1. Farmaci antiaggreganti
Marco Cattaneo
Clinica Medica
Ospedale San Paolo – Università degli Studi di Milano

2. PLATELET
GP IIb/IIIa
Antagonists
GPIIb/IIIa
Adhesive
TxA2 protein ADP
GPIIb/IIIa
TxA2-R P2Y12
Arachidonic
Acid Thienopirydines
COX-1 ASPIRIN
delta
granule
PGH2 TxA2
Tx synthase
PLATELET

3. Characteristics of the ideal
antithrombotic agent
•Potent antithrombotic effect
•Low risk
•Predictable pharmakodynamic profile, making monitoring
unnecessary
•Rapid onset
•Rapid offset*
•Availability of an antidote
•No interaction with food or adjunctive medicines commonly
used
•Low cost
* For safety reasons, a drug with rapid offset is generally preferable to a drug with
long-lasting effects, although the use of the latter might minimize the negative effects
of poor compliance.

4. Kaplan-Meier estimates of mortality during the first 30 days among patients who
developed and those who did not develop major bleeding
Eikelboom, J. W. et al. Circulation 2006;114:774-782

5. Reletionship between inhibition of platelet aggregation
and the risk of thrombosis or bleeding
Inhibition of hemostasis (%)
“Responders”
Thrombosis
Bleeding
“Non Responders”

6. Characteristics of the ideal
antithrombotic agent
•Potent antithrombotic effect
•Low risk
•Predictable pharmakodynamic profile, making monitoring
unnecessary
•Rapid onset
•Rapid offset*
•Availability of an antidote
•No interaction with food or adjunctive medicines commonly
used
•Low cost
* For safety reasons, a drug with rapid offset is generally preferable to a drug with
long-lasting effects, although the use of the latter might minimize the negative effects
of poor compliance.

7. Reletionship between inhibition of platelet aggregation
and the risk of thrombosis or bleeding
Inhibition of hemostasis (%)
“Responders”
Thrombosis
Bleeding
“Non Responders”
Time of treatment

8. Reletionship between inhibition of platelet aggregation
and the risk of thrombosis or bleeding
Inhibition of hemostasis (%)
“Responders”
Thrombosis
Bleeding
“Non Responders”
Time of treatment

9. INR-Specific Incidence of All Adverse Events (All Episodes of Thromboembolism, All Major
Bleeding Episodes, and Unclassified Stroke)
Thrombosis Bleeding
Cannegieter S et al. N Engl J Med 1995;333:11-17

10. Reletionship between inhibition of platelet aggregation
and the risk of thrombosis or bleeding
Inhibition of hemostasis (%)
“Responders”
Thrombosis
Bleeding
“Non Responders”
Time of treatment

11. “Evolution” of antithrombotic treatment
ANTICOAGULANT
Need for laboratory
monitoring
No Need for laboratory
monitoring

12. “Evolution” of antithrombotic treatment
ANTICOAGULANT ANTIPLATELET
Need for laboratory Need for laboratory
monitoring monitoring
No Need for laboratory No need for laboratory
monitoring monitoring

13. ASPIRIN

14. Prevalence of “Aspirin resistance”
But:
Hillarp et al, 2003 122 Arachidonic acid-induced WB aggregation 0.8%
Tantry et al, 2005 223 Arachidonic acid-induced PRP aggregation 0.4%
Fontana et al, 2006 96 Serum TxB2 1.0%
Frelinger et al, 2006 680 Serum TxB2 1.0%
(uncompliant or
under-dosed)
Campbell & Steinhubl, 2005

15. THIENOPYRIDINES

16. agonist ADP
ADP prostacyclin
specific
P2Y12 IP receptor
receptor
Gq Gi Gs
PI3K AC
δ
cAMP
stabilization
Platelet aggregation

17. THIENOPYRIDINES ACTIVE METABOLITES
N HOOC N
S Cl HS Cl
Ticlopidine
O O
CH3 CH3
N HOOC N
S Cl HS Cl
Clopidogrel

18. O
CH3
HOOC N
agonist S Cl
prostacyclin
S ADP
specific
P2Y12 IP receptor
receptor
Gq Gi Gs
AC
δ
cAMP
Platelet aggregation

19. Prevalence of resistance to
antiplatelet agents
• Aspirin (serum TxB2) ≈ 0-5% (*)
• Clopidogrel (P2Y12-specific assays) ≈ 30%
(*) mostly due to non-compliance

20. Schematic representation of the metabolism
of clopidogrel
Mega, J. L. et al. Circulation 2009;119:2553-2560

21. ORs for MACE, according to CYP2C19*2 allele (n=11,959),
and PPI use (n=46,037)
Hulot et al, JACC 2010

22. Risk for cardiovascular death, myocardial infarction, or stroke for subtypes of PPIs.Time-
dependent, propensity score–matched Cox proportional hazards analysis.
Charlot M et al. Ann Intern Med 2010;153:378-386

23. Kaplan–Meier Estimates of the Probability of Remaining Free of Primary Cardiovascular
Events, According to Study Group.
Bhatt DL et al. N Engl J Med 2010. DOI: 10.1056/NEJMoa1007964

24. Other factors affecting the response to
clopidogrel
Higher response Lower response
Age
√
Body weight
√
Diabetes mellitus
√
Renal failure in diabetes m.
√
Smoking
√

25. Response variability (“resistance”) to Clopidogrel
The solution?
“Tailored treatment”:
increase the dose of Clopidogrel in poor responders
(based on the results of platelet function tests)
tests)
Is it the right approach?
approach?

26. Who would dare arguing against?
“Responders”
“Non Responders”

27. Laboratory monitoring of clopidogrel therapy
Questions that need to be answered
• Which test of platelet function?
• Is it really effective?
• Is it the solution for all patients?
• Is it safe?
• Is it cost-effective?

28. Studio GRAVITAS

29. GRAVITAS Trial - Profile
Price, M. J. et al. JAMA 2011;305:1097-1105

30. Cumulative Kaplan-Meier Estimates of the Time to the First
Adjudicated Occurrence of the Primary Efficacy End Point
Price, M. J. et al. JAMA 2011;305:1097-1105

31. Response variability (“resistance”) to Clopidogrel
Another solution?
Change the drug!

32. THIENOPYRIDINES ACTIVE METABOLITES
N HOOC N
S Cl HS Cl
Ticlopidine
O O
CH3 CH3
N HOOC N
S Cl HS Cl
Clopidogrel
O
O O
CH3 O N HOOC N
S F HS F
Prasugrel

33. Schematic representation of the metabolism
of clopidogrel and prasugrel
Mega, J. L. et al. Circulation 2009;119:2553-2560

34. Inhibition of ADP (20µM)-induced platelet aggregation
Prasugrel 60+10
Clopidogrel 600+75
Clopidogrel 300+75
Payne et al, J Cardiovasc Pharmacol 2007

35. Reletionship between IPA by Clopidogrel 300 mg or
Prasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose
“Responders”
“Non Responders”
Brandt et al, Am Heart J 2007

36. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points
during the Follow-up Period, in TRITON-TIMI 38
Wiviott S et al. N Engl J Med 2007

37. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points
during the Follow-up Period, in TRITON-TIMI 38
Wiviott S et al. N Engl J Med 2007

38. Effects of Prasugrel and Clopidogrel active metabolites (AM)
on human platelet aggregation induced by ADP (10 µM)
Sugidachi et al, JTH 2007

39. Reletionship between drug-induced inhibition of hemostasis
and the risk of thrombosis or bleeding
Inhibition of hemostasis (%)
“Responders”
Thrombosis
Bleeding
“Non Responders”

40. Reletionship between IPA by Clopidogrel 300 mg or
Prasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose
“Responders”
Thrombosis
Bleeding
“Non Responders”
Brandt et al, Am Heart J 2007

41. Short-acting, direct P2Y12 antagonists
(Cangrelor) (Ticagrelor)

42. DISPERSE Study: Faster and More Consistent IPA
With AZD6140 Than With Clopidogrel (Final Extent)
Clopidogrel 75 mg qd AZD6140 100 mg bid
Day 1 Day 14 Day 1 Day 14
100 100
80 80
60 60
40 40
20 20
2 4 8 12 2 4 8 12 24 2 4 8 12 2 4 8 12 24
Time, h Time, h
Husted S. Presented at ESC 2005.

43. IPA (%; 20 {micro}mol/L ADP, final extent) by protocol time and treatment
Gurbel, P. A. et al. Circulation 2009;120:2577-2585

44. Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated
Occurrence of the Primary Efficacy End Point
Wallentin L et al. N Engl J Med 2009;361:1045-1057

45. Incidence of the primary end-point and non-CABG related
TIMI-major bleeding events in patients who received ticagrelor vs patients
who received clopidogrel in the PLATO trial.
Events Ticagrelor Clopidogre Hazard p
no/total lno/total Ratio
(%) (%) (95% C.I.)
Primary end point 864/9333 1014/9291 0.84 <0.001
(composite of vascular (9.8) (11.7) (0.77-0.92)
death, myocardial infarction
or stroke)
Non-CABG-related major 221/9235 177/9186 1.25 0.03
bleedings, TIMI criteria (2.8) (2.2) (1.03-1.53)
Wallentin and PLATO Investigators, NEJM 2009

46. Major Efficacy End Points at 12 Months
Wallentin L et al. N Engl J Med 2009;361:1045-1057

47. Held et al, JACC 2011

48. Short-acting, direct P2Y12 antagonists
(Cangrelor) (Ticagrelor)

49. ELINOGREL
• Elinogrel is direct-acting, competitive, reversible P2Y12 non-
nucleotide antagonist
• IC50 ~2-3 µM in ADP aggregation (PRP)
• Highly selective for P2Y12 (does not inhibit P2Y1 or other purinergic
receptors)
• Oral bioavailability ~50%
• T1/2 ~12 h (BID drug) (Elimination: 50% renal, 50% hepatic)
• Tmax 2-6 h

50. INNOVATE PCI - Adverse Events
Clopidogrel Pooled elinogrel Pooled elinogrel
N=208 100 mg 150 mg
N=201 N=207
Any SAE 11.1% 14.9% 12.6%
Drug d/c due to AE or SAE 7.2% 7.5% 10.1%
Dyspnea* 4.3% 15.4% 12.1%
Bradycardia 0.5% 1.0% 0.5%
Syncope 0.5% 1.5% 0.5%
ALT/AST > 3x^ 1.0% 4.0% 4.8%
ALT/AST > 5x 0.5% 2.0% 3.4%
* Dyspnea was generally mild, transient, and infrequently led to discontinuation
^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when treatment
was continued; No Hy’s Law cases.

51. Dyspnea in PLATO trial
Ticagrelor Clopidogrel
All patients (n=9,235) (n=9,186) p value*
Dyspnea, %
Any 13.8 7.8 <0.001
With discontinuation of study treatment 0.9 0.1 <0.001

52. Cangrelor and dyspnoea
• CHAMPION PCI: a dyspnoea adverse event
was reported in 1.0% of patients receiving
cangrelor and 0.4% of patients receiving only
clopidogrel (P = 0.001)
• CHAMPION PLATFORM: a dyspnoea adverse
event was reported in 1.4% of patients receiving
cangrelor and 0.5% of patients receiving
placebo (P = 0.002)