THE CURRENT CLOPIDOGREL LOADING DOSE: IRRELEVANT, TOO LOW, OR TOO LATE? Giuseppe Biondi Zoccai University of Turin, Turin, Italy METCARDIO, Turin, Italy gbiondizoccai@gmail.com Consensus in Cardiologia: Cardiologi a confronto sull’aterotrombosi Roma, 20/6/2008 – 9.00-9.20

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

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?

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?

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

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

THE CURE TRIAL N=12,562 patients with unstable angina or non-ST-elevation myocardial infarction 20% RRR p=0.00009 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;345:494-502

THE CLARITY-TIMI 28 TRIAL Sabatine et al, NEJM 2005;352:1179-89

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

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?

WHEN IS MUCH TOO MUCH?

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

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

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

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

600 MG LOADING IN UNSTABLE PATIENTS – THE ISAR-REACT 2 TRIAL Kastrati et al, JAMA 2006;295:1531-38

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

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

SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING

SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING Lotrionte et al, Am J Cardio 2007;100:1199-1206

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?

WHEN IS EARLY TOO EARLY?

HOW LONG DOES IT TAKE FOR CLOPIDOGREL TO ACT? Hochholzer et al, Circulation 2005;111:2560-64

HOW LONG DOES IT TAKE FOR CLOPIDOGREL TO ACT? 600 mg -> 2 hours Hochholzer et al, Circulation 2005;111:2560-64

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

THE CREDO TRIAL p=0.051 favoring 300 mg clopidogrel loading>6 hours before PCI Steinhubl et al, JAMA 2002;288:2411-20

DOES EARLY 300 MG PRETREATMENT OF STABLE PATIENTS MAKE SENSE?

DOES EARLY 600 MG PRETREATMENT OF STABLE PATIENTS MAKE SENSE?

ANTICIPATING LOADING IN STABLE PATIENTS Widimsky et al, Eur Heart J 2008;29:1495-1503

ANTICIPATING LOADING IN STABLE PATIENTS Widimsky et al, Eur Heart J 2008;29:1495-1503

ANTICIPATING LOADING IN STABLE PATIENTS Widimsky et al, Eur Heart J 2008;29:1495-1503

ANTICIPATING (AND INCREASING) LOADING IN UNSTABLE PATIENTS

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

TAKE HOME MESSAGES

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

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RESERVE SLIDES

WHAT ABOUT OTHER DRUGS? THE PRINCIPLE-TIMI 44 Wiviott et al, Circulation 2007;116:2923-32

WHAT ABOUT OTHER DRUGS? THE PRINCIPLE-TIMI 44 Wiviott et al, Circulation 2007;116:2923-32

WHAT ABOUT OTHER DRUGS? THE TRITON-TIMI 38 Wiviott et al, Lancet 2008;371:1353-63

WHAT ABOUT OTHER DRUGS? THE TRITON-TIMI 38 Wiviott et al, Lancet 2008;371:1353-63

WHAT ABOUT OTHER DRUGS? THE TRITON-TIMI 38 Wiviott et al, Lancet 2008;371:1353-63