The changing world of
adjunctive pharmacology
Rob Storey
Reader and Honorary Consultant in Cardiology,
University of Sheffield
Disclosures
Company Name
• AstraZeneca
Relationship
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
2
Targets for Platelet Inhibition
TERUTROBAN
HEPARINS
FONDAPARINUX
Thromboxane
A2
BIVALIRUDIN
Coagulation
RIVAROXABAN
APIXABAN
DABIGATRAN
Thrombin
TPa
ASPIRIN
x
x
x
5HT
Collagen
x
GPVI
5HT
ADP
5HT2A
ADP
ATP
ADP TICLOPIDINE
CLOPIDOGREL
PRASUGREL
ATP
P2Y1
P2X1
PAR-4
ACTIVE
METABOLITE
PAR-1
SCH 530348
E5555
Thrombin
generation
Shape
change
Dense
granule
PLATELET
ACTIVATION
x
P2Y12
TICAGRELOR
CANGRELOR
Amplification
Alpha
granule
aIIb b3
Coagulation factors
Inflammatory mediators
aIIb b3
Aggregation
x
Fibrinogen
aIIb b3
GP IIb/IIIa ANTAGONISTS
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.
Storey RF. Curr Pharm Des. 2006;12:1255-1259.
P2Y12 as a therapeutic target
Thromboxane
A2
Coagulation
5HT
Collagen
GPVI
Thrombin
TPa
5HT
ADP
5HT2A
ADP
ATP
ADP TICLOPIDINE
CLOPIDOGREL
PRASUGREL
ATP
P2Y1
P2X1
PAR-4
ACTIVE
METABOLITE
PAR-1
Dense
granule
Thrombin
generation
Shape
change
PLATELET
ACTIVATION
x
P2Y12
Amplification
Alpha
granule
aIIb b3
Coagulation factors
Inflammatory mediators
aIIb b3
Aggregation
Fibrinogen
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.
Storey RF. Curr Pharm Des. 2006;12:1255-1259.
aIIb b3
TICAGRELOR
CANGRELOR
Activation/inactivation of clopidogrel
OCH3
O
N
O
CYPs
OCH3
COOH
CYPs
N
O
OCH3
N
O
S
S
Cl
Clopidogrel
Esterases
Cl
2-Oxo-clopidogrel
O
OH
N
S
Cl
SR26334 (Inactive)
CYP5= cytochrome P450.
Farid NA, et al. Clin Pharmacol Ther. 2007;81:735-741.
HS
Cl
R-130964
Platelet aggregation before and 4 hours after
clopidogrel 600 mg in patients undergoing PCI
Whole blood single platelet counting in response to ADP 10 uM
100
Patient with
subacute stent
thrombosis
% aggregation
80
60
40
20
0
Baseline
Smith SMG et al. Platelets 2006; 17: 250-258
Post clopidogrel
VerifyNow P2Y12 assay
7
Multiplate MEA
8
Clinical outcomes according to platelet
aggregometry results with MEA
Sibbing, D. et al. JACC 2009; 53: 849-56
Clopidogrel, CYP 2C19 and stent thrombosis
Sibbing, D. et al. Eur Heart J 2009 30:916-922
Prasugrel
11
Comparison of prasugrel with higher dose
clopidogrel
IPA (%; 20 mM ADP)
N=201
P<0.0001 for each
IPA (%; 20 mM ADP)
P<0.0001
Prasugrel 60 mg
Clopidogrel 600 mg
Hours
Wiviott et al Circ 2007
Clopidogrel Prasugrel
150 mg
10 mg
14 Days
TRITON Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch, CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
TRITON-TIMI study
Balance of Efficacy and Safety
15
138
events
Clopidogrel
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
CV Death / MI / Stroke
Endpoint (%)
10
Prasugrel
5
TIMI Major
NonCABG Bleeds
35
events
Prasugrel
Clopidogrel
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
TRITON-TIMI study
Stent Thrombosis (ARC Definite + Probable)
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
TRITON Diabetic Subgroup
N=3146
18
Clopidogrel
17.0
16
CV Death / MI / Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 46
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
180
Days
270
360
450
TRITON STEMI cohort
Clopidogrel
Prasugrel
15
Primary
EP (CV death, MI and stroke at 15 months)
Proportion of patients (%)
12.4
p=0.02
10.0 RRR=21%
10
9.5
p=0.002
RRR=32%
6.5
5
HR=0.79 (0.65–0.97) NNT=42
Age-adjusted HR=0.81 (0.66-0.99)
0
0
50
100
150
200
250
300
350
400
450
Time (Days)
Montalescot et al. ESC 2008
TRITON Net Clinical Benefit
Bleeding Risk Subgroups
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
Yes
+ 37
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
Ticagrelor
The first oral reversible P2Y12 antagonist
ONSET/OFFSET Study IPA with ADP 5uM (final extent)
Ticagrelor 180mg LD
/ 90 mg bd (n=54)
Clopidogrel 600mg LD
/ 75 mg od (n=50)
100
*
90
*
*
*
*
*
†
*
80

*
70
IPA %
60
50

*
40
‡
30
†
20
10
0
0
.5
1
Onset
Gurbel PA et al. Circulation 2009
2
4
8
24

6 weeks
0
2
Maintenance
Time (hours)
4
8
24
Offset
48
72 120 168 240
PLATELET REACTION UNITS (PRU)
PLATO PLATELET – VerifyNow P2Y12 assay
comparing maintenance therapy with
clopidogrel (C) vs ticagrelor (T)
500
****
****
400
300
235
PRU
200
100
0
C
T
Trough
C
T
Peak
Storey RF et al. Presented at American Heart Association annual scientific sessions Nov 2009
Secondary efficacy endpoints over time
Cardiovascular death
Myocardial infarction
7
6
4
3
2
1
HR 0.84 (95% CI 0.75–0.95), p=0.005
0
0
60
120
180
240
300
360
Clopidogrel
5
Ticagrelor
Cumulative incidence (%)
Cumulative incidence (%)
6
5.8
5
No. at risk
7
6.9
Clopidogrel
5.1
4.0
4
Ticagrelor
3
2
1
HR 0.79 (95% CI 0.69–0.91), p=0.001
0
0
60
120
180
240
300
360
Days after randomisation
Days after randomisation
9,333
8,678
8,520
8,279
6,796
5,210
4,191
9,333
8,294
8,822
8,626
7119
5,482
4,419
Clopidogrel 9,291
8,560
8,405
8,177
6,703
5,136
4,109
9,291
8,865
8,780
8,589
7079
5,441
4,364
Ticagrelor
Total major bleeding
13
NS
12
11.6
Ticagrelor
Clopidogrel
11.2
11
NS
10
7.9
8
K-M estimated rate (% per year)
8.9
NS
9
8.9
7.7
NS
7
5.8
6
5.8
5
4
3
2
NS
1
0.3
0.3
0
PLATO major
bleeding
TIMI major
bleeding
Red cell
transfusion*
PLATO lifethreatening/
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
Non-CABG and CABG-related major bleeding
9
Ticagrelor
Clopidogrel
NS
7.9
8
7.4
K-M estimated rate (% per year)
7
NS
5.8
6
5.3
p=0.026
5
4
4.5
3.8
p=0.025
2.8
3
2.2
2
1
0
Non-CABG
PLATO major
bleeding
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
PLATO - Dyspnoea
All patients
Ticagrelor Clopidogrel
(n=9,235) (n=9,186) p value*
Dyspnoea, %
Any
13.8
7.8
<0.001
With discontinuation of study treatment
0.9
0.1
<0.001
*p values were calculated using Fischer’s exact test
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
Cangrelor
Intravenous reversible P2Y12 antagonist
Inactivation by Dephosphorylation
S
HN
N
N
F
+
4Na
_
O Cl O
O
O
O
O
P
P
P
_ Cl _
_
O
O
O
N
N
S
F
F
O
OH OH
S
HN
N
N
N
HO
O
OH OH
N
F
S
F
F
BRIDGE study design (provisional)
ACS treated with clopidogrel, scheduled for CABG
Stop clopidogrel x days prior to CABG
Placebo infusion
Cangrelor infusion
PD measurements
Stop x hours prior to CABG surgery
Primary objective: To assess safety of cangrelor
compared to placebo prior to CABG surgery
1o end point: Bleeding
2o end points: Inhibition of platelet function, ischaemic events
Elinogrel
Intravenous and oral reversible
P2Y12 antagonist
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
Targeting PAR-1
32
Targets for Platelet Inhibition
TERUTROBAN
HEPARINS
FONDAPARINUX
Thromboxane
A2
BIVALIRUDIN
Coagulation
RIVAROXABAN
APIXABAN
DABIGATRAN
Thrombin
TPa
ASPIRIN
x
x
x
5HT
Collagen
x
GPVI
5HT
ADP
5HT2A
ADP
ATP
ADP TICLOPIDINE
CLOPIDOGREL
PRASUGREL
ATP
P2Y1
P2X1
PAR-4
ACTIVE
METABOLITE
PAR-1
Dense
granule
SCH 530348
E5555
Thrombin
generation
Shape
change
PLATELET
ACTIVATION
x
P2Y12
TICAGRELOR
CANGRELOR
Amplification
Alpha
granule
aIIb b3
Coagulation factors
Inflammatory mediators
aIIb b3
Aggregation
x
Fibrinogen
aIIb b3
GP IIb/IIIa ANTAGONISTS
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.
Storey RF. Curr Pharm Des. 2006;12:1255-1259.
No significant compromise to
haemostasis with SCH 530348
3
*
*
2
1
B leeding tim e
T em p late b leed in g
tim e (m in)
B lo o d L o ss (m ls)
S urgical blood loss (m l/hr)
0
30
*
*
T-2
T-3
20
10
0
Vehicle
T-1
T-2
T-3
T ream ent
T-1 = SCH 530348 1 mg/kg
T-2 = Aspirin (10 mg/kg) plus Clopidogrel (2 mg/kg)
T-3 = SCH 530348, Aspirin plus Clopidogrel
Vehicle
T-1
T reatm ent
Cynomolgus monkey model.
Chintala M et al. Arterioscl Thromb
Vasc Biol. 2008; 28: e138–e139
TRACER Study Design
Moderate- to High-Risk ACS patients
(UA/NSTEMI, PCI,
Medically-Managed, or CABG)
Standard therapy
+ placebo
(N=10,000)
Standard therapy
+ SCH 530548
40 mg LD then 2.5 mg od
12-month minimum exposure
Primary end point:
CV death/MI/stroke/recurrent ischaemia
with rehospitalisation/urgent coronary revascularisation
Study started December 2007
Estimated study completion July 2011
Questions
TERUTROBAN
HEPARINS
FONDAPARINUX
Thromboxane
A2
BIVALIRUDIN
Coagulation
RIVAROXABAN
APIXABAN
DABIGATRAN
Thrombin
TPa
ASPIRIN
x
x
x
5HT
Collagen
x
GPVI
5HT
ADP
5HT2A
ADP
ATP
ADP TICLOPIDINE
CLOPIDOGREL
PRASUGREL
ATP
P2Y1
P2X1
PAR-4
ACTIVE
METABOLITE
PAR-1
SCH 530348
E5555
Thrombin
generation
Shape
change
?
Dense
granule
P2Y12
Coagulation factors
Inflammatory mediators
TICAGRELOR
CANGRELOR
Amplification
Alpha
granule
aIIb b3
x
aIIb b3
Fibrinogen
Aggregation
x
aIIb b3
GP IIb/IIIa ANTAGONISTS
GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.
Storey RF. Curr Pharm Des. 2006;12:1255-1259.