Post on 07-Aug-2020
Nouveaux antithrombotiques dans les SCA
Quel traitement pour quel malade ? Quel
rapport efficacité/risque hémorragique ?
Philippe Gabriel Steg Département de Cardiologie
Hôpital Bichat – Claude Bernard, AP-HP
Université Paris Diderot
INSERM U-698
Paris, France
2
Ph. Gabriel Steg - Disclosures
• Research grant: Servier
• Speaking or consulting: Amgen, Astellas,
AstraZeneca,Bayer, Boehringer Ingelheim, BMS,
Daiichi-Sankyo-Lilly, Eisai, GSK, Merck, Pfizer, Roche,
sanofi-aventis, Servier, The Medicines Company
• Stockholding: Aterovax
Antithrombotiques dans les SCA
• C’est compliqué
Treatment of ACS is a jungle !
Antiplatelet RxASAClopidogrelPrasugrel? TicagrelorGpIIb/IIIa IV blockers? Cangrelor? TRA
Anticoagulant RxUFHEnoxaparinBivalirudinFondaparinuxWarfarin? Anti X? Anti II
RevascularizationPCIStents (BMS/DES)CABG
Bleeding riskComorbidities
Risk of thrombotic event
Patient
Timing
Antithrombotiques dans les SCA
• C’est compliqué
• Les essais cliniques nous donnent quelques
informations
TRITON-TIMI38 Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
Median duration of therapy - 12 months
N= 13,600
Planned PCI for :Mod-High Risk UA/NSTEMI (TRS > 3)STEMI: < 14 days (ischemia or Rx strategy)STEMI: Primary PCI
KnownAnatomy
Clopidogrel (N=6795)
%
Prasugrel (N=6813)%
PCI / CABG 99 / 1 99 / 1
Any Stent 95 94
BMS 47 48
DES 47 47
Multivessel PCI 14 14
UFH / LMWH / Bival 65 / 8 / 3 66 / 9 / 3
GP IIb/IIIa 55 54
LD of Study RxPre PCIDuring PCIPost PCI
25741
26731
Index Procedure
Components of Endpoint
Clopidogrel HRPrasugrel
12.1 0.819.9
2.4 0.892.1
9.5 0.767.3
1.0 1.021.0Nonfatal Stroke
Nonfatal MI
CV Death
CV Death, MI, Stroke
0.5 1 2Prasugrel Better Clopidogrel Better
All Cause Mortality 3.2 0.953.0
HR
Se méfier des analyses en sous-groupe
• La valeur du « p » dans un sous groupe importe
peu
– Faux positifs dans une analyse: 5%
– SI 5 analyses de sous groupe: 23%
– Si 10 analyses: 40%... (PLATO: 31 sous-groupes !)
ISIS 2Subgroup analysis by Astrological Birth Signs Vascular Deaths
(Isis 2, Lancet, 1988, 2,349-360)
Variations
across study
centers in
BHAT
Hazard ratios and 95% CIs for all-cause mortality a ccording to randomization center in the BHAT trial.
O’Shea JC, DeMets DL.Am Heart J 142:21-8
Quand prêter attention à un sous-groupe ?
• Analyse pré-spécifiée
• Plausibilité biologique
• Puissance statistique
• Interaction statistiquement significative entre effet du traitement et sous groupe (rare…)
• Sinon: l’effet du traitement dans chaque sous groupe est au mieux estimé par l’effet global
Antithrombotiques dans les SCA
• C’est compliqué
• Les essais cliniques nous donnent quelques
informations
• Les traitements ont un bénéfice et un risque
Risk versus benefit
Thrombosis
Bleeding
Mor
talit
y (%
)
Days from Randomization
0 30 60 90 120 150 180 210 240 270 300 330 360 3900
5
15
30
10
25
20
1 yearEstimate
Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)
3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%
Impact of MI and Major Bleeding (non-CABG) in the F irst 30 Days on Risk of Death Over 1 Year in the ACUITY tri al
Stone GW. ACC 2007
HR [95% CI] P-valueAttributable
DeathsRisk Factor
Time-updated covariate adjusted Cox model relating 30-day events to outcomes in HORIZONS -AMI
- Complete model with MACE components and major bleeding -
Hazard Ratio [95% CI]0.01 0.1 1 10 100
C-statistic = 0.87 Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HR
*9.7% of 93 total deaths**21.9% of 93 total deaths
Major bleeding(Non CABG)Incidence 238 (6.8%)26 deaths with event
4.66[2.84, 7.63] <0.001 20.4**
[16.8, 22.6]
ReinfarctionIncidence 69 (2.2%)10 deaths with event
9.75[2.72,34.91] <0.001 9.0*
[6.3, 9.7]
Net Clinical Benefit of Prasugrel in the TRITON trial Bleeding Risk Subgroups
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior
Stroke / TIA
Age
Wgt
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysis
Antithrombotiques dans les SCA
• C’est compliqué
• Les essais cliniques nous donnent quelques
informations
• Les traitements ont un bénéfice et un risque
• L’efficacité antithrombotique n’est pas
parfaitement corrélée au bénéfice clinique
“Standard Therapy” clopidogrel 75mg +placebo/day
“Standard Therapy” clopidogrel 75mg +placebo/day
“Tailored Therapy”clopidogrel 150-mg/day
Successful PCI with DES without major complication or GPIIb/IIIa use
Post-PCI VerifyNow P2Y12 Assay (PRU) 12-24 hours po st-PCI
PRU ≥ 230?
Non-Responder
Clinical Follow-up And VerifyNow Assessment at 30 d ays, 6 months
Primary Endpt: 6 month CV Death, Non-Fatal MI, ARC Def/Prob Stent Thrombosis
Yes No
N ~ 6600
N = 1100 N = 583
Responder
A B C
Random Selection
N = 1100
G R A V T A S
GRAVITAS Pharmacodynamics: Effect of SD vs HD Clopi dogrel
500
400
300
200
100
0
PRU value
Post-PCI
High-Dose
30 d 6 mo Post-PCI 30 d 6 mo
Standard-Dose
N=1013 N=940N=1105 N=1012 N=944N=1109
P = 0.98P < 0.001
ITT population
Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001
Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001
Price et al. JAMA 2011;305:1097-1105
GRAVITAS : CV Death, MI, Stent Thrombosis
Antithrombotiques dans les SCA
• C’est compliqué
• Les essais cliniques nous donnent quelques
informations
• Les traitements ont un bénéfice et un risque
• L’efficacité antithrombotique n’est pas parfaitement
corrélée au bénéfice clinique
• L’objectif du traitement est un bénéfice clinique
« Ne pas perdre de vue la balle »
Objectifs du traitement
1. Efficacité anti-thrombotique
2. Prévention des thromboses
3. Réduction des hémorragies
4. Réduction de la morbi-mortalité
« Ne pas perdre de vue la balle »
Objectifs du traitement
1. Efficacité anti-thrombotique
2. Prévention des thromboses
3. Réduction des hémorragies
4. Réduction de la morbi-mortalité
5. Réduction de la morbi-mortalité au meilleur coût
possible en termes de risque hémorragique
Antithrombotiques dans les SCA
• C’est compliqué
• Les essais cliniques nous donnent quelques
informations
• Les traitements ont un bénéfice et un risque
• L’efficacité antithrombotique n’est pas parfaitement
corrélée au bénéfice clinique
• L’objectif du traitement est un bénéfice clinique
• Les principes du traitement: 2 AAP et un anticoagulant
Mechanisms of interindividual variability in
clopidogrel responsiveness
Angiolillo. JACC 2007;49:1505
Clopidogrel for Coronary Stenting
Response Variability, “Drug Resistance”
Gurbel et al. Circulation 2003;107:2908
% N
onre
spon
ders
(D
Agg
r <1
0%)
Elective StentingClopidogrel: LD 300/ MD 75
Light Transmittance Plat AggrN=92
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
End
poin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel1.82.4
138events
35events
Balance of Efficacy and Safety
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
B
OVERALL
No GPIGPI
DESBMS
DMNo DM
>7565-74
<65
FemaleMale
STEMIUA/NSTEMI
0.5 1 2Prasugrel Better Clopidogrel BetterHR
Age
Reduction in risk (%)18
2112
25146
1430
2018
2116
19
21
Pinter = NS
CV Death, MI, StrokeMajor Subgroups
CrCl > 60CrCl < 60 14
20
PLATO: ticagrelor vs clopidogrel in all types of AC SPrimary endpoint time to CV death, MI or stroke
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
121110
9876543210
13
Cum
ulat
ive
inci
denc
e (%
)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin et al NEJM 2009
PLATO: Hierarchical testing major efficacy endpointsPLATO: Hierarchical testing major efficacy endpointsPLATO: Hierarchical testing major efficacy endpointsPLATO: Hierarchical testing major efficacy endpoints
All patients*All patients*All patients*All patients*TicagrelorTicagrelorTicagrelorTicagrelor
(n=9,333•(n=9,333•(n=9,333•(n=9,333•
ClopidogrelClopidogrelClopidogrelClopidogrel
(n=9,291•(n=9,291•(n=9,291•(n=9,291•HR for HR for HR for HR for
(95% CI•(95% CI•(95% CI•(95% CI• p valuep valuep valuep value
Primary objective, n (%•
CV death + MI + stroke 864 (9.8• 1,014 (11.7• 0.84 (0.77 0.92• <0.001
Secondary objectives, n (%•
Total death + MI + stroke
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
CV death
Stroke
901 (10.2•
1,290 (14.6•
504 (5.8•
353 (4.0•
125 (1.5•
1,065 (12.3•
1,456 (16.7•
593 (6.9•
442 (5.1•
106 (1.3•
0.84 (0.77 0.92•
0.88 (0.81 0.95•
0.84 (0.75 0.95•
0.79 (0.69 0.91•
1.17 (0.91 1.52•
<0.001
<0.001
0.005
0.001
0.22
Total death 399 (4.5• 506 (5.9• 0.78 (0.69 0.89• <0.001
The percentages are K-M estimates of the rate of the endpoint at 12 months.
Wallentin et al NEJM 2009
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Cum
ulat
ive
inci
denc
e (%
)
PLATO: Cardiovascular death over time
PLATO : consistency of effect on primary endpoint
Wallentin et al NEJM 2009
Abciximab Placebo Placebo
Follow up through 90 days and 1 year
Primary PCI with Abciximab Infusion (12 h)
FINESSE: Study DesignAcute ST Elevation MI (or New LBBB) within 6h pain onset
Presenting at Hub or Spoke with estimated time to Cath between 1 and 4 hours
PlaceboPlacebo
Reteplase (5U+5U)*Abciximab
PlaceboAbciximab
Randomize 1:1:1N=3000 *Only 5U if ≥≥≥≥75 yr
Transfer To Cath LabASA, unfractionated heparin 40U/kg (max 3000U)
or enoxaparin (0.5 mg/kg IV + 0.3 mg/kg SC) – substu dy only
Double BlindDouble Dummy
Primary Endpoint
p=0.55
Adjunctive antithrombotic Rx for STEMI PCI:
what do the ESC revascularization guidelines say ?
Wijns & Kohl, Eur Heart J 2010
f: primarily if more efficient agents are contraindicatedd: depending on approval and availability
UFH for PCI: no placebo-controlled
randomized trial !
ATOLL Trial design
STEMI ���� Primary PCI
30-day results
Randomization as early as possible (MICU +++)Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before RxSimilar antiplatelet therapy in both groups
ENOXAPARIN IV0.5 mg/kg
with or without GPIIbIIIa
UFH IV50-70 IU with GP IIbIIIa
70-100IU without GP IIbIIIa(Dose ACT-adjusted)
IVRS
Primary PCI ENOXAPARIN SC UFH IV or SC
ATOLL: Enox vs UFH for primary PCI
Primary Endpoint: Death, Complication of MI, Procedure Failure or Maj or Bleeding
Montalescot, ESC 2010
HORIZONS-AMI: ResultsHORIZONS-AMI: Results
1-Year All-Cause Mortality
Number at riskBivalirudin aloneHeparin+GPIIb/IIIa
1800 1705 1684 1669 15201802 1678 1663 1646 1486
Mor
talit
y (%
)
0
1
2
3
4
5
Time in Months
0 1 2 3 4 5 6 7 8 9 10 11 12
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 4.8%
3.4%
Diff [95%CI] =
-1.5% [-2.8,-0.1]
HR [95%CI] =
0.69 [0.50, 0.97]
P=0.029
3.1%
2.1%
∆ = 1.0%
P=0.049
∆ = 1.4%
Mehran, Lancet 2009
HORIZONS: 1-Year Stent Thrombosis
Number at riskBivalirudin aloneHeparin+GPIIb/IIIa
1611 1525 1504 1486 13561591 1495 1475 1457 1315
Ste
nt T
hrom
bosi
s (%
)
0
1
2
3
4
5
Time in Months
0 1 2 3 4 5 6 7 8 9 10 11 12
Bivalirudin alone (n=1611)
Heparin + GPIIb/IIIa (n=1591)
3.5%3.2%
HR [95%CI] =1.11 [0.76, 1.63]
P=0.59
2.7%
2.2%
∆ = 0.5%P=0.31
∆ = 0.3%
Two-Year All-Cause Mortality
1800 1690 1658 1627 13591802 1669 1637 1579 1324
p= 0.049
HR [95%CI]=0.75 [0.56, 1.00]
4.6%
6.1%A
ll-C
ause
Mor
talit
y (%
)
0
1
2
3
4
5
6
7
8
0 3 6 9 12 15 18 21 24
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
Months
3.1%
2.1% 1 monthP=0.049
Number at riskBivalirudin aloneHeparin+GPIIb/IIIa
3680 pts with STEMI with symptom onset > 20 min and
≤12 hours in ambulance or non-PCI hospital
Intent for PPCI
UFH ±±±± routine or bailout GPI (any of
the 3)
Bivalirudin monotherapy
with prolonged infusion
(Gp IIb/IIIa for bailout only)
Aspirin and thienopyridineR
1:1
Primary endpoint
30-day death, MI or non-CABG related major bleeding
Clinical FU at 30 days and 1 year
EUROMAX
Primary PCI ambulance trial
PrePre--Specified Subgroup AnalysesSpecified Subgroup Analyses
0.5 0.7 0.8 1.0 1.2 1.4 1.6 2.0
UFH/Plac better Hazard Ratio
Overall
None
Thrombolytic
Primary PCI
< 112
>=112
12092
2867
5436
3789
5958
6134
11.2%
15.1
13.6
4.9
4.3
18.0
9.7%
12.2
10.9
6.0
4.6
14.5
0.04
0.03
Initial Reperfusion Rx
GRACE Risk Score
N UFH/Placebo
Death or MI at 30 days
FondaInteraction
P value
Fonda better
Adjunctive antithrombotic Rx for STEMI PCI
Wijns & Kohl, Eur Heart J 2010
Mon algorithme
STEMI – Angioplastie primaire
• Aspirine
– Charge 500 mg
– Entretien 75 mg/j
• Prasugrel (sf si age, poids, AVC/AIT*)
– Charge 60 mg
– Entretien 10 mg
• Bivalirudine (prolongée 4 h post PCI)
• Abciximab si bailout
SCA sans sus décalage de ST
• Aspirine
– Charge 500 mg
– Entretien 75 mg/j
• Prasugrel (sf si age, poids, AVC/AIT*)
– Charge 60 mg
– Entretien 10 mg
• Fondaparinux
• Eptifibatide si PCI et troponine +
• Si CI au prasugrel: clopidogrel 600/75• Demain: remplacer Prasugrel par Ticagrelor
Antithrombotiques dans les SCA
• C’est compliqué
• Les essais cliniques nous donnent quelques
informations
• Les traitements ont un bénéfice et un risque
• L’efficacité antithrombotique n’est pas parfaitement
corrélée au bénéfice clinique
• L’objectif du traitement est un bénéfice clinique
• Les principes du traitement
• Nécessité d’un algorithme par consensus local
The spectrum of ACS care
A wide spectrum of clinical presentation
Chest pain
STEMI, NSTEMI, UA
Variations related to age, gender, prior medical history
A spectrum of care locations
Pre-hospital and ambulance
Emergency Room
CCU
Cath lab
Multiple stakeholders
Emergency physicians
CCU Cardiologists
Interventionalists
Cardiac Surgeons
Anesthesiologists, Intensive Care
Referring Cardiologists
Multiple therapeutic strategies
PCI
CABG
Medical therapy
Conclusions
• Le choix d’une stratégie antithrombotique doit intégrer risque
ischémique et risque hémorragique
• La combinaison aux nouveaux agents est intéressante:
– Ex les nouveaux antiplaquettaires oraux peuvent éviter le besoin d’antiGpIIb/IIIa
et optimiser l’efficacité des anticoagulants
• La réduction de la mortalité doit rester le facteur de choix principale
d’une stratégie thérapeutique
• La mise en oeuvre peut être problématique
– Multiplicité des intervenants
– Contecte d’urgence
– Continuité des soins (pre-hospital/Urgences/USIC/Cath lab)
• Nécessité de consensus loco-régionaux
Thank you !
Backup slides
HORIZONS 2 year follow-up
• Cardiac mortality in ITT population
↓41%*
2.5%
4.2%
0
1
2
3
4
5
Months0 3 6 9 12 15 18 21 24
Car
diac
mor
talit
y (%
)
2.1%
3.7 %
↓43%*
1.8%
2.9%
↓38%*
All p≤0.03
Bivalirudin UFH+GPI
Stone et al TCT 2009
0
2
4
6
8
10
12
14
All Death MI UTVR StentThrombosis
CV Death/MI CV Death/MI/UTVR
CV Death/MI/Stroke
p=0.11
p=0.02
p=0.09p=0.02
p=0.007 p=0.03 p=0.02
Pro
port
ion
of p
opul
atio
n (%
)
Clopidogrel
Prasugrel
Montalescot et al. ESC 2008
CV = CardiovascularMI = Myocardial infarctionUTVR = Urgent target-vessel revascularisation
TRITON-STEMI - Efficacy endpoints at 15 months
ESC guidelines:
recommendations for
revascularization in
NSTE-ACS
• Recommendrevasculari
Wijns & Kohl, Eur Heart J 2010
Wijns & Kohl, Eur Heart J 2010
Benefit of early vs delayed intervention according to GRACE
risk score in ACS in the TIMACS trial
High-risk = GRACE risk score > 140
Interaction P = 0.01
Kaplan–Meier Cumulative Risk of the Primary Outcome (death/MI/Stroke)
Mehta et al NEJM 2009:360:2165-75
3031 pts randomized to undergo either routine early intervention (coronary angiography, < 24 hrs) or delayed intervention (coronary angiography >36 hrs)
Invasive vs Cons 7962
10 102 ∞ 11 101020.5 215%0% 10% 0.50.1 2 1012.5%0% 5%
Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence Incidence
Death or MISize Major bleeds
Exp+ Ctrl+ Exp+ Ctrl+ Exp+ Ctrl+
DTI vs UFH 24701
LMWH vs UFH 21946
GP IIb/IIIa vs Ctrl 31402
Heparin vs Ctrl 2858
Aspirin vs Ctrl 3096
15%
0.84
0.88
0.91
0.91
0.55
0.47
63
102
113
111
31
17
1.3
1.1
1.6
2.3
1.4
NSTE-ACS – Summary of Treatment Approaches
RISC ’90
Cohen ’94
Holdright ’94
Gurfinkel ’95
All
399
214
285
143
2859
Theroux ’88
Cohen ’90
243
69
10 102 ∞ 11 101020.25 20% 20% 0.50.1 2 1013%0% 6%
Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence
0.55 (0.39-0.77) 31 (23-62) 2.3 (0.97-5.4)4.7% vs 7.4%
Incidence
1.1% vs 0.5%
Death or MI at end study medicationSize Major bleeds
Heparin + Ctrl+ Heparin + Ctrl+ Heparin + Ctrl+
0.5 140%
FRISC ’96 1506
000
00
0
0
Randomized trials of UFH/LMWH (dark bars ) vs Control
ACUTE-II ’02
INTERACT ’03
A to Z ’04
SYNERGY ’04
All
525
746
3620
9974
21946
ESSENCE ’97
TIMI-11B ’99
3171
3910
10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1015%0% 10%
Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence
0.91 (0.83-0.99) 113 (61-1438) 1.1 (0.96-1.3)10.1% vs 11.0%
Incidence
3.9% vs 3.7%
Death or MI at 30 daysSize Major bleeds
LMWH+ UFH+ LMWH+ UFH+ LMWH+ UFH+
Randomized trials Enoxaparin (dark bars) vs UFH (open bars)
Death/MI/RI: Day 9
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0.05
0.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR 1.01 95% CI 0.90-1.13
Major Bleeding: 9 Days
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7 8 9
HR 0.53 95% CI 0.45-0.62
P<<0.00001
Enoxaparin
Fondaparinux
Mortality: Day 30
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0 3 6 9 12 15 18 21 24 27 30
HR 0.83 HR 0.83 95% CI 0.7195% CI 0.71--0.970.97
P=0.022P=0.022
Enoxaparin
Fondaparinux
Mortality at 6 Months
Days
Cum
ulat
ive
Haz
ard
0.0
0.02
0.04
0.06
0 20 40 60 80 100 120 140 160 180
HR 0.89HR 0.8995% CI 0.7995% CI 0.79--0.99 0.99
P=0.037P=0.037
Enoxaparin
Fondaparinux
OASIS 5: bleeding reduction and mortality benefit f or Fondaparinux vs Enoxaparin
OASIS 5 Investigators. N Engl J Med 2006;354:1464-7 6
OASIS 5 (Randomized trial (n=20, 078) of Fondaparinux vs. Enoxaparin in ACS)
OASIS 5 Trial: Fondaparinux vs. Enoxaparin reduced major bleeding by 48% and mortality by 17% in NSTEACS
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Major Bleeding at 9 days
-
48% relative
risk reduction
Days
0.0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7 8 9
HR: 0.52 95% CI: 0.44 -0.61 p<0.0001
Enoxaparin
Fondaparinux
4.1 %
2.2 %
Mortality at 30 days
Fondaparinux: 295 deathsEnoxaparin: 352 deaths
Days
0 3 6 9 12 15 18 21 24 27 30
0.0
0.01
0.02
0.03
HR: 0.83 95% CI: 0.71 -0.97p=0.02
Enoxaparin
Fondaparinux
0.043.5 %
2.9 %
-
17 % RRR
GUSTO-2B ’95
OASIS pilot ’97
OASIS ’99
Klootwijk ’99
All
12142
909
10141
300
32699
10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1013%0% 6%
Odds ratio and 95% CI NNT and 95% CI Odds ratio and 95% CIIncidence
0.93 (0.85-1.0) 176 (89-∞) 1.0 (0.89-1.2)7.7% vs 8.3%
Incidence
2.3% vs 2.3%
Death or MI at 30 daysSize Major bleeds
DTI+ UFH+ DTI+ UFH+ DTI+ UFH+
ACUITY ’06 9207
Randomized trials Direct thrombin inhibitors (DTIs) (dark bars) vs UFH/LMWH
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and str oke in high risk patients
Antithrombotic Trialists' Collaboration
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Primary Outcome –
MI/Stroke/CV Death
Clopidogrel + ASA*
3 6 9
Placebo + ASA*
Months of Follow-Up
P = 0.00009N = 12,562
0 12
* In addition to other standard therapies.CURE Investigators. N Engl J Med. 2001;345:494
20%Relative RiskReduction
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR
CV Death, MI or Stroke
Mehta et al. Lancet 2010
EARLY ACS no benefit of routine upstream eptifibatide in NSTE -ACS
Dea
th, M
I, R
IUR
or
TB
O (
%)
0
5
10
15
Time Since Randomization (Hours)
10.0%
9.3%
P = 0.23(stratified for intended early
clopidogrel use)
Delayed provisional eptifibatide
Routine early eptifibatide
0 8 16 24 32 40 48 56 64 72 80 88 96
EARLY ACS:
Kaplan-Meier Curves for 30-day Death or MI
Dea
th o
r M
I (%
)
0
5
10
15
Time Since Randomization (Days)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
12.4%
11.2%
P = 0.079
(stratified for intended early clopidogrel use)
Delayed provisional eptifibatide
Routine early eptifibatide
Kastrati et al. JAMA 2006
ISAR REACT -2Death, Myocardial Infarction, or Urgent Target Vess el Revascularization
Kastrati, A. et al. JAMA 2006
ISAR REACT -2Benefit of GpIIb/IIIIa blockade according to Tropon in Levels (>0.03 µg/L)
Wallentin et al. Lancet 2010:376,
Benefit of Ticagrelor over Clopidogrel in PLATO consistent regardless of LOF genotype
0 60 120 180 240 300 360
Days since randomisation
0
2
4
6
8
10
12E
stim
atio
n K
-M (
%)
(K-M) estimate of the primary endpoint in relation to CYP2C 19 lof allele
Nbr of patients
Clopidogrel LOF*Clopidogrel non LOF**
Ticagrelor LOF*Ticagrelor non LOF**
1,3883,516
1,3843,554
1,2753,321
1,3053,352
1,2593,256
1,2743,301
1,2263,186
1,2503,222
1,0272,691
1,0532,718
8012,123
8342,127
6581,757
6831,761
Clopidogrel LOF
Clopidogrel non LOF
Ticagrelor LOF
Ticagrelor non LOF
11.2
10.08.88.6
Shuldiner, A. R. et al. JAMA 2009;302:849-857.
Association of CYP2C19*2 (rs4244285) Loss-of-Functi on Variant With Adenosine Diphosphate-Stimulated Platelet Aggregation Before and After Cl opidogrel
CYP2C19*2 accounts for 12% of the variability
Paraoxonase-1 is a major determinant of clopidogrel efficacyKaplan-Meier curves for individuals with coronary stent implantation and their
pharmacokinetic and pharmacodynamic responses to clopidogrel
Bouman et al. Nat Med 2011;17:110-16
Predictive value of platelet function tests followi ng stentingSurvival free from MI, stent thrombosis and stroke
Breet et al. JAMA 2010;303(8):754-62
Test IMPACT-R
Tau
x d’
évén
emen
ts (
%)
These tests had at best modest predictive value. No ne provided reliable information regarding bleeding ri sk
15
10
5
0Log-rank P=.17
Temps (jours)
15
10
5
0Log-rank P=.42
Test PFA-100 Collagen/ADP
0 100 200 300 400
Test IMPACT-R ADP
Log-rank P=.22
Log-rank P=.001
Test INNOVANCE
0 100 200 300 400
Temps (jours)
Test LTA 5 µmol/L ADP
Tau
x d’
évén
emen
ts (
%)
15
10
5
0Log-rank P<.001
Temps (jours)
15
10
5
0Log-rank P<.001
Test Plateletworks
0 100 200 300 400
Test LTA 20 µmol/L ADP
Log-rank P<.001
Log-rank P<.001
Test VerifyNowPRU
0 100 200 300 400
Temps (jours)
On treatment platelet reactivity
High PR
Normal PR
The problems of bespoke therapyThe problems of bespoke therapyThe problems of bespoke therapyThe problems of bespoke therapyWhen to measure response to clopidogrel ?How to select poor responders ?Which therapy for poor responders ? Where are the clinical proofs of benefit ?
GRAVITAS ?
Trigger-PCI ?
CLOVIS ?
ARCTIC ?
Collet, et al. J Am Coll Cardiol Intv 2011;4:392-402
CLOVIS-2: using high doses of clopidogrel to overc ome genetic resistancePharmacokinetic Response According to CYP2C19*2 and Clopidogrel LDs
The case for ready-to wear antiplatelet therapy
Ford Model T