GUSTO V
Invest., ESC Berlin 2002
5
Abciximab half dose lytics metaanalysis from
Verheugt and Brouwer
intracranial hemorrhage
LA ()
L ()
GUSTO-5
0.6
0.6
ASSENT-3
0.9
0.9
.
SPEED
0.5
0.9
.
TIMI-14
1.7
1.8
ENTIRE
1.3
0.4
TOTAL
0.7
0.7
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
lytic alone better
half lytic/abciximab better
heterogeneity test p ns
Berlin ESC 2002
6
Statistical Plan
Sample Size 1800 Pts
60 Recruiting Centers
25-30 Cath Labs
Recruiting Time 1 Year (30 Pts/Year/Center)
ELECTIVE PCI
RESCUE PCI
Expected Primary EndPoints Rate Death
6 Re-IMA 0.5 Recurrent Ischemia
0.5 Cumulative 7.0
Expected Primary EndPoints Rate Death
9 Re-IMA 2 Recurrent Ischemia 2 Cumulative
12
95 power to test two-sided type 1 error of 0.05
7
MITRA 1994-97 54 hospitals MIR 1996-98 217
hospitals
21092 Q-wave AMI
10166 (48) no reperfusion
10926 (52) reperfusion
4057 (19) unjustified
6109 (29) contraindication
RR 30-day death 1.54
8
The MITRA-MIR Registry
Consecutive patients without contraindications
thrombolysis with lt 12 hrs AMI
Hospital Mortality
16.4
13.4
8.7
9.3
6.9
6.4
P lt 0.002
P lt 0.02
P lt 0.001
Posterior Anterior Previous MI
PCI (n 1327)
Thrombolysis (n 8579)
From Zahn et al , JACC 2001
9
GUSTO V feed back how mortality changes with
regard to different prognostic factors
Age
Younger
2.4
Elder
20.5
gt75
Systolic Press. (mmHg)
lt100
30.1
gt100
7.9
Killip Class
I II
513.5
III IV
32-58
Heart Rate (beats/min)
lt100
7 9
gt100
17
Prior MI
Yes
12
No
6
Diabetes
Yes
11
No
6
10
Study Setting
N 60-70
N 30
Interventional Unit
lt 180 min
Primary CCU
Avg door-to-needlelt 60 min gt100 STEMI/Year
24 hrs/day 7days/week Availability of Senior PTCA
operatordedicated personnel Door-to-Balloon lt
60 min Hospital experience gt 50 primary PTCA/year
11
30-days events in the CAPTIM Study
Pre-hospital thrombolysis (n419)
Primary PCI (n421)
P0.60
P0.13
P0.12
P0.29
8.2
6.2
4.8
3.7
3.8
1.7
1
0
death re-IMA disabling combined
Stroke end-point
34 urgent PCI
From Touboul et al ESC 2001
12
?Why another trial of facilitated PTCA?
Objection!

• With so many other trials addessing the same
  issue sponsored by major Companies CARESS is a
  duplicate that will not recruit enough centers
  and patients
• .. Wrong, CARESS has a unique design and
  evaluates a strategy more than a pharmacologic
  treatment

13
Study Design
PI S. Nissen
Acute MI patients with ST Elevation or New LBBB,
lt 6 hours of pain to qualifying ECG (N 3000)
cath lab availability gt 60 min
Randomize
Primary PCI
Reteplase/abciximabfacilitated PCI
Abciximab facilitated PCI
ASA, unfractionated heparin 40U/kg (max 3000u)
or enoxaparin (0.5 mg/kg IV 0.3 mg/kg SC)
substudy only
Abciximab bolus
Abciximab bolus
Reteplase 5U X2 (X1 if gt75)
Transfer to catheterization lab for angiography
Abciximab bolus
Primary PCI, with abciximab infusion
Primary endpoint at 90 days all-cause mortality,
resuscitated VF occurring gt 48H, cardiogenic
shock, or readmission/ED visit for HF
14
ADVANCE-AMI
PI E. Braunwald
ST? AMI (n 6,000)
PCI
Primary endpoint - 30 day death or heart failure
15
PI v/d Werf
ASSENT 4 - PCI
4000 pts ST?gt 6mm gt 70 Kg if gt70 yrs PCI not
possible within 60 min
Aspirin -UHF
Aspirin -TNK-enoxaparine
PCI (no IIb/IIIa)
PCI (IIb/IIIa if needed)
90 day Death, heart failure, shock at 90 days
v/d Werf , ESC 2002
16
PI Fernandez-Aviles
GRACIA-II trialN 200
PRIMARY
FACILITATED
AMI / ST(lt12 hours)
lt 180 min
Immediately
RANDOMIZATION
TNK Enoxaparin
DIRECT PTCA IRA (stent / abciximab)
3 12 hours
ADEQUATE REVASCULARIZATION(stent / CABG)
Infarct size (CK-MB TnT) ST Resolution LVEF,
LV volume, Wall motion index (6 weeks) Death /
re-AMI / revasc (6 months)
17
CARESS IN AMI
Secondary end-points

• to compare 1-year composite end-point of
  death, reinfarction, refractory ischemia,
  hospital readmission because of heart failure
• to compare overall 1 year hospital resource use,
  including hospital admissions for heart failure
  and new revascularization procedures
• to compare in-hospital stroke and bleeding
  complications.

18
CARESS IN AMI
Average 100 ST Elevation AMI/Center/Year 60-80
non eligible or non randomized 20-40 pts
enrolled/year 1800/30 60 Centers or MICU
(20-30 Interven. Lab) Italy-Bolognese-ANMCO/Germ
any-Zahn-ALKK/France-Maillard/Steg-STENTIM 2
(1/3,1/3,1/3 ) 6-9 Mths Start-Up 1 Year
Enrollment 1 Year Follow-Up 6-9 Mths
Analysis/Study report