rob storey senior lecturer and honorary consultant in cardiology, university of sheffield, sheffield...
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Rob Storey
Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield,
Sheffield UK
Adjunctive TherapyNew Agents – Will They Have A
Role?
My Conflicts of Interest Are:My Conflicts of Interest Are:
Company Name Relationship
AstraZeneca Research grant, honoraria, consultant
Eli Lilly / Daiichi Sankyo Research grant, honoraria
The Medicines Company Honoraria, consultant
Schering-Plough Research grant
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
Targets for Platelet InhibitionTargets 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 530348E5555
x
HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombin
x
Irreversible P2YIrreversible P2Y1212 Receptor Inhibition: Receptor Inhibition:
Thienopyridine active metaboliteThienopyridine active metabolite
Savi P, et al. Proc Natl Acad Sci USA. 2006;103:11069-11074.
5
*P<0.0001 vs clopidogrel. Data are mean ± SD.PRI = platelet reactivity index; PRINCIPLE-TIMI 44 = Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation - Thrombolysis in Myocardial Infarction 44; VASP = vasodilator-stimulated phosphoprotein.Wiviott SD, et al. Circulation. 2007;116:2923-2932.
PRINCIPLE-TIMI 44: Effects of Clopidogrel and PRINCIPLE-TIMI 44: Effects of Clopidogrel and Prasugrel Loading on VASP PhosphorylationPrasugrel Loading on VASP Phosphorylation
Time, h
VA
SP
PR
I, %
21.5*
7.4* 10.3*
75.068.4 64.3
0
20
40
60
80
100
0 4 8 12 16 20 24
Prasugrel 60 mg Clopidogrel 600 mg
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
Wiviott SD et al. N Engl J Med. 2007 Nov 15;357(20):2001-15
7
TRITON-TIMI 38: Bleeding Events
ARD = absolute risk difference; HR = hazard ratio; ICH = intracranial haemorrhage; NNH = number needed to harm; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction.Adapted from Wiviott SD, et al. Presented at: American Heart Association Scientific Sessions 2007; 4-7 November, 2007; Orlando, FL.Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
ARD 0%P=0.74
Eve
nts
, %
ARD 0.6%HR 1.32P=0.03
NNH=167
ARD 0.5%HR 1.52P=0.01
ARD 0.2%P=0.23
ARD 0.3%P=0.002
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
Pts w/ Prior Stroke / TIA (N=518)
Eve
nts
, % P=0.02
ICH
ClopidogrelPrasugrel
Safety Cohort (N=13,457)Safety Cohort (N=13,457)
Ticagrelor (AZD6140)Ticagrelor (AZD6140)The first oral reversible P2YThe first oral reversible P2Y1212 antagonist antagonist
Reversible P2YReversible P2Y1212 Receptor Receptor
Inhibition: CPTPsInhibition: CPTPs
CPTP = cyclo-pentyl-triazolo-pyrimidine.
Effect of ticagrelor on thrombus formation
Data are means ± standard deviation (SD). n=4 animals per group.Patil SBG, et al. Presented at: International Society on Thrombosis and Haemostasis XXIst Congress; 6-12 July, 2007; Geneva, Switzerland.
Laser-Injury Model: Mean Thrombus Area in P2Y12 +/+, +/–, and –/– Mice
+/+
Are
a,
µm
2
0
500
1000
1500
2000
2500
3000
0 20 40 60 80 100
Time, s
+/+Ticagrelor treated
0
500
1000
1500
2000
2500
3000
0 20 40 60 80 100
Are
a,
µm
2
+/–
0
500
1000
1500
2000
2500
3000
0 20 40 60 80 100
Are
a,
µm
2
–/–
0
500
1000
1500
2000
2500
3000
0 20 40 60 80 100
Time, s
Are
a,
µm
2
Clopidogrel 75 mg od
AZD6140 50 mg bd
AZD6140 100 mg bd
AZD6140 200 mg bd
AZD6140 400 mg od
0
250
500
750
1000
1250
1500
AU
C (
IPA
0-1
2 h
, Fin
al)
DISPERSE: AUC for IPA at Day 28 (Final Extent)
AUC = area under the curve; DISPERSE = Dose confirmatIon Study assessing anti-Platelet Effects of AZD6140 vs clopidogRel in NSTEMI; NSTEMI = non-ST-segment elevation myocardial infarction.Storey RF, et al. Presented at: American Heart Association 2006 Scientific Sessions; November 12-15, 2006; Chicago, Ill, USA.
DISPERSE2 Substudy: Clopidogrel 300 mg ld vs Ticagrelor (AZD6140) 90-270 mg ld* in NSTE-ACS
*~50% of ticagrelor patients in each arm received a 270-mg loading dose.NSTE = non-ST-segment elevation.Storey RF, et al. J Am Coll Cardiol. 2006;47(suppl A):204A. Abstract 821-3.
Inhibition of Platelet Aggregation Induced by ADP 20 μM (Final Extent, Day 1)
Ticagrelor 90 mg
Ticagrelor 180 mg
Ticagrelor 270 mg
Clopidogrel 300 mg
0 2 4 6 8 10 120
25
50
75
100
Time Postdose, h
IPA
, %
(M
ea
n ±
SE
M)
Ticagrelor and dyspnoea: DISPERSE2
Cannon CP, et al. Presented at: American Heart Association 2005 Scientific Sessions; November 13-16, 2005; Dallas, TX, USA.
Pat
ien
ts w
ith
Dys
pn
oea
, %
0
5
10
15
20
25
Clopidogrel75 mg od(n=327)
AZD614090 mg bd(n=334)
AZD6140180 mg bd
(n=323)
6.4
10.5
15.8
Recruitment October 2006 to July 2008; estimated final data collection March 2009 and study completion June 2009
PLATO Study Design
Primary end point: CVD/MI/stroke
Secondary end point: CVD/MI/stroke/revascularisation with PCI;CVD/MI/stroke, severe recurrent ischaemia
12-month maximum exposure(Min = 6 mo, Max = 12 mo, Mean = 11 mo)
(N=18,500)
ASA + Clopidogrel300 mg ld/75 mg od
600 mg ld allowed in PCI
ASA + Ticagrelor180 mg ld/90 mg bd
Moderate- to High-Risk ACS patients (UA/NSTEMI/STEMI, PCI,
Medically-Managed, or CABG)
STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.
Cangrelor Cangrelor The first intravenous reversible P2YThe first intravenous reversible P2Y1212 antagonist antagonist
Cangrelor: Stabilised Analogue of ATP
IV = intravenous.van Giezen JJJ, Humphries RG. Semin Thromb Hemost. 2005;31:195-204.
PO
PP
O–
OOO
O– O–
–O
Cl
Cl O
HO OH
O N
N N
HN
N
SMe
SCF3
4Na+
4Na+
O
HO OH
OP
OP
OP
O–
OOO
O– O–
–ON
N N
NH2
N
ATP Cangrelor (IV)
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
Effect of Cangrelor on ADP-Induced Platelet Aggregation in Patients with NSTE-ACS
Whole Blood Impedance Aggregometry
Storey RF, et al. Thromb Haemost. 2001;85:401-407.
Time after onset of infusion, h Time after terminationof infusion
0.05 g/kg/min
0.2 g/kg/min
0.5 g/kg/min
2.0g/kg/min
Infusion dose
0
20
40
60
80
100
0.5 1.5 2.5 3.5 5 24 20 mPost
1 h
IPA
, % (
Mea
n ±
SE
M)
Post
0
Clinical interaction of cangrelor Clinical interaction of cangrelor with clopidogrelwith clopidogrel
Cangrelor = 30 μg/kg IV bolus + 4 μg/kg/min infusion; clopidogrel = 600 mg loading dose.Data are means ± standard error.Steinhubl SR, et al. Thromb Res. 2008;121:527-534.
1 h cangrelor, then clopidogrelClopidogrel Clopidogrel (T=0) + 2 h cangrelor
Time, h
14
16
Imp
edan
ce, o
hm
s
10
12
6
8
2
4
01.0 2.0 3.0 4.0 5.0 6.0 7.0
Whole-Blood Impedance Aggregometry
• N = 9000• SA/NSTEMI/STEMI• April 2008: 5800
enrolled
PCI
PLATFORM
Cangrelor infusion
Placebo infusion
Clopidogrel Placebo
PCI
Placebo
• N = 6400• SA/NSTEMI• April 2008: 2300
enrolled Cangrelor infusion
Placebo infusion
Placebo
PCI
Placebo
Randomization Treatment
R
R
CHAMPION Studies Program
Clopidogrel
Clopidogrel
Clopidogrel
Primary endpoint 48 hours Composite incidence of death, MI and IDR
Secondary endpoints
48 hours
30 days
1-year
•Death/MI•Components of composite•Stroke (distinguished by type)
•Incidence of (threatened) abrupt closure•Need for urgent CABG•Unsuccessful procedure during the index PCI•Death at 6 months
Safety assessment
• Hemorrhage (e.g. ACUITY, GUSTO, TIMI criteria)• Transfusions• SAE/AE through 48 hrs post-randomization.
CHAMPION Program EndpointsCHAMPION Program Endpoints
Platelet
2 1 Integrin
Collagen
vWF
GPIIb/IIIa
P-Selectin
PSGL-1
Mac-1
• Chemotactic Molecules: MCP-1
• Proteolytic Enzymes: MMPs, PA’s
• Pro-thrombotic molecules : Tissue Factor
• Cytokines: Il-1, Il-8, TNF-
• Adhesion Molecules: Mac-1, PSGL-1
Monocyte
• Inflammatory mediators: Il-1, TGF- , PDGF, FGF-2, RANTES, CD40L.
• Platelet Activation/aggregation: ADP, ATP, Thrombin.
• Adhesion Molecules: P-Selectin, GPIIb/IIIa,, Fibrinogen, Fibronectin, vWF.
• Coagulation Factors: PAI-1, Plasminogen, protein S, Factor V, Factor XI.
GP1b
Platelets and inflammation
Role of P2Y12 in Neointima FormationP2Y12+/+ P2Y12 –/–
30 Min Post-injuryAlcian Blue / Elastic van Gieson stain
21 Days Post-injuryAlcian Blue / Elastic van Gieson stain
21 Days Post-injury-smooth-muscle actin antibody
Representative sections. Scale bar = 500 μm.
Evans DJW, et al. Circulation 2009
Neointima at 21 Days Post-injury
P2Y12 +/+ P2Y12 –/–0
1
2
3
*Inti
ma
: M
edia
Ra
tio
Data are mean ± standard error of the mean (SEM); n=4. *P<0.05 vs wild type (Mann-Whitney).Evans DJW, et al. Circulation 2009
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
Targets for Platelet InhibitionTargets 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
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
TIMI major/minor T IMI major T IMI minor
% p
ati
en
ts
Placebo (n=151)
All doses (n=422)
All 10 mg (n=129)
All 20 mg (n=120)
All 40 mg (n=173)
TRA.PCI study PCIcohort: Bleeding results
Moliterno D, et al. American College of Cardiology 2007 Scientific Sessions. March 24, 2007
Moliterno D, et al. American College of Cardiology 2007 Scientific Sessions. March 24, 2007
TRA.PCI study PCI cohort: Cardiac events
0
1
2
3
4
5
6
7
8
9
10
Death/MACE/stroke (%)
Death/MI (%) MI (%)
% p
ati
en
ts
Placebo (n=151)
All doses (n=422)
10 mg (n=129)
20 mg (n=120)
40 mg (n=173)
MACE= MI/ischemia requiring hospitalization/coronary revascularization
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)
x
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.
Targets for Platelet InhibitionTargets 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 530348E5555
x
TERUTROBAN
x
HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABAN
APIXABANAPIXABANDABIGATRAN Thrombin
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
?
DiscussionDiscussion