Post on 16-Dec-2015
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