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The New England Journal of Medicine Aug 2001Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients.
METHODS
We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months.
RESULTS
The first primary outcome--a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke--occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome--the first primary outcome or refractory ischemia--occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86; 95 percent confidence interval, 0.79 to 0.94; P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.2 percent [corrected] vs. 1.8 percent; P=0.13) or hemorrhagic strokes (0.1 percent vs. 0.1 percent).
CONCLUSIONS
The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel.
Topics: Acute Disease; Aged; Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Electrocardiography; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Risk Factors; Ticlopidine
PubMed: 11519503
DOI: 10.1056/NEJMoa010746 -
Current Cardiology Reports Jul 2013Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the... (Review)
Review
Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established critical pathways and specific loci modulating therapeutic responses to commonly used drugs such as clopidogrel, warfarin, and statins. In addition, genomic approaches have defined mechanisms and genetic variants underlying important toxicities with these and other drugs. These findings have not only resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described to date might be deployed in clinical decision making.
Topics: Adrenergic beta-Antagonists; Cardiovascular Agents; Cardiovascular Diseases; Clopidogrel; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polymorphism, Genetic; Practice Guidelines as Topic; Ticlopidine; Warfarin
PubMed: 23689943
DOI: 10.1007/s11886-013-0376-0 -
Circulation Journal : Official Journal... 2015Platelets initiate the formation of a thrombus at the site of an arterial injury, and the clotting cascade is activated as the thrombus matures. After coronary stent... (Review)
Review
Platelets initiate the formation of a thrombus at the site of an arterial injury, and the clotting cascade is activated as the thrombus matures. After coronary stent placement, dual antiplatelet therapy (DAPT) with aspirin and ticlopidine dramatically reduces the risk of stent thrombosis, compared with anticoagulation therapy, and has become the standard of care for prevention of stent thrombosis. Clopidogrel is a second-generation thienopyridine that eliminates the serious side effects of ticlopidine, and new P2Y12 receptor blockers have emerged to overcome the limitations of clopidogrel. Current guidelines recommend DAPT with aspirin and clopidogrel for 1 month after implantation of bare-metal stents, and for 6-12 months after implantation of drug-eluting stents (DES). In patients with acute coronary syndrome (ACS), DAPT administration for 12 months was shown to be superior to aspirin alone for the prevention of recurrent events. Treatment with aspirin and new P2Y12 receptor blockers has further reduced the rate of cardiovascular death, myocardial infarction or stroke after ACS compared with aspirin and clopidogrel. Nonetheless, long-term DAPT increases the risk of major bleeding, requiring a delicate balance between anti-ischemic benefit and bleeding risk. In summary, DAPT should be maintained for at least 6-12 months after implantation of DES, and for at least 12 months after ACS, unless contraindicated.
Topics: Aspirin; Clopidogrel; Coronary Artery Disease; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Stents; Ticlopidine
PubMed: 25744739
DOI: 10.1253/circj.CJ-14-1348 -
AJNR. American Journal of Neuroradiology Dec 2011Clopidogrel is an inhibitor of platelet aggregation, indicated for the prevention of ischemic stroke and in-stent thrombosis. However, it has a number of drawbacks,...
Clopidogrel is an inhibitor of platelet aggregation, indicated for the prevention of ischemic stroke and in-stent thrombosis. However, it has a number of drawbacks, including an increased risk of hemorrhage; a clinical effect that is slow in onset and irreversible; a genetically determined variability in its clinical potency; and interactions with other commonly administered drugs.
Topics: Clopidogrel; Dose-Response Relationship, Drug; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Stroke; Ticlopidine
PubMed: 22135129
DOI: 10.3174/ajnr.A2913 -
The Journal of Thoracic and... Dec 2014
Topics: Acute Coronary Syndrome; Clopidogrel; Coronary Artery Bypass; Humans; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Ticlopidine
PubMed: 25451509
DOI: 10.1016/j.jtcvs.2014.09.093 -
International Journal of Environmental... Mar 2017Clopidogrel has significantly reduced the incidence of recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing... (Review)
Review
Clopidogrel has significantly reduced the incidence of recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). However, recurrence events still remain, which may be partly due to inadequate platelet inhibition by standard clopidogrel therapy. Genetic polymorphisms involved in clopidogrel's absorption, metabolism, and the P2Y12 receptor may interfere with its antiplatelet activity. Recent evidence indicated that epigenetic modification may also affect clopidogrel response. In addition, non-genetic factors such as demographics, disease complications, and drug-drug interactions can impair the antiplatelet effect of clopidogrel. The identification of factors contributing to the variation in clopidogrel response is needed to improve platelet inhibition and to reduce risk for cardiovascular events. This review encompasses the most recent updates on factors influencing pharmacokinetic and pharmacodynamic responses to clopidogrel.
Topics: Acute Coronary Syndrome; Clopidogrel; Comorbidity; Drug Interactions; Humans; Middle Aged; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Receptors, Purinergic P2Y12; Severity of Illness Index; Socioeconomic Factors; Ticlopidine; Treatment Outcome
PubMed: 28335443
DOI: 10.3390/ijerph14030301 -
The Annals of Thoracic Surgery Dec 2011
Topics: Clopidogrel; Humans; Perioperative Care; Platelet Aggregation Inhibitors; Pneumonectomy; Ticlopidine
PubMed: 22115205
DOI: 10.1016/j.athoracsur.2011.08.009 -
Current Cardiology Reports Jul 2013Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and... (Review)
Review
Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with new diagnostic targets and therapeutic strategies hold promise for more effective individualized anti-coagulation and anti-platelet therapy.
Topics: Anticoagulants; Clopidogrel; Humans; Platelet Aggregation Inhibitors; Thrombosis; Ticlopidine; Treatment Outcome; Warfarin
PubMed: 23797323
DOI: 10.1007/s11886-013-0381-3 -
The New England Journal of Medicine Mar 2011
Review
Topics: Anti-Infective Agents; Antineoplastic Agents; Aromatase Inhibitors; Cardiovascular Agents; Clopidogrel; Genome-Wide Association Study; Genomics; Genotype; Humans; Neoplasms; Pharmacogenetics; Polymorphism, Genetic; Ticlopidine; Warfarin
PubMed: 21428770
DOI: 10.1056/NEJMra1010600 -
Circulation Journal : Official Journal... 2012Oral antiplatelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients with acute coronary syndrome and those undergoing... (Review)
Review
Oral antiplatelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopdiogrel, the most important of which is the wide response variability of platelet inhibition. The response to clopidogrel is affected by various clinical variables, genetic variations involved in its activation, and drug-drug interactions. Therefore, clinicians are faced with challenges in situations where high inhibition of platelets is necessary and in cases where the response to clopidogrel may be suboptimal. There are various ways of overcoming the response variability and this review will focus on the practical methods available. Namely, the data and evidence regarding increasing the dose of clopidogrel, adding cilostazol to standard dual antiplatelet therapy, and switching to more recently developed agents will be covered.
Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Clopidogrel; Combined Modality Therapy; Genotype; Humans; Pharmacogenetics; Platelet Aggregation Inhibitors; Ticlopidine
PubMed: 22240602
DOI: 10.1253/circj.cj-11-1494