Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield
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Transcript of Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield
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Rob Storey
Reader and Honorary Consultant in Cardiology, University of Sheffield
The changing world of adjunctive pharmacology
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Disclosures
Company Name Relationship• AstraZeneca Research grants, speaker
fees, consultant, travel
• Eli Lilly / Daiichi Sankyo Research grant, speaker fees, consultant, travel
• Schering-Plough Research grant, consultant
• Teva Consultant
• Novartis Consultant
• The Medicines Company Consultant
• Dynabyte Research consumables
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GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
Targets for Platelet Inhibition
ThromboxaneA2
5HT
P2Y12
ADP ADPADP
5HT
PLATELETACTIVATION
P2Y15HT2A
PAR-1
PAR-4
Densegranule
Thrombingeneration
Shapechange
IIb3
IIb3
FibrinogenIIb3
Aggregation
AmplificationAmplificationAlpha
granule
Coagulation factorsInflammatory mediators
TP
Coagulation
GPVI
Collagen
ATPATP
P2X1
ASPIRIN
x TICLOPIDINECLOPIDOGRELPRASUGREL
ACTIVE METABOLITE
x TICAGRELOR CANGRELOR
GP IIb/IIIa ANTAGONISTS
xx
SCH 530348SCH 530348E5555
x
TERUTROBAN
x
HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombin
x
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GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
P2YP2Y1212 as a therapeutic target as a therapeutic target
ThromboxaneA2
5HT
P2Y12
ADP ADPADP
5HT
PLATELETACTIVATION
P2Y15HT2A
PAR-1
PAR-4
Densegranule
Thrombingeneration
Shapechange
IIb3
IIb3
FibrinogenIIb3
Aggregation
AmplificationAmplificationAlpha
granule
Coagulation factorsInflammatory mediators
TP
Coagulation
GPVI
Collagen
ATPATP
P2X1
TICLOPIDINECLOPIDOGRELPRASUGREL
ACTIVE METABOLITE
x TICAGRELOR CANGRELOR
ThrombinThrombin
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Activation/inactivation of clopidogrel
CYP = cytochrome P450.Farid NA, et al. Clin Pharmacol Ther. 2007;81:735-741.
S
N
O
Cl SO
N
O
Cl
N
SH
COOHO
Cl
S
N
OHO
Cl
Clopidogrel
CYPs
Esterases
CYPs
2-Oxo-clopidogrel R-130964
SR26334 (Inactive)
OCH3 OCH3OCH3
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Platelet aggregation before and 4 hours after clopidogrel 600 mg in patients undergoing PCIWhole blood single platelet counting in response to ADP 10 uM
Baseline Post clopidogrel0
20
40
60
80
100
% a
gg
reg
ati
on
Patient with subacute stentthrombosis
Smith SMG et al. Platelets 2006; 17: 250-258
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VerifyNow P2Y12 assay
7
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Multiplate MEA
8
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Clinical outcomes according to platelet aggregometry results with MEA
Sibbing, D. et al. JACC 2009; 53: 849-56
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Sibbing, D. et al. Eur Heart J 2009 30:916-922
Clopidogrel, CYP 2C19 and stent thrombosisClopidogrel, CYP 2C19 and stent thrombosis
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Prasugrel
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Comparison of prasugrel with higher dose clopidogrel
P<0.0001 for each
IPA (%; 20 M ADP)
Hours 14 Days
IPA (%; 20 M ADP)
P<0.0001
Prasugrel 10 mg
Clopidogrel 150 mg
Wiviott et al Circ 2007
N=201
Prasugrel 60 mg
Clopidogrel 600 mg
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TRITON Study Design
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
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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
TRITON-TIMI study TRITON-TIMI study Balance of Efficacy and SafetyBalance of Efficacy and Safety
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
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TRITON-TIMI study TRITON-TIMI study Stent Thrombosis (ARC Definite + Probable)
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
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TRITON Diabetic Subgroup
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 = 46
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
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TRITON STEMI cohortPrimary EP (CV death, MI and stroke at 15 months)
Montalescot et al. ESC 2008
Time (Days)
5
10
15
00 50 100 150 200 250 300 350 400 450
Pro
po
rtio
n o
f p
atie
nts
(%
)
9.5
6.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=42
p=0.02RRR=21%
p=0.002RRR=32%
Clopidogrel
Prasugrel
Age-adjusted HR=0.81 (0.66-0.99)
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TRITON Net Clinical BenefitBleeding 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 analysisPost-hoc analysis
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Ticagrelor Ticagrelor The first oral reversible P2YThe first oral reversible P2Y1212 antagonist antagonist
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Time (hours) Onset Maintenance Offset
100
90
80
70
60
50
40
30
20
10
0
IPA
%Ticagrelor 180mg LD / 90 mg bd (n=54)Clopidogrel 600mg LD / 75 mg od (n=50)
0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240
*
*
* * *
*
*
*
*
‡
†
†
ONSET/OFFSET Study IPA with ADP 5uM (final extent)
Gurbel PA et al. Circulation 2009
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PLATO PLATELET – VerifyNow P2Y12 assay comparing maintenance therapy with
clopidogrel (C) vs ticagrelor (T)
C T C T0
100
200
300
400
500
Trough Peak
**** ****
235PRU
PL
AT
EL
ET
RE
AC
TIO
N U
NIT
S (
PR
U)
Storey RF et al. Presented at American Heart Association annual scientific sessions Nov 2009
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No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cum
ula
tive
inci
denc
e (%
)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
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
Myocardial infarction Cardiovascular death
Cum
ula
tive
inci
denc
e (%
)
Secondary efficacy endpoints over time
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Total major bleeding
NS
NS
NS
NS
NS
0K-M
est
imat
ed r
ate
(% p
er y
ear)
PLATO major bleeding
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major bleeding
Red cell transfusion*
PLATO life-threatening/fatal bleeding
Fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant
11.611.2
7.9 7.7
8.9 8.9
5.8 5.8
0.3 0.3
TicagrelorClopidogrel
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Non-CABG and CABG-related major bleeding
p=0.026
p=0.025
NS
NS
9K
-M e
stim
ated
rat
e (
% p
er y
ear)
Non-CABGPLATO majorbleeding
8
7
6
5
4
3
2
1
0Non-CABGTIMI major bleeding
CABGPLATO major bleeding
CABG TIMI major bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
TicagrelorClopidogrel
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PLATO - Dyspnoea
All patientsTicagrelor(n=9,235)
Clopidogrel(n=9,186) p value*
Dyspnoea, %
Any
With discontinuation of study treatment
13.8
0.9
7.8
0.1<0.001
<0.001
*p values were calculated using Fischer’s exact test
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PLATO Conclusions• Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in
comparison with clopidogrel in a broad population with ST- and non-ST-elevation
ACS provides
– Reduction in myocardial infarction and stent thrombosis
– Reduction in cardiovascular and total mortality
– No change in the overall risk of major bleeding
• Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of
ischaemic events, stent thrombosis and death in the acute and long-term treatment of
patients with ACS• Clinicians will need to learn how to identify and manage dyspnoea associated with ticagrelor
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Cangrelor Cangrelor Intravenous reversible P2YIntravenous reversible P2Y1212 antagonist antagonist
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HOO
OH OH
N
N
N S F
FF
N
HNS
_
O_
P
O_
O Cl
ClP
O
O
OP
O
_O
OO
OH OH
N
N
N S F
FF
N
HNS
4Na+
Inactivation by Dephosphorylation
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BRIDGE study design (provisional) ACS treated with clopidogrel, scheduled for CABG
Stop clopidogrel x days prior to CABG
Cangrelor infusionPlacebo infusion
1o end point: Bleeding2o end points: Inhibition of platelet function, ischaemic events
Primary objective: To assess safety of cangrelor compared to placebo prior to CABG surgery
Stop x hours prior to CABG surgery
PD measurements
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Elinogrel Elinogrel Intravenous and oral reversible Intravenous and oral reversible
P2YP2Y1212 antagonist antagonist
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Elinogrel
• Reversible P2Y12 inhibitor in phase 2/3 development
• IV and oral formulations
• Half-life ~12 hours
• Competitive mechanism of action – competes with ADP for binding to receptor, greater IPA for low vs high concentrations of ADP
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Targeting PAR-1
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GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
Targets for Platelet Inhibition
ThromboxaneA2
5HT
P2Y12
ADP ADPADP
5HT
PLATELETACTIVATION
P2Y15HT2A
PAR-1
PAR-4
Densegranule
Thrombingeneration
Shapechange
IIb3
IIb3
FibrinogenIIb3
Aggregation
AmplificationAmplificationAlpha
granule
Coagulation factorsInflammatory mediators
TP
Coagulation
GPVI
Collagen
ATPATP
P2X1
ASPIRIN
x TICLOPIDINECLOPIDOGRELPRASUGREL
ACTIVE METABOLITE
x TICAGRELOR CANGRELOR
GP IIb/IIIa ANTAGONISTS
xx
SCH 530348SCH 530348E5555
x
TERUTROBAN
x
HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombin
x
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No significant compromise to haemostasis with SCH 530348
Surgical blood loss (ml/hr)
Vehicle T-1 T-2 T-30
1
2
3
* *
Treament
Blo
od
Lo
ss (m
ls)
Bleeding time
Vehicle T-1 T-2 T-30
10
20
30 * *
TreatmentT
emp
late
ble
edin
gti
me
(min
)T-1 = SCH 530348 1 mg/kgT-2 = Aspirin (10 mg/kg) plus Clopidogrel (2 mg/kg)T-3 = SCH 530348, Aspirin plus Clopidogrel
Cynomolgus monkey model.
Chintala M et al. Arterioscl Thromb Vasc Biol. 2008; 28: e138–e139
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Study started December 2007
Estimated study completion July 2011
TRACER Study Design
Primary end point: CV death/MI/stroke/recurrent ischaemia
with rehospitalisation/urgent coronary revascularisation
12-month minimum exposure
(N=10,000)
Standard therapy + placebo
Standard therapy + SCH 530548
40 mg LD then 2.5 mg od
Moderate- to High-Risk ACS patients (UA/NSTEMI, PCI,
Medically-Managed, or CABG)
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GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
ThromboxaneA2
5HT
P2Y12
ADP ADPADP
5HT
P2Y15HT2A
PAR-1
PAR-4
Densegranule
Thrombingeneration
Shapechange
IIb3
IIb3
FibrinogenIIb3
Aggregation
AmplificationAmplificationAlpha
granule
Coagulation factorsInflammatory mediators
TP
Coagulation
GPVI
Collagen
ATPATP
P2X1
ASPIRIN
x TICLOPIDINECLOPIDOGRELPRASUGREL
ACTIVE METABOLITE
x TICAGRELOR CANGRELOR
GP IIb/IIIa ANTAGONISTS
xx
SCH 530348E5555
x
TERUTROBAN
x
HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombinx
?
QuestionsQuestions