CLopidogrel as Adjunctive ReperfusIon TherapY –

Thrombolysis In Myocardial Infarction (TIMI) 28

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.

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 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

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

Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours

StudyDrug

30-day clinical follow-up

Open-labelclopidogrelper MD in

both groups

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 OrganizationTrial Organization

TIMI Study GroupTIMI Study Group Eugene Braunwald, MD Eugene Braunwald, MD Brigham and Women’s HospitalBrigham and Women’s Hospital Christopher P. Cannon, MDChristopher P. Cannon, MDHarvard Medical SchoolHarvard Medical School Marc S. Sabatine, MD, MPHMarc S. Sabatine, MD, MPH

Amy C. McCagg, MBAAmy C. McCagg, MBA

TIMI Angio Core LabTIMI Angio Core Lab C. Michael Gibson, MD, MSC. Michael Gibson, MD, MS

Data Coordinating CenterData Coordinating Center Allan M. Skene, PhDAllan M. Skene, PhDNottingham Clinical ResearchNottingham Clinical Research Karen A. Hill, BSKaren A. Hill, BS

Sponsors:Sponsors:Sanofi-AventisSanofi-Aventis Bernard Job, MDBernard Job, MD

Christophe Gaudin, MDChristophe Gaudin, MD& Bristol-Myers Squibb& Bristol-Myers Squibb Ravinder Saini, MDRavinder Saini, MD

Leigh Townes, BS, RNLeigh Townes, BS, RN

Top Enrolling CountriesTop 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 CentersTop Enrolling Centers

PrincipalPrincipal ResearchResearchHospitalHospital InvestigatorInvestigatorCoordinatorCoordinator

AZ Klina, BelgiumAZ Klina, Belgium F. CoolsF. Cools S. S.

VanhagendorenVanhagendoren

Canisius-Wih. Ziek., NLCanisius-Wih. Ziek., NL D.P. HertzbergerD.P. Hertzberger A. SchutA. Schut

Hosp. de Cabueñes, SpainHosp. de Cabueñes, Spain A. BatallaA. Batalla

Centre Hosp., FranceCentre Hosp., France A. BonneauA. Bonneau L. SoulatL. Soulat

Scarborough Card. Res., CAScarborough Card. Res., CA Kassam/HalperinKassam/Halperin P. ParsonsP. Parsons

Celso da Puccamp, Brazil Celso da Puccamp, Brazil J.F. Kerr Saraiva J.F. Kerr Saraiva C. Travaini C. Travaini

GarciaGarcia

Centre Hospitalier, FranceCentre Hospitalier, France Y. LambertY. Lambert J. M. J. M.

CaussanelCaussanel

Szpital Miejski, PolandSzpital Miejski, Poland J. GesselJ. Gessel L. L.

PawlowiczPawlowicz

St. Petersburg Med Acad, RUSt. Petersburg Med Acad, RU S. BolduevaS. Boldueva

Royal Victoria Hospital, UKRoyal Victoria Hospital, UK J. AdgeyJ. Adgey T. T.

McAllisterMcAllister

Baseline CharacteristicsBaseline Characteristics

CharacteristicCharacteristic ClopidogrelClopidogrel(n=1752)(n=1752)

PlaceboPlacebo(n=1739)(n=1739)

Age Age (yrs(yrsSD)SD) 57 57 10 10 57 57 10 10

Male Male (%)(%) 8080 8181

Hypertension Hypertension (%)(%) 4343 4444

Hyperlipidemia Hyperlipidemia (%)(%) 3232 3333

Current smoker Current smoker (%)(%) 5151 5050

Diabetes Diabetes (%)(%) 1717 1616

Prior MI Prior MI (%)(%) 99 99

Anterior MI Anterior MI (%)(%) 4141 4040

Initial TherapyInitial Therapy

CharacteristicCharacteristic Clopidogrel (%)Clopidogrel (%) Placebo (%)Placebo (%)

Fibrin-specific lyticFibrin-specific lytic 6969 6969

Non-fibrin specific lyticNon-fibrin specific lytic 3131 3131

Initial AspirinInitial Aspirin 9999 9999

UFHUFH 4646 4646

LMWHLMWH 3030 2929

BothBoth 55 55

NeitherNeither 1919 2020

Beta-blockersBeta-blockers 8989 8989

StatinsStatins 8080 8181

ACEI or ARBACEI or ARB 7373 7272

InterventionsInterventions

ParameterParameter ClopidogrelClopidogrel PlaceboPlacebo

Sx onset to fibrinolyticSx onset to fibrinolytic 2.7 2.7 hrshrs 2.6 2.6 hrshrs

Fibrinolytic to study drugFibrinolytic to study drug 10 10 minsmins 10 10 minsmins

Median # doses of study medMedian # doses of study med 44 44

AngiographyAngiography 93.9%93.9% 94.2%94.2%

Study drug to angiographyStudy drug to angiography 3.5 3.5 daysdays 3.5 3.5 daysdays

Coronary revascularizationCoronary revascularization 62.8%62.8% 62.4%62.4%

PCIPCI 57.2%57.2% 56.6%56.6%

CABGCABG 5.9%5.9% 6.0%6.0%

Primary Endpoint:Primary Endpoint:Occluded Artery Occluded Artery (or D/MI thru Angio/HD)(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

(%

)

PlaceboPlaceboClopidogrelClopidogrel

P=0.00000036P=0.00000036P=0.00000036P=0.00000036

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

1.00.4 0.6 0.8 1.2 1.6

ClopidogrelClopidogrelbetterbetter

PlaceboPlacebobetterbetter

n=1752 n=1739

36%Odds Reduction

36%Odds Reduction

ClopidogrelClopidogrel

PlaceboPlacebo

OVERALLOVERALL 3636 15.015.0 21.721.7AgeAge

<65 yr<65 yr 4242 13.213.2 21.021.065 yr65 yr 2222 19.019.0 23.123.1

GenderGenderMaleMale 3535 14.514.5 20.820.8FemaleFemale 3838 16.916.9 24.724.7

Infarct locationInfarct locationAnteriorAnterior 3333 15.015.0 20.720.7Non-anteriorNon-anterior 3838 15.015.0 22.222.2

FibrinolyticFibrinolyticFibrin-specificFibrin-specific 3131 14.714.7 20.120.1Non-fibrin specificNon-fibrin specific 4444 15.715.7 24.924.9

Predominant heparinPredominant heparinLow-molecular-weightLow-molecular-weight 3131 11.411.4 15.715.7UnfractionatedUnfractionated 4242 17.817.8 27.127.1NoneNone 2626 17.117.1 21.921.9

Subgroups – Primary EndpointSubgroups – Primary EndpointOdds Event Rates (%)

Reduction

1.00.4 0.6 0.8 1.2 1.6Clopidogrel betterClopidogrel better Placebo betterPlacebo better

Characteristic Odds Ratio (95% CI)

All interactionsnon-significant

Angiographic Angiographic (%)(%)

TIMI Flow Grade 3TIMI Flow Grade 3 67.867.8 60.860.8 1.361.36 <0.001<0.001

TIMI Myocardial TIMI Myocardial Perfusion 3Perfusion 3

55.855.8 51.251.2 1.211.21 0.0080.008

ThrombusThrombus 43.043.0 50.850.8 0.730.73 <0.001<0.001

Primary & Angiographic Primary & Angiographic Outcomes Outcomes (median 3.5 days)(median 3.5 days)

OutcomeOutcome ClopidogrelClopidogrel PlaceboPlacebo OddsOddsRatioRatio P valueP value

Primary End Point Primary End Point (%)(%) 15.015.0 21.721.7 0.640.64 <0.001<0.001

TIMI Flow Grade 0/1TIMI Flow Grade 0/1 11.711.7 18.418.4 0.590.59 <0.001<0.001

MIMI 2.52.5 3.63.6 0.700.70 0.080.08

Death Death 2.62.6 2.22.2 1.171.17 0.490.49

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 orAdditional Treatment

21% P=0.01

21% P=0.005

16% P=0.07

Early Angio(w/in 48 hrs)

Urgent Revasc(index hosp)

GP IIb/IIIaif PCI

CV Death, MI, RI CV Death, MI, RI Urg Revasc Urg Revasc

days

Per

cen

tag

e w

ith

en

dp

oin

t (%

)P

erce

nta

ge

wit

h e

nd

po

int

(%)

05

1015

0 5 10 15 20 25 30

PlaceboPlacebo

ClopidogrelClopidogrel

Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65-0.97)(95% CI 0.65-0.97)

P=0.026P=0.026

20%20%20%20%

CV Death or MICV Death or MI 1717 8.48.4 9.99.9

StrokeStroke 4646 0.90.9 1.71.7

Recurrent ischemia Recurrent ischemia leading to urgent revascleading to urgent revasc 2424 3.53.5 4.54.5

CV Death, MI, or StrokeCV Death, MI, or Stroke 1818 9.19.1 10.910.9

CV Death, MI, Stroke,CV Death, MI, Stroke,or RI or RI Urg Revasc Urg Revasc 2121 12.312.3 15.015.0

Clinical Endpoints through 30dClinical Endpoints through 30d

OddsOddsReductionReduction

Clopidogrel Clopidogrel betterbetter

PlaceboPlacebobetterbetter

Odds Ratio (95% CI)Odds Ratio (95% CI)

1.00.4 0.6 0.8 1.2 1.6

Event Rates (%)Event Rates (%)ClopidogrelClopidogrel PlaceboPlacebo

BleedingBleeding

OutcomeOutcome Clopidogrel Clopidogrel (%)(%)

Placebo Placebo (%)(%)

P valueP value

Through angiographyThrough angiography

TIMI major TIMI major (Hgb (Hgb >5 g/dL or ICH) >5 g/dL or ICH) 1.31.3 1.11.1 NSNS

TIMI minor TIMI minor (Hgb (Hgb 3-5 g/dL) 3-5 g/dL) 1.01.0 0.50.5 NSNS

Intracranial hemorrhageIntracranial hemorrhage 0.50.5 0.70.7 NSNS

Through 30 daysThrough 30 days

TIMI majorTIMI major 1.91.9 1.71.7 NSNS

In those undergoing CABGIn those undergoing CABG 7.57.5 7.27.2 NSNS

CABG w/in 5 d of study medCABG w/in 5 d of study med 9.19.1 7.97.9 NSNS

TIMI minorTIMI minor 1.61.6 0.90.9 NSNS

SummarySummary

In patients with STEMI In patients with STEMI 75 yrs, receiving a standard 75 yrs, receiving a standard fibrinolytic regimen, a loading dose of 300 mg of fibrinolytic regimen, a loading dose of 300 mg of clopidogrel followed by 75 mg daily resulted in:clopidogrel followed by 75 mg daily resulted in:

• 36% 36% reduction in the odds of an occluded infarct-reduction in the odds of an occluded infarct-related artery, or death/MI by angio (NNT = 16)related artery, or death/MI by angio (NNT = 16)

• Highly consistent benefit across all major subgroupsHighly consistent benefit across all major subgroups

• 20% reduction in CV death, MI, or recurrent ischemia 20% reduction in CV death, MI, or recurrent ischemia leading to urgent revasc through 30 days (NNT = 36)leading to urgent revasc through 30 days (NNT = 36)

• No excess in TIMI major or minor bleeding (including No excess in TIMI major or minor bleeding (including in those undergoing CABG) or in ICHin those undergoing CABG) or in ICH

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 (%

)

TPATPASKSK

Evolution of Pharmacologic Reperfusion

TIMI 1

ASA +ASA +ClopidogrelClopidogrel

ASAASA

NEJM 1985;312:932

APRICOT

PlaceboPlacebo ASAASA

Circ 1993;87:1524

36% P<0.00136% P<0.001

90 mins 3 mos 3.5 d

47% P<0.00147% P<0.001

22% P=0.2622% P=0.26

Clopidogrel offers an effective, Clopidogrel offers an effective, simple, inexpensive, and safe simple, inexpensive, and safe means by which to improve means by which to improve

infarct-related artery patency and infarct-related artery patency and reduce ischemic complications.reduce ischemic complications.

ConclusionConclusion