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
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?
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
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
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
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)
