dominick j. angiolillo, md, phd, facc, fesc director of cardiovascular research assistant professor...
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Dominick J. Angiolillo, MD, PhD, FACC, FESCDirector of Cardiovascular Research
Assistant Professor of Medicine
Update on Novel Antiplatelet Agents Under Advanced Clinical Development
CRT 2008 Wednesday February 13th, 2008
Presenter Disclosure Information
Name: Dominick J Angiolillo
Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below.
Company Name: Relationship:
Bristol Myers Squibb Consultant/Speaker bureau
Sanofi-Aventis Consultant/Speaker bureau
Eli Lilly Consultant/Speaker bureau
Daiichi Sankyo Consultant/Speaker bureau
Portola Consultant
GSK Educational Grant
Novel ADP P2YNovel ADP P2Y1212 receptor antagonist receptor antagonist
PrasugrelPrasugrel
AZD6140AZD6140
CangrelorCangrelor
Novel ADP P2YNovel ADP P2Y1212 receptor antagonist receptor antagonist
PrasugrelPrasugrel
AZD6140AZD6140
CangrelorCangrelor
Ticlopidine
(1st generation)
N
SCl
Clopidogrel
(2nd generation)
N
SCl
O
O CH3C
Prasugrel (CS-747) (LY640315)
(3rd generation)
N
F
O
S
O
OCH3
The Thienopyridine Family
Active Metabolite FormationActive Metabolite Formation
HOOCHOOC
* HS* HS
NN
OO
FF
NN
SS
OO
CC HH33
CCOO
FF
Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite
PrasugrelPrasugrel
Sankyo Ann Report 51:1,1999
ClopidogrelClopidogrel
Pro-drugPro-drugPro-drugPro-drug
Hepatic MetabolismHepatic MetabolismCytochrome P450Cytochrome P450
Hepatic MetabolismHepatic MetabolismCytochrome P450Cytochrome P450
Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite
NN
SS
OO
FFOO
HOOCHOOC
* HS* HS
NN
OO
ClCl
OCH3OCH3
Sem Vasc Med 3:113, 2003
Pre-hepatic Pre-hepatic metabolismmetabolismEsterases in blood Esterases in blood (? Small Intestine)(? Small Intestine)
Pre-hepatic Pre-hepatic metabolismmetabolismEsterases in blood Esterases in blood (? Small Intestine)(? Small Intestine)
OO
85% Inactive 85% Inactive MetabolitesMetabolites
Esterases in bloodEsterases in blood
85% Inactive 85% Inactive MetabolitesMetabolites
Esterases in bloodEsterases in blood
OONN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
NN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
NN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
Healthy volunteer crossover studyHealthy volunteer crossover study IPA (20 IPA (20 M ADP) at 24 hoursM ADP) at 24 hours
Brandt J et al. AHJ 2006Brandt J et al. AHJ 2006
––2020
00
2020
4040
6060
8080
100100In
hib
itio
n o
f p
late
let
agg
reg
atio
n (
%)
Inh
ibit
ion
of
pla
tele
t ag
gre
gat
ion
(%
)
Response to prasugrelResponse to prasugrel60 mg60 mg
Response to clopidogrel Response to clopidogrel 300 mg300 mg
N=64N=64
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
Wiviott et al NEJM 2007
Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(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
Diabetic SubgroupDiabetic 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 = 21
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
Wiviott et al NEJM 2007
Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Wgt
Risk (%)
+ 54
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysisPost-hoc analysis
Wiviott et al NEJM 2007
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
ConclusionsConclusionsHigher IPA to Support PCIHigher IPA to Support PCI
Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balanceimprove the benefit : risk balance
PRINCIPLE – TIMI 44 Comparison 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 Circulation 2007.
N=201
Prasugrel 60 mg
Clopidogrel 600 mg
Novel ADP P2YNovel ADP P2Y1212 receptor antagonist receptor antagonist
PrasugrelPrasugrel
AZD6140AZD6140
CangrelorCangrelor
AZD6140 (Ticagrelor)AZD6140 (Ticagrelor) A non-thienopyridine, in the chemical class CPTP
(CycloPentylTriazoloPyrimidine)
First oral reversible ADP P2Y12 receptor antagonist
Direct acting via the P2Y12 receptor - metabolism not required for activity
More potent platelet inhibitor than clopidogrel
A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)
First oral reversible ADP P2Y12 receptor antagonist
Direct acting via the P2Y12 receptor - metabolism not required for activity
More potent platelet inhibitor than clopidogrel
HO
HN
HO OH
O S
F
F
NN
N
NN
DISPERSE: Faster, Greater and More Consistent IPA with AZD6140 vs clopidogrel
Time, hours Time, hours
0
20
40
60
80
100
AZD6140 (100 mg bd)
8 12 8 12
Inh
ibit
ion
, %
24
Clopidogrel
Inh
ibit
ion
, %
Day 1 Day 14 Day 1 Day 14
0
20
40
60
80
100
8 12 8 12 24424242 42
Husted SE et al Eur Heart J 2006; 27: 1038-1047
DISPERSE2 Study Design
DISPERSE2 was a double-blind, randomized study of AZD6140 compared with clopidogrel, both on a background of aspirin (75–100 mg od) 50% of patients in each AZD6140 arm received a loading dose of 270 mg In the clopidogrel arm, thienopyridine treatment-naïve patients received a 300-mg loading dose
Randomization
Visit 1
Day 1
Visit 2 Visit 3 Visit 4 Follow-up
Week 4 Week 8 Week 12 Final Visit+7 days
AZD6140 90 mg bid
AZD6140 180 mg bid
Clopidogrel 75 mg qd
NSTE-ACS patients with onset of chest pain <48 hours
n = 334
n = 329
n = 327
Cannon CP et al. J Am Coll Cardiol 2007
DISPERSE2 Adjudicated Bleeding Rates (%)Week 4 and Overall
0
2
4
6
8
10
Week 4
To
tal B
leed
ing
Ra
te (
%)
0
Overall
To
tal B
leed
ing
Ra
te (
%)12
2
4
6
8
10
12
9.6%
7.7% 8.0%
10.2% 10.2%9.2%
AZD614090 mg bidN = 334
AZD6140180 mg bid
N = 323
Clopidogrel75 mg qdN = 327
AZD614090 mg bidN = 334
AZD6140180 mg bid
N = 323
Clopidogrel75 mg qdN = 327
Minor bleeding* Major bleeding
• Adjudicated total bleeding rates were similar for all groups• No evidence of dose-response for major bleeds
* Minor bleeding without major bleeding Cannon CP et al. J Am Coll Cardiol 2007
DISPERSE-2: Non-bleeding adverse events
0
2
4
6
8
10
12
14
16
18
ClopClopAZD6140AZD6140
90 mg90 mg
AZD6140AZD6140
180 mg180 mg
0
2
4
6
8
10
12
14
16
18
ClopClopAZD6140AZD6140
90 mg90 mg
AZD6140AZD6140
180 mg180 mg
4.4%4.4%5.6%5.6%
9.9%9.9%
6.4%6.4%
10.5%10.5%
15.8%15.8%
Ventricular Pauses >2.5 SecondsDyspnea% %
Discontinuation rates from non-bleeding adverse events were low and similar between groups
Primary endpoint: CVD/MI/stroke
Secondary endpoint: CVD/MI/stroke/revascularization with PCI;CVD/MI/stroke, severe recurrent ischemia
12-month maximum exposure12-month maximum exposure(Min = 6 mo, Max = 12 mo, Mean = 11 mo)(Min = 6 mo, Max = 12 mo, Mean = 11 mo)
(N=18,000)(N=18,000)
ASA + Clopidogrel300 mg ld/75 mg qd
600 mg ld allowed in PCI
ASA + AZD6140180 mg ld/90 mg bid
Moderate- to high-risk ACS patients (UA/NSTEMI/STEMI, PCI,
medically managed, or CABG)
ASA = acetylsalicylic acid; bid = twice daily; CVD = cardiovascular disease; ld = loading dose; MI = myocardial infarction; NSTEMI = non-ST-segment elevation MI; qd = once daily; STEMI = ST-segment elevation MI; UA = unstable angina.
ClinicalTrials.gov Identifier: NCT00391872
Novel ADP P2YNovel ADP P2Y1212 receptor antagonist receptor antagonist
PrasugrelPrasugrel
AZD6140AZD6140
CangrelorCangrelor
Cangrelor (AR-C69931MX)Parenteral ADP-P2Y12 receptor antagonist
ATP analogue
Direct and Reversible P2Y12 inhibitor
More potent than clopidogrel ~90% inhibition of platelet aggregation at
1 - 4 mcg/kg/min iv
Plasma half-life of 5-9 min.; 20 min. for return to normal platelet function
O- O- O-
O-O OHO OH
P P PO O
N
HN
NN
N
N
S
S
CF3
O
Cl
Cl-O
% I
nhib
ition
of
Agg
reg
atio
n
Fol
d In
cre
ase
in B
leed
ing
Tim
e
0
20
40
60
80
100
0
1
2
3
4
5
6
7
8
50 100 500 1000 2000
AggregationAggregation
Bleeding timeBleeding time
+ aspirin/heparin/GTN
+ placebo
AR-C69931 (ng.kg-1.min-1) Stepped infusion period Recovery period
7 15 20 45 60 min
Key Phase I resultRapid reversal of dose-dependent effect
Phase II clinical data: Compared with Abciximab in PCI
Double-blind randomized trial performed in US
5.7%5.4%
2.1%
1.0%
Death, MI, revascularization Major bleed (TIMI criteria)
Incidence of events up to 7-days
AR-C69931MX report number SC931-5129 Part 2
Abciximab (N=94)
Cangrelor (N=105)
Greenbaum et al. Am Heart J. 2006;151:689.e1-689.e10 Greenbaum et al. Am Heart J. 2006;151:689.e1-689.e10
CHAMPION-PCIPCI
(with or without stent)
1:1 Double blind, double dummy
Placebocapsules
(to match)
Cangrelorbolus (30µg/kg) &
infusion (4µg/kg/hour)
Clopidogrelcapsules(600mg)
Placebobolus & infusion
(to match)
1º Endpoint: Death, MI, and uRevasc at 48 hours
2 º Endpoints:Death, MI, uRevasc at 30 daysDeath at 6 months and 1 year
Index ProcedureStudy drug infusion (for at least 2 hours or
the duration of the procedure, whichever is longer)
Clopidogrelcapsules(600 mg)
Placebocapsules(to match)
Clopidogrel Maintenance(at physician discretion)
+ +
Platelet StimuliPlatelet Stimuli
GP IIb/IIIa integrinGP IIb/IIIa integrinGP IIb/IIIa integrinGP IIb/IIIa integrin
ADPADP
EpinephrineEpinephrine
CollagenCollagen
ThrombinThrombin
Platelet AggregationPlatelet AggregationPlatelet AggregationPlatelet Aggregation
SerotoninSerotoninShear rateShear rate
AA
TxA2
COX-1
ThrombinThrombin
ThrombinThrombin
ThrombinThrombin
TxATxA22TxATxA22
Thrombin
ADPADP
TXATXA22
ADP P2Y12
ADPADP
(fibrinogen(fibrinogenreceptor)receptor)
GP IIb/IIIaGP IIb/IIIaActivation
COX-1
clopidogrel bisulfate
aspirin
cAMP
Oral Anti-PAR-1 receptors
SCH 530348E 5555
adapted from Schafer AI. Am J Med. 1996;101:199-209.
TRA (SCH 530348) Program(29,500 pts)
1o EP: Composite of CV death, MI, Stroke, and urgent
revascularization
TRA (SCH 530348) ProgramEvaluation of Efficacy and Safety in Acute and Chronic Atherothrombosis
CER
NSTEACS10,000 pts
2º Prevention19,500 pts
SCH 530348 Placebo SCH 530348 Placebo
F/U: 30 days, 4,8,12 months, and 6 months thereafter
F/U 1 yr minimum
1o EP: Composite of CV death, MI, Stroke, urgent
revascularization and Recurrent Ischemia w/ Rehosp
…………. to be continued !!!!!!!!!!!. to be continued !!!!!!!!!!!