Robert F. Storey

Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield,

Sheffield, UK

Stent thrombosisFuture directions

Disclosures

RF Storey has received research grant support and/or consultancy fees from AstraZeneca, Lilly, The Medicines Company, Merck Sharp & Dohme, Sanofi Aventis, and Bristol Myers Squibb

Platelet Activation Mechanisms

Storey RF. Current Pharmaceutical Design 2006

Thrombin

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR1

PAR4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

xCLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x AZD6140 CANGRELOR

GPIIB/IIIA ANTAGONISTS

x

On chronic ASA 7 days post ASA Post ASA 300 mg0

20

40

60

80

100

% a

gg

reg

ati

on

Arachidonic acid-induced platelet aggregation in 190 IHD patients

Compliance rather than aspirin resistance

Schwartz et al. Am J Cardiol 2005

Storey RF et al. Platelets 2002; 13: 407-413

Variable response to clopidogrel with incomplete P2Y12 receptor blockadeFinal response to 20 µM ADP before and after clopidogrel 300 mg followed by 75 mg daily for 4-7 days in patients undergoing PCI +/- 150 nM cangrelor added in vitro

0

20

40

60

80

100

Baseline PostClopidogrel

PostClopidogrel+ cangrelor

Mea

n %

Pla

tele

t A

ggre

gatio

n

*

*

* P<0.05

Subacute stent thrombosis

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

Prasugrel

• Novel thienopyridine (CS-747) in phase III development (PCI in ACS patients)

• Different pathways of metabolism to clopidogrel and higher potency probably related to more efficient production of active metabolite

Prasugrel 5-20 mg daily vs clopidogrel 75 mg daily in healthy volunteers – inhibition of ADP induced platelet

aggregation at 10 days

0

20

40

60

80

100

Prasugrel 5 mg

Prasugrel10 mg

Prasugrel20 mg

Clopidogrel75 mg

JA Jakubowski et al. ACC Annual Scientific Session 2005.

Clinical Target Vessel Thrombosis

0.4%0.6%

1.0%0.5%

2.4%

0.0%

2.0%

4.0%

6.0%

Clop Pras 40/7.5 60/10 60/15

P= NS

Target Vessel Revasc or Documented Total Occlusion

RR=0.25 [0.1, 0.9]

P = 0.03

Prasugrel LD/MDTreatment Group

Significant Non-CABG Bleeding 30 d (%)

(TIMI Major + Minor) – Primary Endpoint

1.6%1.7% 1.5%2.0%

1.2%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

Clop Pras 40/7.5 60/10 60/15

P= NSP = 0.77

Prasugrel LD/MDTreatment Group

TRITON – TIMI 38TRITON – TIMI 38

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGRELPRASUGREL CLOPIDOGRELCLOPIDOGREL

11oo endpoint: endpoint: CV death, MI, StrokeCV death, MI, Stroke22oo endpoints: endpoints: CV death, MI, Stroke, Re-ischemiaCV death, MI, Stroke, Re-ischemia

CV death, MI, UTVRCV death, MI, UTVR

Median duration of therapy - 12 months

N= 13,000

AZD6140

• Class: CPTP* (non-thienopyridine)

• Reversible platelet P2Y12 receptor antagonist

• Orally active

• Rapid onset of action (2 h) with or without a loading dose

• Acts directly (no metabolic activation required)

• Plasma t½ ~12 h

*cyclo-pentyl-triazolo-pyrimidine

Comparison of clopidogrel 300 mg loading dose vs AZD6140 90-270 mg

loading doses in ACS patients

0 2 4 6 8 10 120

25

50

75

100

Clopidogrel

AZD6140 90mg

AZD6140 180mg

AZD6140 270mg

Time post dose (h)

Mea

n %

in

hib

tio

n

Inhibition of platelet aggregation induced by ADP 20 M

Suppression of residual platelet aggregation response by AZD6140 in clopidogrel-pretreated ACS patients

0 2 4 6 8 10 120

20

40

60

80

Clopidogrel

AZD6140 90mg

AZD6140 180mg

AZD6140 270mg

Time post dose (h)

Mea

n %

pla

tele

t ag

gre

gat

ion

Platelet aggregation induced by ADP 20 M

PLATOPLATO

Double-blind

ACS (STEMI or NSTEMI)ACS (STEMI or NSTEMI)

ASA

AZD6140AZD6140 CLOPIDOGRELCLOPIDOGREL

N= 16,000

• Estimated number of countries: 40

• Estimated number of sites: 1,000

• Estimated trial size: 16,000 patients

• Patient recruitment to start late 2006

Cangrelor

• Stabilised ATP analogue

• Reversible platelet P2Y12 receptor antagonist

• Intravenous use only

• Onset of action within minutes

• Acts directly (no metabolic activation required)

• Plasma t½ < 9 minutes

• Phase 3 studies - CHAMPION

Higher incidence of late stent thrombosis seen with DES in BASKET-LATE study and in follow up studies of Taxus and Cypher stents

Heparin coated stents – no convincing evidence of clinical benefit

Stem cells – under investigation to assess whether they can be used to promote endothelialisation

Need for new agents, either systemic or stent coated, that reduce neointima formation without impairing endothelialisation

Stent coatings

CONCLUSIONS (1)

True aspirin resistance is rare

Compliance is important – patients should be advised of the reasons for antiplatelet therapy, intended duration of treatment and risks of poor compliance

CONCLUSIONS (2)

Inadequate P2Y12 receptor blockade by clopidogrel in some patients is probably a major risk factor for stent thrombosis and 3 new P2Y12 antagonists are in phase 3 development to address this:

Prasugrel (oral thienopyridine)

AZD6140 (oral reversible antagonist)

Cangrelor (short-acting iv antagonist)

CONCLUSIONS (3)

DES appear to increase the risk of late stent thrombosis and further work is required to establish whether novel stent coatings or systemic agents can reduce subacute and late thrombosis risk