background fibrinolytic rx in stemi is limited by inadequate reperfusion and/or reocclusion in ~25%...
TRANSCRIPT
Background
Fibrinolytic Rx in STEMI is 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.
0 8 16 24 32 40 480
5
10
15
20
Occluded
Patent
Weeks
Mo
rtal
ity
(%)
Dalen, Gore, Braunwald et al.Am J Cardiol 1988;62:179.
Evidence for the open artery hypothesis:
TIMI 1
Clopidogrel
Oral antiplatelet medication that blocks ADP receptor and works synergistically with aspirin
Modified from Schafer. Am J Med 1996;101:199-209.
Study Design of CLARITY TrialDouble-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 years with STEMI < 12 hours
Fibrinolytic, ASA, heparin
Clopidogrel300 mg + 75 mg qd
Coronary angiogram(2-8 days)
Primary endpoint:Occludedartery (TIMI Flow Grade 0/1)or D/MI by timeof angio
randomize
Placebo Studydrug
30-day clinical follow-up
Open-labelclopidogrelper MD in
both groups
As presented by Dr Marc Sabatine to ACC 2005
Sabatine et al. N Engl J Med 2005;352:1179-1189.
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%
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Interventions
Parameter Clopidogrel Placebo
Sx onset to fibrinolytic 2.7 hrs 2.6 hrs
Fibrinolytic to study drug 10 mins 10 mins
Median # doses of study med 4 4
Angiography 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%
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Primary Endpoint:Occluded Artery (or D/MI thru Angio/HD)
15.0
21.7
0
5
10
15
20
25
Occ
lud
ed A
rter
y o
r D
eath
/MI
(%
)
PlaceboClopidogrel
P=0.00000036P=0.00000036
Odds ratio 0.64(95% CI 0.53-0.76)
Odds ratio 0.64(95% CI 0.53-0.76)
1.00.4 0.6 0.8 1.2 1.6
Clopidogrelbetter
Placebobetter
n=1752 n=1739
36%Odds reduction
36%Odds reduction
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Subgroups – Primary Endpoint
1.00.4 0.6 0.8 1.2 1.6Clopidogrel better Placebo better
Characteristic Odds ratio (95% CI)
All interactionsnon-significant
OddsOdds Event rates (%)Event rates (%)reductionreduction Clopidogrel
Placebo
OVERALL 36% 15.0 21.7Age
<65 yr 42% 13.2 21.065 yr 22% 19.0 23.1
GenderMale 35% 14.5 20.8Female 38% 16.9 24.7
Infarct locationAnterior 33% 15.0 20.7Non-anterior 38% 15.0 22.2
FibrinolyticFibrin-specific 31% 14.7 20.1Non-fibrin specific 44% 15.7 24.9
Predominant heparinLow-molecular-weight 31% 11.4 15.7Unfractionated 42% 17.8 27.1None 26% 17.1 21.9
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Primary & Angiographic Outcomes (median 3.5 days)
Outcome Clopidogrel Placebo Oddsratio P value
Primary Endpoint 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
Angiographic Outcome
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
Sabatine et al. N Engl J Med 2005;352:1179-1189.
15.4
18.6 19.5
23.3
29.3
33.0
0
5
10
15
20
25
30
35
(%)
Clopidogrel
Placebo
Need for Urgent or Additional Treatment
Early Angio(< 48 hrs)
Urgent Revasc(index hosp)
GP IIb/IIIaif PCI
21% P=0.01
21% P=0.005
16% P=0.07
Sabatine et al. N Engl J Med 2005;352:1179-1189.
CV Death, MI, RI Urg Revasc
Days
Per
cen
t w
ith
en
dp
oin
t
05
1015
0 5 10 15 20 25 30
Placebo
Clopidogrel
Odds ratio 0.80(95% CI 0.65-0.97)
P=0.026
20%20%
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Oddsreduction
Clopidogrel better
Placebobetter
Odds ratio (95% CI)
1.00.4 0.6 0.8 1.2 1.6
Event rates (%)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 urgent revasc 21% 12.3 15.0
Clinical Endpoints Through 30 Days
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Bleeding
Outcome Clopidogrel (%)
Placebo (%) P value
Through angiography
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
Through 30 days
TIMI major 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
TIMI minor 1.6 0.9 NS
Sabatine et al. N Engl J Med 2005;352:1179-1189.
Summary
In patients with STEMI 75 years, 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 infarct-related artery or death / MI by time of 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 of TIMI major or minor bleeding (including in those undergoing CABG) or of ICH
Sabatine et al. N Engl J Med 2005;352:1179-1189.
57
30 32
25
18.4
11.7
0
10
20
30
40
50
60
Occ
lud
ed I
nfa
rct-
Rel
ated
A
rter
y (%
)
TPASK
Evolution of Pharmacologic Reperfusion
TIMI 1
ASA +Clopidogrel
ASA
N Engl J Med 1985;312:932
APRICOT
Placebo ASA
Circulation 1993;87:1524
36% P<0.00136%
P<0.001
47% P<0.00147%
P<0.001
22% P=0.2622% P=0.26
90 mins 3 mos 3.5 d
Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve infarct-related artery patency and reduce ischemic complications in STEMI patients receiving aspirin and standard fibrinolytic therapy.
Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E for the CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-1189.
ACC 2005 LBCT Slide Set available at www.timi.org.
Conclusion
M A R C H 9, 2 0 0 5
To determine whether, following admission for acute MI, the addition of clopidogrel to aspirin (& early metoprolol) can produce a further reduction in either
the composite endpoint of in-hospital death, MI, or stroke; or
mortality alone
COMMIT / CCS-2(ClopidOgrel and Metoprolol in Myocardial Infarction Trial)
As presented by Dr Zhengming Chen to ACC 2005
COMMIT: Study Design
Treatment Clopidogrel 75 mg daily vs placebo (aspirin 162 mg daily in both groups)
Inclusion Suspected acute MI (ST change or LBBB) within 24 h of symptom onset
Exclusion Primary PCI or high risk of bleeding
1 Outcomes Death & death, re-MI, or stroke up to 4 weeks in hospital (or prior discharge)
Mean treatment + follow-up = 16 days
As presented by Dr Zhengming Chen to ACC 2005
Characteristic Clopidogrel Placebo (n=22,960) (n=22,891)
Age 70+ years 26.0% 26.0%
Female 27.7% 27.9%
Time delay <6 h 33.8% 33.7%
STEMI / LBBB 93.1% 93.1%
Killip class II/III 24.1% 24.0%
Fibrinolytic: All patients 49.7% 49.8%
STEMI <12h 67.8% 67.7%
COMMIT: Baseline Characteristics
As presented by Dr Zhengming Chen to ACC 2005
Therapy Clopidogrel Placebo (n=22,958) (n=22,891)
Anticoagulants 74.1% 75.0%
ACE inhibitors 68.2% 68.3%
Anti-arrhythmics 22.4% 22.2%
Nitrates 94.1% 94.3%
Diuretics 23.3% 23.3%
Calcium antagonists 11.8% 11.8%
COMMIT: Concomitant Therapy
As presented by Dr Zhengming Chen to ACC 2005
COMMIT: Effects of Clopidogrel on Death, Re-MI, or Stroke
Days since randomization (up to 28 days)
Ev
ent
(%)
9% (SE3) relative risk
reduction (2P=0.002)
Placebo + ASA: 2311 events (10.1%)
Clopidogrel + ASA:2125 events (9.3%)
As presented by Dr Zhengming Chen to ACC 2005
COMMIT: Effect of Clopidogrel on Death in Hospital
De
ad
(%
)Placebo + ASA: 1846 deaths (8.1%)
Clopidogrel + ASA:1728 deaths (7.5%)
7% (SE3) relative riskreduction (2P=0.03)
Days since randomization (up to 28 days)
As presented by Dr Zhengming Chen to ACC 2005
COMMIT: Effects of CLOPIDOGREL on Death, Re-MI, or Stroke by Day of Event
Clopidogrel Placebo Odds ratio & 95% CIClopid. better Placebo better
Day of event(22,958) (22,891)
0 463 523(2.0%) (2.3%)
1 486 527(2.1%) (2.3%)
2-3 449 451(2.0%) (2.0%)
4-7 432 463(1.9%) (2.0%)
8-28 295 347(1.3%) (1.5%)
ALL 2125 2311(9.3%) (10.1%)9% SE 3
(2P = 0.002)
0.4 0.6 0.8 1.0 1.2 1.4 1.6
As presented by Dr Zhengming Chen to ACC 2005
Clopidogrel Placebo Type (n=22,958) (n=22,891)
CerebralFatal 39 40Non-fatal 16 15
Non-cerebralFatal 36 37Non-fatal 46 36
Any major bleed 134 124 (0.58%) (0.54%)
COMMIT: Major Bleed in Hospital
As presented by Dr Zhengming Chen to ACC 2005
COMMIT / CCS-2: Conclusions
Adding 75 mg daily clopidogrel to aspirin in acute MI prevents ~10 major vascular events per 1000 treated
No excess of cerebral, fatal, or transfused bleeds (even with fibrinolytic therapy and in older people)
Treating each million MI patients for ~2 weeks would avoid 5000 deaths and 5000 non-fatal events
As presented by Dr Zhengming Chen to ACC 2005
Milestones in the Evolution of Thrombolysis in Myocardial Infarction
Year Trial Agent Mortality
1988 ISIS-2 SK 25% ASA 23%
1993 GUSTO-1 TPA 14%
2005 COMMIT / CCS-2
Clopidogrel 7%
Double-bolus TPA Bivalirudin
TNK Hirudin
rPA Pexulizamab
nPA Magnesium
GP IIb/IIIa inhibition + lytic Adenosine
Oral GP IIb/IIIa inhibitors PSGL
GIK
etc…
Drugs that Have Failed to Show Mortality Reduction in STEMI in Past Decade
ST-Elevation MI: Clopidogrel Trials
COMMIT / CCS-2
46,000 patientsMortality, D / MI / CVAAMI < 24 hrsAge up to 100 ~ 50% lyticNo loading dose ChinaNon-invasive strategy
3,500 PatientsInfarct artery patencyAMI < 12 hrsAge < 75 100% fibrinolyticLoading dose Europe / N. AmericaInvasive strategy
Special Considerations for Clinical Use
Bolus vs no bolus Benefit on clinical endpoints emerged in first 24 hrs
in both trials CLARITY-TIMI 28: 20% benefit COMMIT / CCS-2: 9% benefit
(~13% in patients <12 hrs)
Elderly: evidence for benefit in COMMIT In patients > 75 years: no loading dose In patients < 75 years: 300 mg loading dose
Worldwide public health benefit: 1 month ~$100 vs TPA $2,200
No excess major bleeding in CABG
Clopidogrel in STEMI
Evidence from 2 large trials in ~50,000 patients
Benefit in opening infarct-related artery and in reducing mortality and morbidity
No excess of major bleeding
Low cost
A new addition to the treatment of STEMI
www.theheart.orgAccessed 3/20/2005