2-oxo-clopidogrel and Acute-Coronary-Syndrome

Background A significant number of ischemic events occur even when adhering to dual antiplatelet therapy including aspirin and clopidogrel. Objectives The aim of our study was to determine predictors of long-term patient clinical outcome, among variables such as prodrug clopidogrel and intermediary metabolite 2-oxoclopidogrel concentrations, as well as patients' clinical characteristics. Setting Department for the Treatment of Acute Coronary Syndrome in tertiary teaching hospital, Serbia. Methods This study enrolled 88 consecutive patients with first STEMI, treated with primary PCI, within 6 h of the chest pain onset and followed them 40 months. On the third day of hospitalization, blood samples were collected from each patient to measure clopidogrel and its metabolite 2-oxo-clopidogrel concentration by UHPLC-DAD-MS method. Main outcome measure Mortality from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke or hospitalization for urgent myocardial revascularization or heart failure. Results The composite clinical outcome of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for urgent myocardial revascularization or heart failure, was registered in 31 patients (35.2%) during the 40-month follow-up. Lower clopidogrel (p < 0.05) and dose-adjusted clopidogrel concentrations (p < 0.05) were associated with the higher incidence of composite outcome events. Their low plasma concentrations may be predicted by fentanyl administration (p < 0.001) and creatinine clearance (p < 0.01). The decrease in dose-adjusted clopidogrel unit for each ng/ml/mg increases the risk 21.7 times (p < 0.05). Conclusion Clopidogrel dose-adjusted plasma concentration in STEMI patients, as well as multivessel coronary artery disease, showed significance in predicting an unfavorable composite clinical outcome after 40-month follow-up.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Chest Pain; Clopidogrel; Coronary Artery Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prognosis; ST Elevation Myocardial Infarction; Ticlopidine; Treatment Outcome

To observe the relationship between ATP-binding cassette subfamily B member 1 (ABCB1) and cytochrome P450 (CYP)2C19 polymorphisms and the effect of clopidogrel post percutaneous coronary intervention in patients with coronary artery disease.. A total of 300 consecutive patients with acute coronary syndrome undergoing selected percutaneous coronary intervention in General Hospital of the People's Liberation Army from October 2010 to August 2012 and treated with clopidogrel were enrolled and retrospectively analyzed. Antiplatelet responsiveness of clopidogrel was estimated by thrombelastograph. The patients were divided into 3 groups: remarkable efficacy group (adenosine diphosphate pathway inhibition rate >80%, 105 cases), effective group (adenosine diphosphate pathway inhibition rate of 50%-80%, 100 cases), and poor responsiveness group (adenosine diphosphate pathway inhibition rate <50%, 95 cases). CYP2C19 and ABCB1 polymorphisms were detected by PCR combined with restrictive fragment length polymorphism (PCR-RELP) method in all patients. A total of 200 patients were performed by high performance liquid chromatography with electrospray tandem mass spectrum methods (HTLC-MS/MS), which was applied for determining the plasma concentration level of clopidogrel metabolites between remarkable efficacy group and poor responsiveness group. Major adverse cardiovascular events and bleeding events were observed through follow-up.. (1) There were significantly differences in gender, smoking and alanine transaminase level among 3 groups(P<0.01 or 0.05). (2)There was no significant difference in the ratio of TT, CC and CT genotype of ABCB1 gene among 3 groups(P>0.05). There was significant difference in the ratio of poor, middle and strong metabolizer genotype of CYP2C19 gene (P<0.05). (3)Recurrent angina rates were 8.6%(9/105), 6.0%(6/100) and 18.9%(18/95) (P<0.05), and bleeding events rates were 1.0% (1/105), 1.0%(1/100) and 8.4%(8/95)respectively (P<0.01) in remarkable efficacy group, effective group and poor responsiveness group during the 1 year follow up. There were no significant difference in rates of myocardial infarction, heart failure, ischemic stroke and death among 3 groups (all P>0.05) during follow up. Rates of major adverse cardiovascular events and bleeding events were similar in patients with TT, CC and CT genotype of ABCB1 (14.6%(13/89), 12.8(19/148)and 11.6%(5/43), P>0.05). Rates of major adverse cardiovascular events and bleeding events were 9.5%(2/21), 17.8(27/152) and 7.5%(8/107) in poor, middle and strong metabolizer genotype of CYP2C19 gene patients (P<0.05). (4) Plasma concentration of clopidogrel was significantly lower and relative concentration of acid metabolites was significantly higher in poor responsiveness group than in remarkable efficacy group(P<0.01 or 0.05). There was no significantly different in plasma relative concentration of 2-oxo-clopidogrel between remarkable efficacy group and poor responsiveness group.. ABCB1 gene polymorphism is not but CYP2C19 gene polymorphisms is related with antiplatelet responsiveness of clopidogrel and clinical cardiovascular disease events in patients with acute coronary syndrome undergoing selected percutaneous coronary intervention.

Topics: Acute Coronary Syndrome; Alleles; Angina Pectoris; ATP Binding Cassette Transporter, Subfamily B; Clopidogrel; Coronary Artery Disease; Cytochrome P-450 CYP2C19; Genotype; Hemorrhage; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Tandem Mass Spectrometry; Ticlopidine