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Antiplatelet therapy for acute coronary syndrome treated with PCI: New developments. Amber Malik Director Cath Lab Services Shaikh Zayed Hospital, Lahore. Platelet aggregation contributes to atherothrombosis which in turn is associated with Acute Coronary Syndromes - PowerPoint PPT Presentation
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Amber MalikDirector Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet aggregation contributes to atherothrombosis which in turn is associated with Acute Coronary Syndromes
ACS often precipitates cardiovascular death
No ST elevation ST elevation
Acute coronary syndrome
Antiplatelet Rx
Antithrombin Rx
Complete obstruction
Partial flow
UA/NSTEMI STEMI
X TF/ VIIa
VaCa++
FGN
FGN
IXa
XI
VIIIa
FGN
FibrinXa
Plt
Prothrom Thrombin
Collagen fibrils
Inactive platelet
GP Ia/IIa
GP VI
Platelet activation: Release of contents,
surface receptor expression
ADP
Collagen
Thrombin
Epinephrine
Tx A2
Serotonin
Ca++
PGG2-PGH2
AA release
Tx A2
COX
Tx Syn
Tx A2
RBCs
Endothelial cells
ADP
Collagen
Thrombin
Epinephrine
Tx A2
Serotonin
GP IIb/IIIareceptoractivation
IIb/IIIa
Shear forces
FGN
IIb/IIIa inhibitor
Risk during and after ACS can be reduced by optimal anticoagulation and antiplatelet treatment in conservatively treated as well as revascularised patients
In PCI with stents effective AP inhibition is highly mandatory as the processes themselves are thrombogenic and add to the risk
Prothrombin Thrombin
Xa
X
Va,Ca2+
Platelet
UFH
LMWHUFH
DTIs
GP IIb/IIIa
inhibitor
ASAClopidogrel
LMWH, pentasaccharide
DAPT ( aspirin and clopidogrel) for NSTEMI for 1 year (CURE trial )
DAPT for STEMI for at least 30 days (CLARITY- TIMI 28 trial )
DAPT mandatory post PCI with stents• BMS at least 1 month• DES at least 1 year
Even though CURE shows a RRR of 20% of composite end point which occurred in 9.3% vs 11.4 % on placebo .
The 9.35 % event rate is still quite high inspite of DAPT, which rose to 16.3% when recurrent ischemia was included.
Hence the desire to improve outcome even further
Cox inhibitors :Aspirin
ADP receptor antagonist :TiclopidineClopidogrelPrasugrelCangrelorTicagrelor(AZD6140)
Phosphodiesterase inhibitors :CilostazolDipyridamole
Thrombin inhibitor :Bivalirudin
Glycoprotein IIb/IIIA inhibitors :AbciximabEptifibatideTirofiban
Ticlopidine
(1st generation)
N
SCl
N
SCl
COOCH3
N
F
O
SO
OC H3
Clopidogrel
(2nd generation)
Prasugrel (CS-747) (LY640315)
(3rd generation)
Slow onset: requires prolonged pretreatment for PCI efficacy
Optimal interval from delivery to max drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30% depending on the measure of platelet aggregation used
ESC guidelines recommend 300mg loading dose > 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad hoc PCI with very little time for optimal dosing etc and exposing patients to an increased risk of bleeding
PRAGUE 8 concluded that non selective treatment of pts with high dose clopidogrel should not be routinely undertaken
Failure of Therapy = Drug Resistance
Failure of Therapy Successful Therapy
Lesser Response
Greater Response
PrasugrePrasugrell
Sankyo Ann Report 51:1,1999
Pro-drugPro-drugPro-drugPro-drug
OxidationOxidation(Cytochrome (Cytochrome
P450)P450)
OxidationOxidation(Cytochrome (Cytochrome
P450)P450)
HOOCHOOC
* HS* HS
NN
OO
FF
Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite
NN
SS
OO
FFOO
Sem Vasc Med 3:113, 2003
HydrolysisHydrolysis(Esterases)(Esterases)
HydrolysisHydrolysis(Esterases)(Esterases)
NN
SS
OO
CCHH33
CCOO
FFOONN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
ClopidogreClopidogrell
85% Inactive 85% Inactive MetabolitesMetabolites
EsterasesEsterases
85% Inactive 85% Inactive MetabolitesMetabolites
EsterasesEsterases
NN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
OONN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite
HOOCHOOC
* HS* HS
NN
OO
ClCl
OCH3OCH3
-20.0-20.0
0.00.0
20.020.0
40.040.0
60.060.0
80.080.0
100.0100.0
Inhib
itio
n o
f Pla
tele
t A
ggre
gati
on (
%)
Inhib
itio
n o
f Pla
tele
t A
ggre
gati
on (
%)
Response Response to to
PrasugrelPrasugrel
Response to Response to ClopidogrelClopidogrel
Clopidogrel ResponderClopidogrel Non-responder
**Responder = Responder = 25% IPA at 4 and 24 25% IPA at 4 and 24 hh
Inte
rpati
en
t V
ari
ab
ility
Inte
rpatie
nt
Varia
bility
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :• Less dependent on CYP450 for metabolism• More extensively metabolised to its active
metabolite• Reaches higher concentrations with a 60mg LD and
10mg MD vs 300mgLD and 75mg MD as well as high dose 600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers and CAD pts.
TRITON-TIMI 38TRITON-TIMI 38AHA 2007AHA 2007
Orlando, FloridaOrlando, Florida
Disclosure StatementDisclosure Statement: : The TRITON-TIMI 38 trial was supported by a research grant to the Brigham The TRITON-TIMI 38 trial was supported by a research grant to the Brigham
and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007 www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine Ticlopidine ClopidogrelClopidogrel Clinical need to improve on benefits observed with Clinical need to improve on benefits observed with clopidogrelclopidogrel PrasugrelPrasugrel
Novel thienopyridineNovel thienopyridine
Efficient generation of active metaboliteEfficient generation of active metabolite
High levels of IPA achieved rapidlyHigh levels of IPA achieved rapidly
High IPA in High IPA in clopidogrelclopidogrel “hyporesponders”“hyporesponders”
Encouraging Phase 2 dataEncouraging Phase 2 data
1.To test the hypothesis that higher and less variable IPA prevents clinical ischemic events.
2.To evaluate the safety of a regimen that produces higher IPA.
These goals were achieved by evaluating the efficacy and safety of prasugrel compared to clopidogrel in mod/high risk patients with ACS undergoing PCI on a background of ASA.
Trial Leadership: TIMI Study GroupTrial Leadership: TIMI Study GroupEugene Braunwald,Chairman, Elliott M. Antman,PI, Eugene Braunwald,Chairman, Elliott M. Antman,PI, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Sabina A. Murphy, Susan McHale Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra Tomas Bocanegra
Data Center and Site Management: Quintiles IncData Center and Site Management: Quintiles Inc
Data Safety Monitoring BoardData Safety Monitoring Board David Williams (Chair) , Christophe Bode, Spencer King, David Williams (Chair) , Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets Ulrich Sigwart, David DeMets
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
•Inclusion Criteria Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)STEMI: < 14 days (ischemia or Rx
strategy)STEMI: Primary PCI
•Major Exclusion Criteria:– Severe comorbidity– Increased bleeding risk– Prior hemorrhagic stroke or any stroke < 3
mos– Any thienopyridine within 5 days– No exclusion for advanced age or renal
function
KnownAnatomy
30 Countries30 Countries 707 Sites707 Sites LTFU = 14 (0.1%) LTFU = 14 (0.1%)
Argentina (195)Argentina (195) Finland (116)Finland (116) New Zealand (49)New Zealand (49)
Australia (217)Australia (217) France (146)France (146) Poland (1938)Poland (1938)
Austria (182)Austria (182) Germany (999)Germany (999) Portugal (67)Portugal (67)
Belgium (287)Belgium (287) Hungary (695)Hungary (695) Slovakia (140)Slovakia (140)
Brazil (225)Brazil (225) Iceland (10)Iceland (10) South Africa (404)South Africa (404)
Canada (251)Canada (251) Israel (1219)Israel (1219) Spain (178)Spain (178)
Chile (114)Chile (114) Italy 782)Italy 782) Sweden (154)Sweden (154)
Czech Rep (340)Czech Rep (340) Latvia (21)Latvia (21) Switzerland (136)Switzerland (136)
Denmark (33)Denmark (33) Lithuania (54) Lithuania (54) United Kingdom (73)United Kingdom (73)
Estonia 134)Estonia 134) Netherlands (390)Netherlands (390) United States (4059)United States (4059)
Clopidogrel (N=6795)
%
Prasugrel (N=6813)
%
UA/NSTEMI 74 74
STEMI 26 26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR) < 60 kg
83 kg (72, 92)5.3
84 kg (73, 93)4.6
Female 27 25*
Diabetes 23 23
Prior MI 18 18
CrCl (ml/min)>60<60
8812
8911
*P<0.05
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 Rx Pre PCI
During PCI Post PCI
25741
26731
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
HR 0.80P=0.0003
HR 0.77P=0.0001
Days
Pri
mary
En
dp
oin
t (%
)
12.1(781)9.9 (643)
Primary EndpointPrimary EndpointCV Death,MI,StrokeCV Death,MI,Stroke
NNT= 46
ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)
This was primarily driven by a reduction in the rate of non-fatal MI 7.3 vs 9.5%; p<0.0001 at 6- 15 months
There was no significant difference between the incidence of rates of CV death or nonfatal stroke
Prasugrel compared to clopidogrel reduces the incidence of recurrent MI
Also reduces the severity of recurrent MI
• Overall MI RRR – 24%• MI followed by death RRR - 42%
The rapid onset time of prasugrel upto 30 mins means that the physician can afford to take the time to determine coronary anatomy ( rule out urgent CABG), yet still have time to achieve high levels of IPA for ?proceed PCI
• LD and day 3 RRR 19 %• MD and day 450 RRR 31%
0
2
4
6
8
0 1 2 3
1
0
3060 90 180 270 360 450
HR 0.82P=0.01
HR 0.80P=0.003
5.6
4.7
6.9
5.6
Days
Pri
mary
En
dp
oin
t (%
)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of BenefitTiming of Benefit(Landmark Analysis)(Landmark Analysis)
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48P <0.0001
Prasugrel
Clopidogrel2.4(142)
NNT= 77
1.1 (68)
Days
En
dp
oin
t (%
)
Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844
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
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)P=0.03
Prasugrel
Clopidogrel1.82.4
138 events
35 events
Balance of Balance of Efficacy and SafetyEfficacy and Safety
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
1.8
0.9 0.9
0.10.3
2.4
1.41.1
0.4 0.3
0
2
4
TIMI MajorBleeds
LifeThreatening
Nonfatal Fatal ICH
% E
ven
ts%
Even
ts
ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03NNH=167 NNH=167
ClopidogrelClopidogrel PrasugrelPrasugrel
ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01
ARD 0.2%ARD 0.2%P=0.23P=0.23
ARD 0%ARD 0%P=0.74P=0.74
ARD 0.3%ARD 0.3%P=0.002P=0.002
ICH in Pts w ICH in Pts w Prior Stroke/TIA Prior Stroke/TIA (N=518)(N=518)
Clop 0 (0) %Clop 0 (0) % Pras 6 (2.3)%Pras 6 (2.3)% (P=0.02) (P=0.02)
0
5
10
15
0 30 60 90 180 270 360 450Days
En
dp
oin
t (%
)
HR 0.87P=0.004
13.9
12.2
Prasugrel
ClopidogrelITT= 13,608ITT= 13,608
-23
6
-25
-20
-15
-10
-5
0
5
10
Events per 1000 ptsEvents per 1000 pts
MIMI Major BleedMajor Bleed(non CABG)(non CABG)
++All CauseAll CauseMortalityMortality
Clop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %P=0.64P=0.64
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, CV Death, MI, StrokeStrokeMajor SubgroupsMajor Subgroups
CrCl > 60CrCl < 60 14
20
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 analysisPost-hoc analysis
Significant Net Clinical Benefit with Prasugrel80%
MD MD 10 mg10 mg
Reduced MD
Guided by PK
Age > 75 or
Wt < 60 kg
16%
Avoid
Pra
sugre
l
Prio
r
CV
A/T
IA 4%4%
Safety
Significant increase in serious bleeding(32% increase)
Avoid in pts with prior CVA/TIA
Efficacy
1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%
MI 24%
2. An early and sustained benefit
3. Across ACS spectrum
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balancebenefit : risk balance
Prasugrel compared with clopidogrel significantly reduced the incidence of ischemic events , both in the acute and long term
The increased efficacy of prasugrel was associated with an increased risk of bleeding.
The balance of efficacy and safety revealed an early and sustained net clinical benefit over the entire spectrum of ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients with DM and AMI derived the greatest net clincal benefit from prasugrel as compared to clopidogrel
STEMI 3534 pts Primary PCI 2438(69%) Secondary PCI 1094(31%)
Baseline characteristics well matched More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit of prasugrel across the overall spectrum of ACSs but particularly pronounced in STEMI pts.
Primary end point significant reduction
• 6.5 vs 9.5%; p=0.002
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction
Loading dose Maintenance dose
MI (%)
6
4
2
00 1 2 3 60 180 270 360 450
Prasugrel
HR 0.69(0.58-0.83)P < 0.0001
HR 0.81(0. 70-0.95)P = 0.008
Prasugrel
Clopidogrel
Clopidogrel
5.24
4.27
4.79
3.40
Time (days)
Secondary end point of CV death, MI and UTVR at 30 days was reduced
6.7%vs 8.8% p=0.02
Benefit persisted through 15 months
Multivariate analyses were performed to identify predictors of CV death, MI and UTVR
Common indicators of high risk remained the same :• Gp11b111a use , BMS, multivessel PCI, prior
MI >75yrs age. Only factor that reduced HR was
treatment with prasugrel
Efficacy profile Reduced rate of :
• single end points of all cause death , MI and stent thromboses
• Dual end points of CV death and MI• Non significant trend towards a reduced
rate of UTVR Efficacy profile was maintained
throughout 15 months
Safety profile :
• After 15 months rate of TIMI major non- CABG bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel due to increased Gp2b3a use.
Net clinical benefit analysis CV death , MI, non fatal stroke, or
TIMI major non CABG bleed after 15 months of treatment with prasugrel vs
clopidogrel significant benefit
12.2 vs 14.6% p=0.02
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 21
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
The primary end point was again driven by a reduction in the rate of MI in pts treated with Prasugrel
• 8.2 vs 13.2% p<0.001
A total of 21 pts with DM would need to be treated with prasugrel to avoid one case of the primary end point if the pt was treated with clopidogrel
In the overall study population the efficacy of prasugrel is at the expense of an increased risk of bleeding.
In this analysis in the DM subset prasugrel did not significantly increase the risk of non CABG bleed
Multiple sub group analysis showed that the reductions in the rate of stent thrombosis were in favour of prasugrel as compared with clopidogrel in every instance
Randomized 13,608
Stent Placed 12,844 (94%)
STENT ANALYSIS
BMS Only 6461 (47%)
DES Only 5743 (42%)
Both BMS/DES 640 (5%)
PES Only 2766 (20%)
SES Only 2454 (18%)
Other/Mixed523 (4%)
Any Stent (N=12844)
94 %
UA/NSTEMI 75
STEMI 25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female 26
Diabetes 23
Smoker 38
North America 32
Prior MI 17
CrCl (ml/min)>60<60
8911
STENT ANALYSIS
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomizationLate > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
25.9
2.6
0
5
10
15
20
25
30
Stent Thrombosis No Stent Thrombosis
Clopidogrel
Mortality During Follow up (%) Post-Stent Thrombosis
STENT ANALYSIS
N=210 N=12634
HR 13.1 (9.8 – 17.5) P<0.0001
% o
f Subje
cts
25.9
2.6
Stent thrombosisNo SAT
CLOPIDOGREL
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
% o
f Subje
cts
HR 0.48 [0.36-0.64] P<0.0001
1 year: 1.06 vs 2.15%HR 0.48 [0.36-0.65],
P<0.0001
2.35%
1.13%
52%
DAYS
CLOPIDOGREL
PRASUGREL
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 450
% o
f Subje
cts
HR 0.41 [0.29-0.59]P<0.0001
HR 0.60 [0.37-0.97]P=0.03
DAYS
EARLY ST LATE ST
STENT ANALYSIS
1.56%
0.64%
59% 0.82%
0.49%
40%
CLOPIDOGREL
PRASUGREL
STENT ANALYSIS
DEF/PROBHR 0.48 (0.36-
0.64) P<0.0001
DEFINITEHR 0.42 (0.31-
0.59) P<0.0001
DEF/PROB/POSSHR 0.56 (0.43-
0.73) P<0.0001
CLOPIDOGREL
PRASUGREL
% o
f Subje
cts
BB
BB
BB
B
B
B
B
BB
B
B
BB
B
B
MenWomen
Age < 75Age >=75
No DMDM
GPINo GPI
Prior MINo Prior MI
CrCl< 60CrCl >=60
Bifurcation StentNo Bifurcation Stent
Stent <= 20 mmStent > 20 mm
UA/NSTEMISTEMI
0.1 1 2PRASUGREL
BETTERCLOPIDOGREL
BETTER
PRAS
CLOP
RISK (%)
1.6 2.8 42%1.0 2.2 57%
1.4 2.9 53%0.9 1.9 52%
1.1 2.2 50% 1.4 4.6 69%
1.1 2.1 51%1.1 3.9 70%
1.2 2.1 45%0.8 3.4 75%0.9 2.0 54%1.3 2.6 51%2.0 3.6 48% 0.9 2.0 55% 1.8 3.4 44%1.0 2.2 54%0.9 2.3 61% 1.2 2.4 50%
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
% o
f Subje
cts
HR 0.36 [0.22-0.58]P<0.0001
1 year: 0.74% vs 2.05% HR 0.35 [0.21-0.58],
P<0.0001
2.31%
0.84%
64%
STENT ANALYSIS
DAYS
CLOPIDOGREL
PRASUGREL
% o
f Subje
cts
HR 0.29 [0.15-0.56]P=0.0001
HR 0.46 [0.22-0.97]P=0.04
DAYS
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 450
STENT ANALYSIS
EARLY ST LATE ST
1.44%
0.42%
71%
0.91%
0.42%
54%
CLOPIDOGREL
PRASUGREL
2.41%
1.27%
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
% o
f Subje
cts
HR 0.52 [0.35-0.77] P=0.0009
1 year: 1.22 vs 2.27%HR 0.53 [0.36-0.79],
P=0.0014
48%
STENT ANALYSIS
DAYS
CLOPIDOGREL
PRASUGREL
% o
f Subje
cts
HR 0.45 [0.28-0.73] P=0.0009
HR 0.68 [0.35-1.31]P=0.24
DAYS
0
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 4500
0.5
1
1.5
2
2.5
0 5 10 15 20 25 30
STENT ANALYSIS
EARLY ST LATE ST
1.66%
0.75%
55%
0.78%
0.53%
32%
CLOPIDOGREL
PRASUGREL
Intensive antiplatelet therapy with PRASUGREL in stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
STENT ANALYSIS
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA w/o ST
Even
ts p
er
100
0 p
ati
ents
tre
ate
d
+5
-15
-12
TIMI MajorNon CABG bleed
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a high mortality. Efforts to reduce ST have focused on compliance w/ and duration of ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a broad array of clinical procedural characteristics
STENT ANALYSIS
www.thelancet.com
In addition to reducing ST prasugrel also reduced the primary end point , in the stented population, the BMS pop, and the DES pop.
STENT ANALYSIS
Net Clinical BenefitSTENT ANALYSIS
HR 0.88(0.77-1.01)
p=0.07
HR 0.86 (0.77-0.95)
p=0.002
HR 0.84(0.72-0.98)
p=0.025
N=12844 N=6461 N=5743
% o
f Subje
cts
Any BMS DES
13.712
13.612.3
13.4
11.4
HR 0.84P=0.025
CVD/MI/CVA MAJOR BLEEDING
STENT ANALYSIS
HR 0.80(0.69-0.93)
p=0.003
HR 0.81 (0.72-0.90)
p=0.0001
HR 0.82 (0.69-0.97)
p=0.02
HR 1.37 (0.95-1.99)
p=0.09
HR 1.27 (0.99-1.63)
p=0.06
HR 1.19 (0.83-1.72)
p=0.34
N=12844 N=6461 N=5743
CLOPIDOGREL
PRASUGREL
Prasugrel as compared to clopidogrel significantly reduced :• Incidence of combined end point of CV
death, MI and nonfatal stroke• NNT 46; p<0.0001
This benefit came at the cost of an increase in major non-CABG bleeds • NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for the prevention of ischemic events including stent thrombosis, in ACS pts undergoing PCI esp high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention driven
Safety profile is comparable to that of clopidogrel in this high risk subset
0
1 08
Placebo APTC CURE TRITON-TIMI 38Single Antiplatelet Rx
Dual Antiplatelet Rx
Higher IPA
ASA ASA + Clopidogrel ASA +
Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction inIschemicEvents
Increase in Major Bleeds
ACS can lead to CV death Post PCI – SAT , death, MI or UTVR Clopidogrel is not enough PRASUGREL
• Pharmacokinetics• Pharmacodynamics• Good clinical impact as it reduces MI Prasugrel better Bleeding risk ????
THANKYOU