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      Effect of Atorvastatin and Clopidogrel Co-Administration After Coronary Stenting in Korean Patients With Stable Angina

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          Abstract

          Background and Objectives

          It was reported that atorvastatin co-administered with clopidogrel for 8 months did not affect the anti-platelet potency of clopidogrel in Korean patients with acute coronary syndrome, but not in patients with stable angina. We investigated whether co-administration of statins with clopidogrel affected the anti-platelet efficacy of clopidogrel in Korean patients with stable angina.

          Subjects and Methods

          This was a randomized, open-label and two-period crossover design study conducted at two centers. Two hundreds thirty three patients with stable angina scheduled for coronary stenting were randomized into two groups. In Group A, 119 patients first received atorvastatin (10 mg) followed by fluvastatin (80 mg) for 12 weeks per treatment. In Group B, 114 patients received the same treatments in reverse order.

          Results

          Baseline adenosine diphosphate (ADP, 10 µmol/L)-induced platelet aggregation was 54.4±9.1% in Group A and 53.8±9.0% in Group B (p=0.44), and significant differences were noted after each treatment period (p<0.001). Inhibition of platelet aggregation was similar between Group A and Group B at 24 hours following clopidogrel loading (29.2±11.0% vs. 30.4±12.7%; p=0.42). The two treatment least square means of 12-week ADP (10 mol/L)-induced platelet aggregation [29.50±0.79 {standard error (SE)}% on the atorvastatin treatment group vs. 28.16±0.70 (SE)% in the fluvastatin treatment group] in a 2×2 cross-over study were not significantly different (p=0.204).

          Conclusion

          Statin and clopidogrel co-administration for 12 weeks is not associated with attenuated anti-platelet activity of clopidogrel in Korean patients with stable angina after coronary stenting, in support of the findings of similar studies conducted in Caucasian populations.

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          Most cited references32

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          A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.

          (1996)
          Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.
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            A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.

            The clinical benefit of coronary-artery stenting performed in conjunction with coronary angioplasty is limited by the risk of thrombotic occlusion of the stent as well as hemorrhagic and vascular complications of intensive anticoagulation. We compared antiplatelet therapy with conventional anticoagulant therapy with respect to clinical outcomes 30 days after coronary-artery stenting. After successful placement of Palmaz-Schatz coronary-artery stents, 257 patients were randomly assigned to receive antiplatelet therapy (ticlopidine plus aspirin) and 260 to receive anticoagulant therapy (intravenous heparin, phenprocoumon, and aspirin). The primary cardiac end point was a composite measure reflecting death from cardiac causes or the occurrence of myocardial infarction, aortocoronary bypass surgery, or repeat angioplasty. The primary noncardiac end point comprised death from noncardiac causes, cerebrovascular accident, severe hemorrhage, and peripheral vascular events. Of the patients assigned to antiplatelet therapy, 1.6 percent reached a primary cardiac end point, as did 6.2 percent of those assigned to anticoagulant therapy (relative risk, 0.25; 95 percent confidence interval, 0.06 to 0.77). With antiplatelet therapy, there was an 82 percent lower risk of myocardial infarction than in the anticoagulant-therapy group, and a 78 percent lower need for repeat interventions. Occlusion of the stented vessel occurred in 0.8 percent of the antiplatelet-therapy group and in 5.4 percent of the anticoagulant-therapy group (relative risk, 0.14; 95 percent confidence interval, 0.02 to 0.62). A primary noncardiac end point was reached by 1.2 percent of the antiplatelet-therapy group and 12.3 percent of the anticoagulant-therapy group (relative risk, 0.09; 95 percent confidence interval, 0.02 to 0.31). Hemorrhagic complications occurred only in the anticoagulant-therapy group (in 6.5 percent). An 87 percent reduction in the risk of peripheral vascular events was observed with antiplatelet therapy. As compared with conventional anticoagulant therapy, combined antiplatelet therapy after the placement of coronary-artery stents reduces the incidence of both cardiac events and hemorrhagic and vascular complications.
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              Identification and biological activity of the active metabolite of clopidogrel.

              Like ticlopidine, the ADP receptor antagonist clopidogrel is inactive in vitro and must be administered i.v. or orally to exhibit antiaggregatory and antithrombotic activities. We have previously shown that hepatic metabolism is necessary for activity. This study demonstrates that an active metabolite can be generated from human liver microsomes incubated with clopidogrel. Using several analytical methodologies (LC/MS, NMR, chiral supercritical fluid chromatography), we have identified its structure. In vitro, this highly unstable compound, different from that formed from ticlopidine, exhibited all the biological activities of clopidogrel observed ex vivo: Irreversible inhibition of the binding of 33P-2MeS-ADP to washed human platelets (IC50) = 0.53 microM), selective inhibition of ADP-induced platelet aggregation (IC)50 = 1.8 microM) and ADP-induced adenylyl cyclase down-regulation. The irreversible modification of the ADP-receptor site which is responsible for the biological activity could be explained by the formation of a disulfide bridge between the reactive thiol group of the active metabolite and a cysteine residue of the platelet ADP receptor.
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                Author and article information

                Journal
                Korean Circ J
                KCJ
                Korean Circulation Journal
                The Korean Society of Cardiology
                1738-5520
                1738-5555
                January 2011
                31 January 2011
                : 41
                : 1
                : 28-33
                Affiliations
                [1 ]Cardiovascular Center, Sun General Hospital, Daejeon, Korea.
                [2 ]Department of Neurology, Sun General Hospital, Daejeon, Korea.
                [3 ]Cardiovascular Center, Chungnam National University Hospital, Daejeon, Korea.
                [4 ]Department of Cardiology, Soonchunhyang University of College of Medicine, Seoul, Korea.
                Author notes
                Correspondence: Jeong Kyung Kim, MD, Cardiovascular Center, Sun General Hospital, 10-7 Mok-dong, Jung-gu, Daejeon 301-725, Korea. Tel: 82-42-220-8817, Fax: 82-42-335-1431, mdzoa@ 123456paran.com
                Article
                10.4070/kcj.2011.41.1.28
                3040400
                21359066
                d692ad7a-4ad0-47a4-a23f-2996871de77e
                Copyright © 2011 The Korean Society of Cardiology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 May 2010
                : 21 June 2010
                Categories
                Original Article

                Cardiovascular Medicine
                atorvastatin,cytochrome p450 3a4 protein, human,clopidogrel,cardiovascular diseases,stents

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