background fibrinolytic rx in stemi is limited by inadequate reperfusion and/or reocclusion in ~25%...

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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 48 0 5 10 15 20 Occluded Patent Weeks Mortality (%) Dalen, Gore, Braunwald et al. Am J Cardiol 1988;62:179. Evidence for the open artery hypothesis: TIMI 1

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Page 1: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 2: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

Clopidogrel

Oral antiplatelet medication that blocks ADP receptor and works synergistically with aspirin

Modified from Schafer. Am J Med 1996;101:199-209.

Page 3: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 4: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 5: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 6: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 7: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 8: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 9: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 10: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 11: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 12: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 13: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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.

Page 14: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 15: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 16: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 17: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 18: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 19: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 20: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 21: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 22: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 23: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 24: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 25: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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%

Page 26: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 27: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 28: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 29: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

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

Page 30: Background Fibrinolytic Rx in STEMI is limited by inadequate reperfusion and/or reocclusion in ~25% of pts. An occluded infarct-related artery is associated

www.theheart.orgAccessed 3/20/2005