Prasugrel Compared With High Loading– and Maintenance–Dose Clopidogrel in Patients With Planned Percutaneous Coronary Intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 Trial

Background— The increasing use of higher-than-approved doses of clopidogrel in clinical practice is based in part on the desire for greater levels of inhibition of platelet aggregation (IPA). Prasugrel is a new thienopyridine that is more potent than standard-dose clopidogrel in healthy subjects and patients with stable coronary artery disease. The relative antiplatelet effects of prasugrel versus high-dose clopidogrel in percutaneous coronary intervention patients are unknown. Methods and Results— Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) was a randomized, double-blind, 2-phase crossover study of prasugrel compared with high-dose clopidogrel in patients undergoing cardiac catheterization for planned percutaneous coronary intervention. The primary end point of the loading-dose phase (prasugrel 60 mg versus clopidogrel 600 mg) was IPA with 20 &mgr;mol/L ADP at 6 hours. Patients with percutaneous coronary intervention entered the maintenance-dose phase, a 28-day crossover comparison of prasugrel 10 mg/d versus clopidogrel 150 mg/d with a primary end point of IPA after 14 days of either drug. In this study, 201 subjects were randomized. IPA at 6 hours was significantly higher in subjects receiving prasugrel (mean±SD, 74.8±13.0%) compared with clopidogrel (31.8±21.1%; P<0.0001). During the maintenance-dose phase, IPA with 20 &mgr;mol/L ADP was higher in subjects receiving prasugrel (61.3±17.8%) compared with clopidogrel (46.1±21.3%; P<0.0001). Results were consistent across all key secondary end points; significant differences emerged by 30 minutes and persisted across all time points. Conclusions— Among patients undergoing cardiac catheterization with planned percutaneous coronary intervention, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Maintenance therapy with prasugrel 10 mg/d resulted in a greater antiplatelet effect than 150 mg/d clopidogrel.

[1]  K. Kent,et al.  Clopidogrel loading dose (300 versus 600 mg) strategies for patients with stable angina pectoris subjected to percutaneous coronary intervention. , 2006, The American journal of cardiology.

[2]  E. Antman,et al.  Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). , 2006, American heart journal.

[3]  W. Herzog,et al.  The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. , 2005, Journal of the American College of Cardiology.

[4]  K. Winters,et al.  Cytochrome P450 3A Inhibition by Ketoconazole Affects Prasugrel and Clopidogrel Pharmacokinetics and Pharmacodynamics Differently , 2007, Clinical pharmacology and therapeutics.

[5]  A. Gori,et al.  Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. , 2007, Journal of the American College of Cardiology.

[6]  K. Winters,et al.  A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. , 2007, British journal of clinical pharmacology.

[7]  Carl J Pepine,et al.  ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients , 2002, Journal of the American College of Cardiology.

[8]  K. Winters,et al.  Increased Active Metabolite Formation Explains the Greater Platelet Inhibition With Prasugrel Compared to High-dose Clopidogrel , 2007, Journal of cardiovascular pharmacology.

[9]  H. Hod,et al.  Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction , 2004, Circulation.

[10]  Lippincott Williams Wilkins,et al.  ACC/AHA/SCAI Practice Guidelines, February 21, 2006 , 2006 .

[11]  Joseph P Ornato,et al.  ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to update the 2001 Guidelines for Percutaneous Coronary Intervention , 2006, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[12]  E. Antman,et al.  Clopidogrel resistance: a new chapter in a fast-moving story. , 2004, Circulation.

[13]  G. Lamas,et al.  ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients wi , 2004, Journal of the American College of Cardiology.

[14]  A. Kastrati,et al.  Absorption, Metabolization, and Antiplatelet Effects of 300-, 600-, and 900-mg Loading Doses of Clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial , 2005, Circulation.

[15]  F. Neumann,et al.  Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. , 2006, Journal of the American College of Cardiology.

[16]  V. Pasceri,et al.  Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention: Results From the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study* , 2005, Circulation.

[17]  A. Siegbahn,et al.  Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. , 2006, European heart journal.

[18]  M. Furman,et al.  Current options in platelet function testing. , 2006, The American journal of cardiology.

[19]  E. Antman,et al.  Prasugrel versus clopidogrel in patients with acute coronary syndromes. , 2007, The New England journal of medicine.

[20]  J. Jakubowski,et al.  Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. , 2005, Seminars in thrombosis and hemostasis.

[21]  A. Siegbahn,et al.  Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. , 2007, European heart journal.

[22]  K. Winters,et al.  A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. , 2007, American heart journal.

[23]  S. Wiviott.  Clopidogrel response variability, resistance, or both? , 2006, The American journal of cardiology.

[24]  J. Ornato,et al.  ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). , 2006, Circulation.

[25]  Antonio Colombo,et al.  Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. , 2005, European heart journal.

[26]  A. Kastrati,et al.  Loading With 600 mg Clopidogrel in Patients With Coronary Artery Disease With and Without Chronic Clopidogrel Therapy , 2004, Circulation.

[27]  Kevin P. Bliden,et al.  Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity , 2003, Circulation.

[28]  Deepak L. Bhatt,et al.  Variability in platelet responsiveness to clopidogrel among 544 individuals. , 2005, Journal of the American College of Cardiology.

[29]  D. Angiolillo,et al.  Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients With Diabetes Mellitus and Coronary Artery Disease: Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) Study , 2007, Circulation.

[30]  K. Winters,et al.  Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status. , 2007, The American journal of cardiology.

[31]  F. Neumann,et al.  Time Dependence of Platelet Inhibition After a 600-mg Loading Dose of Clopidogrel in a Large, Unselected Cohort of Candidates for Percutaneous Coronary Intervention , 2005, Circulation.

[32]  J. Ornato,et al.  ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: A report of the American college of cardiology/American heart association task force on practice guidelines(ACC/AHA/SCAI writing committee to update the 2001 guidelines for percutaneous coronary intervention) , 2006, Journal of the American College of Cardiology.

[33]  G. Montalescot,et al.  A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. , 2006, Journal of the American College of Cardiology.

[34]  M. O’Donoghue,et al.  Clopidogrel Response Variability and Future Therapies: Clopidogrel: Does One Size Fit All? , 2006, Circulation.

[35]  Carl J Pepine,et al.  ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients , 2002, Circulation.

[36]  C. Macaya,et al.  High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. , 2004, European heart journal.

[37]  P. Gurbel,et al.  Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets: Results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) Study , 2005, Circulation.

[38]  P. Gurbel,et al.  Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. , 2005, Journal of the American College of Cardiology.

[39]  Li Zhang,et al.  A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. , 2008, European heart journal.

[40]  K. Hagihara,et al.  The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite , 2007, Journal of thrombosis and haemostasis : JTH.

[41]  Joseph P Ornato,et al.  ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). , 2006, Journal of the American College of Cardiology.