,

, MD

Atherothrombosis has Multiple

Manifestations
Ischemic stroke

Myocardial
infarction

Transient ischemic
attack (TIA)
Angina:
Stable
Unstable

Peripheral arterial disease :

Intermittent claudication
Rest pain
Gangrene
Necrosis
Adapted from: Drouet L. Cerebrovasc Dis 2002;13(suppl 1):16

- - - -

Tsoumani, et al. Current Vascular Pharmacology, Accepted

Angiolillo et al. Circ 2011; 123: 798-813

1986

2009
1997

2010

1990

-1

G2

H2

I2

A2

 P2Y12


ADP P2Y12
OCH3

N
S

N
S

Cl

Clopidogrel

Ticlopidine

Prasugrel
(CS-747, LY640315)

O
CH3

Cl

N
O

:
:

P450

,

P2Y12 .

ADP

A

/

Meadows TA, et al. Circ Res. 2007;100(9):1261-1275; Beitelshees A, et al. Arterioscler Thromb Vasc Biol. 2006;26:1681-1683; Wiviott S, et al.
Circulation. 2010; 122: 394-403; Cattaneo M. Eur Heart J. 2008;10(Suppl I):I33-I3; Ibanez B, et al. Eur Heart J. 2006:8:G.3

Ahmad T, et al. Nat. Rev. Cardiol. 8, 2011;560571

CAPRIE
COMMIT

PCI-

(CCS--2)
(CCS

STEMI

. 30

..
NSTEMI
.12

PCI

/ /

-/

.12

. 3

Clopidogrel Efficacy and Safety Profile Has been

Established in More than 100,000 Patients

Published Trials

Indication in
STEMI
patients

CASPAR

CASPAR

CHARISMA

CHARISMA

CHARISMA

CHARISMA

COMMIT
CCS2

COMMIT
CCS2

COMMIT
CCS2

COMMIT
CCS2

COMMIT
CCS2

CLARITY

CLARITY

CLARITY

CLARITY

CLARITY

CLARITY

CARESS

CARESS

CARESS

CARESS

CARESS

CARESS

CARESS

MATCH

MATCH

MATCH

MATCH

MATCH

MATCH

MATCH

MATCH

CREDO

CREDO

CREDO

CREDO

CREDO

CREDO

CREDO

CREDO

Indication in
UA/NSTEMI
patients

CREDO

Ongoing
CURRENT
TrialsCURRENT
CASPAR

Published Trials

Indication in
patients after
MI, IS, or with
established
PAD

ACTIVE

CURE
CURE
CURE
CURE
CURE
CURE
(PCI-CURE) (PCI-CURE) (PCI-CURE) (PCI-CURE) (PCI-CURE) (PCI-CURE)

CURE
(PCI-CURE)

CURE
CURE
(PCI-CURE) (PCI-CURE)

CURE
(PCI-CURE)

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CLASSICS

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

CAPRIE

1996

2000

2001

2002

2004

2004

2005

2005

2006

2007

2008

Publication Date

2008

CURRENTOASIS 7

he use of a double dose of

clopidogrel for 7 days, as compared
with the standard dose, did not
reduce the incidence of the primary
outcome of cardiovascular death,
myocardial infarction or stroke at 30
days.

The CURRENTOASIS 7 Investigators.

NEJM. 2010;363:930-42.

CURRENTOASIS 7
In patients undergoing PCI for ACS, a 7day double-dose clopidogrel regimen was
associated with a reduction in
cardiovascular
events
and
stent
thrombosis compared with the standard
dose. A double-dose clopidogrel regimen
can be considered for all patients with
acute coronary syndromes treated with
an early invasive strategy and intended
early PCI.

Mehta SR. Lancet. 2010; 376: 123343.

Variability in response to thienopyridine platelet inhibition

Ahmad T, et al. Nat. Rev. Cardiol. 8, 560571 (2011)

CYP1A2

36%

CYP2B6

19%

oral ingestion CYP2C19

(dosage, compliance)

45%

CYP2B6

33%

CYP2C9

7%

CYP2C19

20%

CYP3A4/5 40%

10 - 15%

esterases

absorption

50%

85 - 90%

metabolis
m

2%


CYP2C19*1/*2
CYP2C19*1/*3

CYP2C19*2/*2
CYP2C19*1/*1

CYP2C19*2/*3
CYP2C19*2/*3

Clopidogrel Resistance
Kaplan-Meier analysis for the cumulative incidence of stent
Thrombosis and for the composite of death or stent thrombosis

Sibbing D, et al. J Am Coll Cardiol 2009;53:84956


CYP2C19*2

Mega JL, et al. N Engl J Med 2009;360:354-62

Mega JL, et al. JAMA 2011;306(20):2221-2228


2 Hours

24 Hours
Resistanc
e

Resistance = 63%

12

Aggregation (%)

Aggregation (%)

5 Days

30 Days

Resistance

Resistance =
15%

Resistance = 31%

Patients (%)

Patients (%)

Resistance = 31%

Patients (%)

Patients (%)

Resistance

Resistance

Aggregation (%)

Gurbel PA, et al. Circulation. 2003;107: 2908-2913.

Aggregation (%)

Kalantzi KI, et al. J Thromb Haemost. 2011;9:875-878

Responders

Nonresponders

Responders

Nonresponders

Kalantzi KI, et al. Platelets. 2011; In Press

Prasugrel
O
O
CH3

N
O

Active Metabolite Plasma Concentrations

After the Loading Dose
Active Metabolite Concentration
(ng/mL; mean SD)

800

Clopidogrel
600 mg LD

600

Clopidogrel
300 mg LD
400

Prasugrel
60 mg LD
200

0
0

Time (hours)

SD=Standard deviation; LD=Loading dose

Winters K, et al. Eur Heart J. 2007;28:218

Inhibition of Platelet Aggregation After Loading

Dose in Patients With Elective PCI
100

***

***

***

IPA % (20 M ADP)

80

60

Prasugrel 60 mg
***

40

Clopidogrel 600 mg

20

***p<0.0001 Prasugrel vs. Clopidogrel

0
0.5

IPA=inhibition of platelet aggregation;

PCI=Percutaneous coronary intervention

12

16

20

24

Hours
Wiviott SD et al. Circulation 2007;116(25):2923-2932

The Incidence of the Primary Safety End Point of Non-CABG-Related

Major TIMI Bleeding in the TRITON-TIMI 38 Study Analyses

Spinler SA, et al. J Manag Care Pharm. 2009;15(5):383-95.

TRITON TIMI 38 Subgroups

of particular concern
Previously known stroke
Elderly(>75 y)
Low body weight (<60 Kg)
favourable effects
Diabetes mellitus
STEMI

Ticagrelor (AZD 6140)

HO

N
N

N
H
N

HO
O

N
S

OH

Cyclo-pentyl-triazolo-pyrimidine (CPTP)

Ticagrelor P2Y12 receptor binding

Ticagrelor is highly selective for the

P2Y12 receptor, compared with its effect

at other P2 receptors (van Giezen 2008)
Unlike thienopyridines ticagrelor does
not interfere with ADP binding (van Giezen
2008)

Ticagrelor prevents ADP- mediated

P2Y12 receptor activation (van Giezen 2008)

Upon discontinuation, ticagrelor has a
predictable and reliable offset reflecting
the gradual fall in plasma concentration
(Husted 2006; Gurbel 2009; van Giezen 2008)

Platelet activity returns as ticagrelor is

eliminated (van Giezen 2008)

van Giezen JJJ. Eur Heart J. 2008;10 (Suppl D):D23-D29; Husted S, et al. Eur Heart J. 2006;27:1038-1047; Gurbel PA, et al. Circulation. 2009;120:2577-2585.

PLATO
Kaplan-Meier estimate of time to first primary efficacy endpoint
(composite of CV death, MI or stroke)1

Wallentin L, et al. N Engl J Med 2009;361:1045-1057

K-M estimated rate (% per year)

PLATO Major or Fatal Bleeding

13
12
11
10
9
8
7
6
5
4
3
2
1
0

Ticagrelor
Clopidogrel

NS
11.6

11.2
NS
8.9

NS
7.9

8.9

7.7
NS
5.8

5.8

NS
0.3

PLATO major
bleeding

TIMI major
bleeding

Red cell
transfusion

PLATO lifethreatening/
fatal bleeding

0.3

Fatal
bleeding

Wallentin L, et al. N Engl J Med 2009;361:1045-1057

K-M estimated rate (% per year)

Non-CABG & CABG related bleeding

9

Ticagrelor
Clopidogrel

NS
7.9

7.4

NS
5.8

6
5
4

5.3

p=0.026
4.5
3.8

p=0.025
2.8

2.2

2
1
0

Non-CABG
PLATO major
bleeding

Non-CABG
TIMI major
bleeding

CABG
PLATO major
bleeding

CABG
TIMI major
bleeding

Wallentin L, et al. N Engl J Med 2009;361:1045-1057

Bradyarrhythmias and clinical bradyarrhythmic events

The PLATO trial

A genetic substudy
Kaplan-Meier estimates of events of the primary efficacy outcome
in relation to the CYP2C19 genotype

Wallentin L, et al. Lancet 2010; 376: 132028

The RESPOND Study

Inhibition of platelet aggregation to ADP in clopidogrel-responsive patients

Before and after crossover

Patients maintained on constant therapy

Gurbel PA, et al. Circulation 2010;121;1188-1199

NSTEMI/UA ESC Guidelines

2011
P2Y12 inhibitor

should be added to aspirin as soon as possible and

maintained over 12 months, unless there are contraindications like excessive risk of

bleeding.
Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended for all patients
at moderate to high risk of ischaemic events, regardless of initial treatment strategy and
including those pretreated with clopidogrel (which should be discontinued when

ticagrelor is commenced)
If ticagrelor is not available, prasugrel (60 mg loading dose, 10 mg daily dose) is
recommended for P2Y12 inhibitor nave patients in whom coronary anatomy is known and
who are proceeding to PCI unless there is a high risk of life-threatening bleeding or

other contraindications
Clopidogrel (300 mg loading, 75 mg daily dose) is recommended for patients who cannot
receive ticagrelor or prasugrel.

Summary and Recommendations

new antiplatelets vs clopidogrel
More rapid, more consistent (fewer poor
responders), more potent (higher the IPA)
Higher efficacy and lower safety

X
P2Y12

NAI

NAI

OXI

DPY

2-4

30
30

()

3-10

5-10

3-4

CABG()

STEMI

non STEMI

X
P2Y12

CAPRIE,CURE
CARISMA,COMMIT,CLARITY
CREDO,CURRENT OASIS 7

TRITON

PLATO

>120.000

13.608

18.624

..

..

..

+45%

+4%

..

X
P2Y12

1/10<<1/100
(15%)

>75

<60 Kgr

1,16

2,19

3,56

GENERICS

 ;
;

in vivo

,

48h.

Kim S-D, et al. Clin Ther. 2009;31:793-803

Kim S-D, et al. Clin Ther. 2009;31:793-803

 P-

Neubauer H, et al. Clin Res Cardiol (2009) 98:533540

Neubauer H, et al.
Clin Res Cardiol (2009) 98:533540



(CB)


(CHS)

Tsoumani , et al. Treatment Strategies Cardiology. 2011; 3 (2) : 40-43

Tsoumani , et al. Angiology. 2011 Dec 5 [Epub ahead of print]


follow-up

follow-up

6-
(n=41)
CHS (Plavix) 75 mg/day

1-

(n=86)

(100 mg/day)
A (40 mg/day)

CHS (Plavix) 75 mg/day

(n=45)
(100 mg/day)
(40 mg/day)
Tsoumani , et al. Treatment Strategies Cardiology. 2011; 3 (2) : 40-43
Tsoumani , et al. Angiology. 2011 Dec 5 [Epub ahead of print]

CB (Clovelen) 75 mg/day
(100 mg/day)
(40 mg/day)


:
VASP
PRI.

DP (10, 5, 2.5 ), AA (10 )

TRAP ((10 )
(LTA).

:
P-
-
100 M
ADP.

(n=86)

()

70.59.9

, / (n)

65 / 21

, n (%)

14 (16.3)

, n (%)

51 (59.3)

, n (%)

40 (46.5)

, n (%)

32 (37.2)

, n (%)

42 (48.8)

49 (57.0)

, n (%)

16 (18.6)

, n (%)

0 (0)

(x 10 /L)

10.04.1

5.02.7

0.80.2

(x 10 /L)
(x 10 /L)
9

(x 10 /L)

22361

, MPV (fl)

11.01.3

(mg/dL)

19947

HDL- (mg/dL)

4711

(mg/dL)

12946

LDL- (mg/dL)

11737

-, n (%)

58 (67.4)

, n (%)

10 (11.6)

32 (37.2)

, n (%)
ARBs, n (%)

18 (20.9)

PPi, n (%)

42 (48.8)

, n (%)

27 (31.4)
Tsoumani , et al. Treatment Strategies Cardiology. 2011; 3 (2) : 40-43
Tsoumani , et al. Angiology. 2011 Dec 5 [Epub ahead of print]

 VASP
PRI 5% 70.1%

CB
PRI ( ,
37.114.2%)

CHS
PRI ( ,
38.612.7%)
Tsoumani , et al. Treatment Strategies Cardiology. 2011; 3 (2) : 40-43
Tsoumani , et al. Angiology. 2011 Dec 5 [Epub ahead of print]

 , %

, %

80

CHS
CHS

70

CHS
CB

CHS
CB

60
50
40
30
20
10
0

2.5

5.0

CHS
CHS

60

2.5

10

5.0

ADP, M

ADP, M

1-

6-
CHS
CB

CHS
CB

50
40
30
20
10
0
AA

TRAP
1-

AA

TRAP
6-

10

1-
CHS CB
CHS CHS
(n = 45)

(n = 41)

6-
CB
(n = 45)

P-(MFI)

ADP

CHS
(n = 41)

NS
6.23.8

5.43.3

4.22.6

3.32.4

28.811.6

30.710.2

25.39.4

29.912.7

(%)

NS

12.85.5

146.3

9.92.8

11.33.9

ADP

36.111.7

40.310.1

33.410.8

36.29.6

(%)

NS

115.9

94.5

124.8

115.6

ADP

237.3

259

185.6

216.0



CB
CHS
.




PCI

Tsoumani M, et al. Expert Opinion on Pharmacotherapy, Accepted

5-

(baseline)

(n=96)

(n=45)
CHS (Plavix) 600 mg ,
75 mg/
A 325 mg , 100 mg/
LMWH () 1mg/Kg/12h
(40 mg/day)

1-

(n=51)
CB (Clovelen) 600 mg ,
75 mg/
325 mg loading dose, 100 mg/
LMWH () 1mg/Kg/12h
(40 mg/)

72 .
PCI 4 .

(n=96)

, /
()

76 / 20
63.910.7

, n (%)

(x 109/L)
(x 109/L)
(x 109/L)
(x 109/L)
, MPV (fl)
(mg/dL)
HDL- (mg/dL)
(mg/dL)
LDL- (mg/dL)

40 (41.7)
57 (59.4)
44 (45.8)
16 (16.6)
39 (40.6)
58 (60.4)

, n (%)

0 (0)

ACS, n (%)

PCI

28 (29.2)
68 (70.8)

(Plavix)
(Clovelen)

45
51

, n(%)
-

ACE
ARBs
PPi

19 (19.8)
22 (22.9)
37 (38.5)
24 (25.0)
96 (100.0)
11 (11.5)

8.93.8
4.82.7
1.72.9
22168
12.02.3
20839
44.09.8
13239
13735

 VASP
5-

CB

23,5%

1-

11,8%

76,5%

88,2%

CHS
11,1%

22,2%
77,8%

88,9%

 , %

, %

ADP 5-
1-
100
90
80
70
60
50
40
30
20
10
0

5-
1-M

ADP, 2.5 M

ADP, 5
CHS

ADP, 10

ADP, 2.5 M

ADP, 5

ADP, 10

100
90
80
70
60
50
40
30
20
10
0

CB

 CHS CB 5-
1-
ADP
60
CHS

IPA, %

50

CB

40
30
20
10
0
2.5

10

2.5

ADP, M

ADP, M

5-

1-

10

IPA; Inhibition of Platelet Aggregation =

 , %

A
TRAP
TRAP-14 5-
1-
100
90
80
70
60
50
40
30
20
10
0

5-
1-M

AA

TRAP-14

, %

CHS
100
90
80
70
60
50
40
30
20
10
0
AA

TRAP-14
CB

 CHS CB 5-
1-
AA TRAP
TRAP-14
80

CHS
70

CB

IPA, %

60
50
40
30
20
10
0

AA

TRAP-14

5-

AA

TRAP-14

1-M

 P-
/
CHS CB

Baseline

5-

1-

Baseline

5-

1-

P(MFI)

5621

2818*

237**

5216

2415*

218**

(%)

5014

309*

246**

5312

2712*

217**

(%)

3511

2312*

167**

3310

246*

126**

. *P<0.01 **P<0.001
baseline (baseline: )

 P-
/
CHS CB
-
70
60
50

P-

40

5-

30

1-

20

62

10

60

58

CHS

CB

56
54

5-

52

1-

50
48

70

46

60

44
CHS

CB

50
40

5-

30

1-

20
10
0
CHS

CB


CB
CHS
PCI, 5 1-
.




,




,
,

.



,




.