Transcript CLARITY LBCT FINAL - Clinical Trial Results

CLopidogrel as Adjunctive ReperfusIon TherapY –
Thrombolysis In Myocardial Infarction (TIMI) 28
Disclosure statement: Dr. Sabatine is supported in part by grants (R01
HL072879 and R01 HL072872) from the NHLBI, and receives research grant
support from and serves as a consultant to Bristol-Myers Squibb, SanofiAventis, and AstraZeneca.
Background
Fibrinolytic Rx for STEMI limited by inadequate
reperfusion and/or reocclusion in ~25% of pts.
An occluded infarct-related artery is associated
with a doubling of long-term mortality.
Evidence for the open
artery hypothesis:
TIMI 1
Dalen, Gore, Braunwald et al.
Am J Cardiol 1988; 62:179.
Mortality (%)
20
Occluded
15
10
5
0
Patent
0
8
16
24
Weeks
32
40
48
Clopidogrel
Oral anti-platelet medication that blocks ADP
receptor and works synergistically with aspirin.
Modified from Schafer. Am J Med 1996;101:199–209
Hypothesis
The addition of clopidogrel to standard
fibrinolytic regimens that include aspirin
would:
• Improve infarct-related artery patency
• Decrease ischemic complications
Study Design
Double-blind, randomized, placebo-controlled trial in
3491 patients, age 18-75 yrs with STEMI < 12 hours
Fibrinolytic, ASA, Heparin
randomize
Clopidogrel
300 mg + 75 mg qd
Placebo
Study
Drug
Coronary Angiogram
(2-8 days)
Open-label
clopidogrel
per MD in
both groups
30-day clinical follow-up
Primary endpoint:
Occluded
artery (TIMI Flow
Grade 0/1)
or D/MI by time
of angio
Major Exclusion Criteria
• Clopidogrel within 7 days or planned Rx with
clopidogrel or GP IIb/IIIa before angiography
• Contraindications to lysis (stroke, ICH, brain tumor)
• Cardiogenic shock
• Intention of angiography within 48 hours in absence
of a new clinical indication
• < 67 kg & > 4000 U bolus UFH or
> 67 kg & > 5000 U bolus UFH
Trial Organization
TIMI Study Group
Brigham and Women’s Hospital
Harvard Medical School
Eugene Braunwald, MD
Christopher P. Cannon, MD
Marc S. Sabatine, MD, MPH
Amy C. McCagg, MBA
TIMI Angio Core Lab
C. Michael Gibson, MD, MS
Data Coordinating Center
Allan M. Skene, PhD
Karen A. Hill, BS
Nottingham Clinical Research
Sponsors:
Sanofi-Aventis
& Bristol-Myers Squibb
Bernard Job, MD
Christophe Gaudin, MD
Ravinder Saini, MD
Leigh Townes, BS, RN
Top Enrolling Countries
Spain
J. Lopez-Sendon
364
France
G. Montalescot
265
Canada
P. Theroux
261
Belgium
M. Claeys
242
Russia
M. Ruda
237
Germany
U. Zeymer
211
UK
A. Gershlick & R. Wilcox
205
Israel
B. Lewis
198
Top Enrolling Centers
Hospital
Principal
Investigator
Research
Coordinator
AZ Klina, Belgium
F. Cools
S. Vanhagendoren
Canisius-Wih. Ziek., NL
D.P. Hertzberger
A. Schut
Hosp. de Cabueñes, Spain
A. Batalla
Centre Hosp., France
A. Bonneau
Scarborough Card. Res., CA
Kassam/Halperin P. Parsons
Celso da Puccamp, Brazil
J.F. Kerr Saraiva
C. Travaini Garcia
Centre Hospitalier, France
Y. Lambert
J. M. Caussanel
Szpital Miejski, Poland
J. Gessel
L. Pawlowicz
St. Petersburg Med Acad, RU
S. Boldueva
Royal Victoria Hospital, UK
J. Adgey
L. Soulat
T. McAllister
Baseline Characteristics
Clopidogrel
Placebo
(n=1752)
(n=1739)
57  10
57  10
Male (%)
80
81
Hypertension (%)
43
44
Hyperlipidemia (%)
32
33
Current smoker (%)
51
50
Diabetes (%)
17
16
Prior MI (%)
9
9
Anterior MI (%)
41
40
Characteristic
Age (yrsSD)
Initial Therapy
Characteristic
Clopidogrel (%)
Placebo (%)
Fibrin-specific lytic
69
69
Non-fibrin specific lytic
31
31
Initial Aspirin
99
99
UFH
46
46
LMWH
30
29
Both
5
5
Neither
19
20
Beta-blockers
89
89
Statins
80
81
ACEI or ARB
73
72
Interventions
Parameter
Clopidogrel
Placebo
Sx onset to fibrinolytic
2.7 hrs
2.6 hrs
Fibrinolytic to study drug
10 mins
10 mins
4
4
93.9%
94.2%
Study drug to angiography
3.5 days
3.5 days
Coronary revascularization
62.8%
62.4%
PCI
57.2%
56.6%
CABG
5.9%
6.0%
Median # doses of study med
Angiography
Primary Endpoint:
Occluded Artery or Death/MI (%)
Occluded Artery (or D/MI thru Angio/HD)
25
36%
21.7
Odds Ratio 0.64
(95% CI 0.53-0.76)
Odds Reduction
20
P=0.00000036
15.0
15
10
5
0
n=1752
n=1739
Clopidogrel
Placebo
0.4
0.6
0.8 1.0 1.2
Clopidogrel
better
1.6
Placebo
better
Subgroups – Primary Endpoint
Characteristic
Odds Ratio (95% CI)
Odds
Reduction
OVERALL
Age
<65 yr
65 yr
Gender
Male
Female
Infarct location
Anterior
Non-anterior
Fibrinolytic
Fibrin-specific
Non-fibrin specific
Predominant heparin
Low-molecular-weight
Unfractionated
None
All interactions
non-significant
0.4
0.6
0.8 1.0 1.2
Clopidogrel better
Event Rates (%)
Clopidogrel Placebo
36
15.0
21.7
42
22
13.2
19.0
21.0
23.1
35
38
14.5
16.9
20.8
24.7
33
38
15.0
15.0
20.7
22.2
31
44
14.7
15.7
20.1
24.9
31
42
26
11.4
17.8
17.1
15.7
27.1
21.9
1.6
Placebo better
Primary & Angiographic
Outcomes (median 3.5 days)
Outcome
Clopidogrel Placebo
Odds
P value
Ratio
Primary End Point (%)
15.0
21.7
0.64
<0.001
TIMI Flow Grade 0/1
11.7
18.4
0.59
<0.001
MI
2.5
3.6
0.70
0.08
Death
2.6
2.2
1.17
0.49
TIMI Flow Grade 3
67.8
60.8
1.36
<0.001
TIMI Myocardial
Perfusion 3
55.8
51.2
1.21
0.008
Thrombus
43.0
50.8
0.73
<0.001
Angiographic (%)
Need for Urgent or
Additional Treatment
16% 
P=0.07
35
30
(%)
25
21% 
P=0.01
21% 
P=0.005
15
29.3
Clopidogrel
Placebo
23.3
20
18.6
33.0
19.5
15.4
10
5
0
Early Angio
(w/in 48 hrs)
Urgent Revasc
(index hosp)
GP IIb/IIIa
if PCI
Placebo
10
20%
Clopidogrel
5
Odds Ratio 0.80
(95% CI 0.65-0.97)
P=0.026
0
Percentage with endpoint (%)
15
CV Death, MI, RI  Urg Revasc
0
5
10
15 days 20
25
30
Clinical Endpoints through 30 d
Odds Ratio (95% CI)
Event Rates (%)
Odds
Reduction Clopidogrel Placebo
CV Death or MI
17
8.4
9.9
Stroke
46
0.9
1.7
Recurrent ischemia
leading to urgent revasc
24
3.5
4.5
CV Death, MI, or Stroke
18
9.1
10.9
CV Death, MI, Stroke,
or RI  Urg Revasc
21
12.3
15.0
0.4
0.6
0.8 1.0 1.2
Clopidogrel
better
1.6
Placebo
better
Bleeding
Outcome
Clopidogrel Placebo P value
(%)
(%)
TIMI major (Hgb  >5 g/dL or ICH)
1.3
1.1
NS
TIMI minor (Hgb  3-5 g/dL)
1.0
0.5
NS
Intracranial hemorrhage
0.5
0.7
NS
1.9
1.7
NS
In those undergoing CABG
7.5
7.2
NS
CABG w/in 5 d of study med
9.1
7.9
NS
1.6
0.9
NS
Through angiography
Through 30 days
TIMI major
TIMI minor
Summary
In patients with STEMI  75 yrs, receiving a standard
fibrinolytic regimen, a loading dose of 300 mg of
clopidogrel followed by 75 mg daily resulted in:
• 36% reduction in the odds of an occluded infarctrelated artery, or death/MI by angio (NNT = 16)
• Highly consistent benefit across all major subgroups
• 20% reduction in CV death, MI, or recurrent ischemia
leading to urgent revasc through 30 days (NNT = 36)
• No excess in TIMI major or minor bleeding (including
in those undergoing CABG) or in ICH
Evolution of Pharmacologic
Reperfusion
TIMI 1
90 mins
Occluded Infarct-Related
Artery (%)
60
50
APRICOT
57
3 mos
3.5 d
47% 
P<0.001
22% 
40
P=0.26
30
30
32
36% 
25
20
P<0.001
18.4
10
11.7
0
SK
TPA
NEJM 1985;312:932
Placebo
ASA
Circ 1993;87:1524
ASA
ASA +
Clopidogrel
M A R C H 9, 2 0 0 5
Conclusion
Clopidogrel offers an effective, simple,
inexpensive, and safe means by which to
improve infarct-related artery patency
and reduce ischemic complications.
Sabatine MS, Cannon CP, Gibson CM,
Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ,
Cools F, Hill KA, Skene AM, McCabe CH and Braunwald E
for the CLARITY-TIMI 28 Investigators.
N Engl J Med 2005;352 www.nejm.org.
ACC 2005 LBCT Slide Set available at www.timi.org.