Ticagrelor versus clopidogrel in patients with acute coronary syndromes.

BACKGROUND Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. METHODS In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. RESULTS At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. CONCLUSIONS In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

[1]  E. Veys,et al.  HL-A AND INFECTIVE SACROILEITIS , 1974 .

[2]  E. Boersma,et al.  Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials ☆ , 2002 .

[3]  S. Yusuf,et al.  Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. , 2006, JAMA.

[4]  C. Cannon,et al.  Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. , 2007, Journal of the American College of Cardiology.

[5]  Michael Weis,et al.  Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. , 2008, European heart journal.

[6]  Jeffrey L. Anderson.  ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction—A Summary Article , 2011 .

[7]  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.

[8]  G. Biondi-Zoccai,et al.  Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention. , 2007, The American journal of cardiology.

[9]  Salim Yusuf,et al.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study , 2001, The Lancet.

[10]  S. Yusuf,et al.  Benefits and Risks of the Combination of Clopidogrel and Aspirin in Patients Undergoing Surgical Revascularization for Non–ST-Elevation Acute Coronary Syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial , 2004, Circulation.

[11]  L. Bolognese,et al.  RANDOMISED TRIAL OF INTRAVENOUS STREPTOKINASE, ORAL ASPIRIN, BOTH, OR NEITHER AMONG 17 187 CASES OF SUSPECTED ACUTE MYOCARDIAL INFARCTION: ISIS-2 , 1988, The Lancet.

[12]  B. Horne,et al.  Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation , 2007, Circulation.

[13]  P. Serruys,et al.  Clinical End Points in Coronary Stent Trials: A Case for Standardized Definitions , 2007, Circulation.

[14]  C. Cannon,et al.  Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. , 2007, Journal of the American College of Cardiology.

[15]  Françoise Dignat-George,et al.  Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. , 2009, The American journal of cardiology.

[16]  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.

[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]  J. Bassand,et al.  Impact of anaemia, bleeding, and transfusions in acute coronary syndromes: a shift in the paradigm. , 2007, European heart journal.

[19]  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.

[20]  D. Chua,et al.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction. , 2005, The New England journal of medicine.

[21]  Catherine Sudlow,et al.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients , 2002, BMJ : British Medical Journal.

[22]  B. Lewis,et al.  Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. , 2005, JAMA.

[23]  D. Dodd.  The Society for Cardiovascular Angiography and Interventions , 2007 .

[24]  P. Sandset,et al.  Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. , 2006, European heart journal.

[25]  William Wijns,et al.  [Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes]. , 2007, Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology.

[26]  G. Montalescot,et al.  Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose: The Reload With Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term With Dual Antiplatelet Therapy (RELOAD) Study , 2008, Circulation.

[27]  R. Collins,et al.  Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial , 2005, The Lancet.

[28]  B. Lewis,et al.  Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. , 2005, JAMA.

[29]  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.

[30]  Jeroen J. Bax,et al.  Universal definition of myocardial infarction. , 2007 .

[31]  A. Skene,et al.  Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. , 2009, American heart journal.

[32]  S. Yusuf,et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. , 2001, The New England journal of medicine.

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

[34]  B. Gersh,et al.  Bivalirudin during primary PCI in acute myocardial infarction. , 2008, The New England journal of medicine.

[35]  Salim Yusuf,et al.  Comparison of fondaparinux and enoxaparin in acute coronary syndromes. , 2006, The New England journal of medicine.

[36]  S. Yusuf,et al.  Early and Late Effects of Clopidogrel in Patients With Acute Coronary Syndromes , 2003, Circulation.

[37]  A. Skene,et al.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. , 2005, The New England journal of medicine.