1. THE CURRENT CLOPIDOGREL LOADING DOSE: IRRELEVANT, TOO LOW, OR TOO LATE?
Giuseppe Biondi Zoccai
University of Turin, Turin, Italy
METCARDIO, Turin, Italy
Consensus in Cardiologia: Cardiologi a confronto sull’aterotrombosi
Roma, 20/6/2008 –

2. DISCLOSURE
Consultant: Boston Scientific, Cordis, genae, Invatec, Mediolanum Cardio Research
Lecture fees: Bristol-Myers Squibb, Sanofi Aventis
Research grants: AIFA

3. LEARNING GOALS
What is the currently approved loading dose of clopidogrel and why?
Is it worthwhile to increase the clopidogrel loading dose?
Is it worthwhile to anticipate the loading dose?

4. LEARNING GOALS
What is the currently approved loading dose of clopidogrel and why?
Is it worthwhile to increase the clopidogrel loading dose?
Is it worthwhile to anticipate the loading dose?

5. RESHAPING THE EVIDENCE BASE IS CHALLENGING
300 MG LOADING: IMMEDIATELY IN ACS OR >6 HOURS BEFORE PCI

6. Steinhubl et al, JAMA 2002;288:2411-20
THE CREDO TRIAL
Steinhubl et al, JAMA 2002;288:

7. THE CURE TRIAL N=12,562 patients with unstable angina
or non-ST-elevation myocardial infarction
20% RRR p=
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Placebo + ASA
Cumulative hazard rate of CV death, MI or stroke
Clopidogrel 300 mg loading and then 75
mg/d + ASA 3 6 9 12
Yusuf et al, NEJM 2001;345:

8. THE CLARITY-TIMI 28 TRIAL
Sabatine et al, NEJM 2005;352:

9. COMMIT Investigators, Lancet 2005;366:1607-21
THE COMMIT TRIAL
COMMIT Investigators, Lancet 2005;366:

10. LEARNING GOALS
What is the currently approved loading dose of clopidogrel and why?
Is it worthwhile to increase the clopidogrel loading dose?
Is it worthwhile to anticipate the loading dose?

11. WHEN IS MUCH TOO MUCH?

12. Von Beckerath et al, Circulation 2005;112:2946-50
600 or 900 MG LOADING?
Von Beckerath et al, Circulation 2005;112:

13. Von Beckerath et al, Circulation 2005;112:2946-50
600 or 900 MG LOADING?
Von Beckerath et al, Circulation 2005;112:

14. Montalescot et al, J Am Coll Cardiol 2006;48:931-8
600 or 900 MG LOADING?
Montalescot et al, J Am Coll Cardiol 2006;48:931-8

15. 600 MG LOADING IN STABLE PATIENTS – THE ISAR-REACT TRIAL
600 mg of clopidogrel at least 2 hours before PCI
Kastrati et al, NEJM 2004;350:232-8

16. 600 MG LOADING IN UNSTABLE PATIENTS – THE ISAR-REACT 2 TRIAL
Kastrati et al, JAMA 2006;295:

17. 600 MG LOADING IN AMI – THE BRAVE-3 STUDY
p>0.05 %
p>0.05
Mehilli et al, ACC 2008

18. 600 MG RELOADING: THE ARMYDA-RELOAD TRIAL
Patients on 75 mg/d of clopidogrel for >10 days 9
6.8 %
0.5
Placebo
600 mg Clopidogrel reload
DiSciascio et al, ACC 2008

19. SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING

20. SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING
Lotrionte et al, Am J Cardio 2007;100:

21. LEARNING GOALS
What is the currently approved loading dose of clopidogrel and why?
Is it worthwhile to increase the clopidogrel loading dose?
Is it worthwhile to anticipate the loading dose?

22. WHEN IS EARLY TOO EARLY?

23. HOW LONG DOES IT TAKE FOR CLOPIDOGREL TO ACT?
Hochholzer et al, Circulation 2005;111:

24. HOW LONG DOES IT TAKE FOR CLOPIDOGREL TO ACT?
600 mg -> 2 hours
Hochholzer et al, Circulation 2005;111:

25. Steinhubl et al, JAMA 2002;288:2411-20
THE CREDO TRIAL
Steinhubl et al, JAMA 2002;288:

26. THE CREDO TRIAL
p=0.051 favoring 300 mg clopidogrel loading>6 hours before PCI
Steinhubl et al, JAMA 2002;288:

27. DOES EARLY 300 MG PRETREATMENT OF STABLE PATIENTS MAKE SENSE?

28. DOES EARLY 600 MG PRETREATMENT OF STABLE PATIENTS MAKE SENSE?

29. ANTICIPATING LOADING IN STABLE PATIENTS
Widimsky et al, Eur Heart J 2008;29:

30. ANTICIPATING LOADING IN STABLE PATIENTS
Widimsky et al, Eur Heart J 2008;29:

31. ANTICIPATING LOADING IN STABLE PATIENTS
Widimsky et al, Eur Heart J 2008;29:

32. ANTICIPATING (AND INCREASING) LOADING IN UNSTABLE PATIENTS

33. ANTICIPATING (AND INCREASING) LOADING IN UNSTABLE PATIENTS
Patients with ACS (UA/NSTEMI or STEMI) planned for early invasive
strategy, i.e. intend for PCI as early as possible within 72 hrs of randomization
RANDOMIZE
Clopidogrel High Dose Group
Clopidogrel 600mg loading dose Day 1
followed by 150mg from Day 2 to Day 7;
then 75mg from Day 8 to 30
Clopidogrel Standard Dose Group
Clopidogrel 300mg (+placebo) Day 1 followed by 75mg (+placebo) from Day 2 to Day 7; 75mg from Day 8 to 30
RANDOMIZE
RANDOMIZE
ASA low dose group
At least 300mg Day1;
75–100mg from D2 to D30
ASA high dose group
At least 300mg Day1;
300mg–325mg from D2 to D30
ASA low dose group
At least 300mg Day1;
75–100mg from D2 to D30
ASA high dose group
At least 300mg Day1;
300mg–325mg from D2 to D30

34. TAKE HOME MESSAGES

35. TAKE HOME MESSAGES
Several trials and guidelines support a clopidogrel loading dose of at least 300 mg
A 600 mg loading dose is recommended in patients at high risk of ischemic events and low bleeding risk who are undergoing PCI
These loading doses should be administered immediately at diagnosis in patients with acute coronary syndromes, and between 2 hours before and just before PCI in stable patients

36. For further slides on these topics please feel free to visit the metcardio.org website:

37. RESERVE SLIDES

38. WHAT ABOUT OTHER DRUGS? THE PRINCIPLE-TIMI 44
Wiviott et al, Circulation 2007;116:

39. WHAT ABOUT OTHER DRUGS? THE PRINCIPLE-TIMI 44
Wiviott et al, Circulation 2007;116:

40. WHAT ABOUT OTHER DRUGS? THE TRITON-TIMI 38
Wiviott et al, Lancet 2008;371:

41. WHAT ABOUT OTHER DRUGS? THE TRITON-TIMI 38
Wiviott et al, Lancet 2008;371:

42. WHAT ABOUT OTHER DRUGS? THE TRITON-TIMI 38
Wiviott et al, Lancet 2008;371: