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      Drug Design, Development and Therapy (submit here)

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      The clinical outcomes of triple antiplatelet therapy versus dual antiplatelet therapy for high-risk patients after coronary stent implantation: a meta-analysis of 11 clinical trials and 9,553 patients


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          The optimal antiplatelet regimen after in-coronary intervention among patients presenting with complex coronary artery lesions or acute coronary syndrome (ACS) has remained unclear. This study sought to evaluate the clinical outcomes of triple antiplatelet treatment (TAPT) (cilostazol added to aspirin plus clopidogrel) in these patients.


          The PubMed, EMBASE, MEDLINE, and other Internet sources were searched for relevant articles. The primary end point was major adverse cardiac events (MACE), including all-cause mortality, myocardial infarction, and target vessel revascularization. The incidence of definite/probable stent thrombosis and bleeding were analyzed as the safety end points.


          Eleven clinical trials involving 9,553 patients were analyzed. The risk of MACE was significantly decreased following TAPT after stent implantation in the ACS subgroup (odds ratio [OR]: 0.72; 95% confidence interval [CI]: 0.61–0.85; P<0.001), which might mainly result from the lower risk of all-cause mortality in this subset (OR: 0.62; 95% CI: 0.48–0.80; P<0.001). The risk of bleeding was not increased with respect to TAPT.


          TAPT after stent implantation was associated with feasible benefits on reducing the risk of MACE, especially on reducing the incidence of all-cause mortality among patients suffering from ACS, without higher incidence of bleeding. Larger and more powerful randomized trials are still warranted to prove the superiority of TAPT for such patients.

          Most cited references28

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          Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study.

          Stent thrombosis is a safety concern associated with use of drug-eluting stents. Little is known about occurrence of stent thrombosis more than 1 year after implantation of such stents. Between April, 2002, and Dec, 2005, 8146 patients underwent percutaneous coronary intervention with sirolimus-eluting stents (SES; n=3823) or paclitaxel-eluting stents (PES; n=4323) at two academic hospitals. We assessed data from this group to ascertain the incidence, time course, and correlates of stent thrombosis, and the differences between early (0-30 days) and late (>30 days) stent thrombosis and between SES and PES. Angiographically documented stent thrombosis occurred in 152 patients (incidence density 1.3 per 100 person-years; cumulative incidence at 3 years 2.9%). Early stent thrombosis was noted in 91 (60%) patients, and late stent thrombosis in 61 (40%) patients. Late stent thrombosis occurred steadily at a constant rate of 0.6% per year up to 3 years after stent implantation. Incidence of early stent thrombosis was similar for SES (1.1%) and PES (1.3%), but late stent thrombosis was more frequent with PES (1.8%) than with SES (1.4%; p=0.031). At the time of stent thrombosis, dual antiplatelet therapy was being taken by 87% (early) and 23% (late) of patients (p<0.0001). Independent predictors of overall stent thrombosis were acute coronary syndrome at presentation (hazard ratio 2.28, 95% CI 1.29-4.03) and diabetes (2.03, 1.07-3.83). Late stent thrombosis was encountered steadily with no evidence of diminution up to 3 years of follow-up. Early and late stent thrombosis were observed with SES and with PES. Acute coronary syndrome at presentation and diabetes were independent predictors of stent thrombosis.
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            High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.

            High residual platelet reactivity (HRPR) in patients receiving clopidogrel has been associated with high risk of ischemic events after percutaneous coronary intervention (PCI). To test the hypothesis that HRPR after clopidogrel loading is an independent prognostic marker of risk of long-term thrombotic events in patients with acute coronary syndromes (ACS) undergoing an invasive procedure and antithrombotic treatment adjusted according to the results of platelet function tests. Prospective, observational, referral center cohort study of 1789 consecutive patients with ACS undergoing PCI from April 2005 to April 2009 at the Division of Cardiology of Careggi Hospital, Florence, Italy, in whom platelet reactivity was prospectively assessed by light transmittance aggregometry. All patients received 325 mg of aspirin and a loading dose of 600 mg of clopidogrel followed by a maintenance dosage of 325 mg/d of aspirin and 75 mg/d of clopidogrel for at least 6 months. Patients with HRPR as assessed by adenosine diphosphate test (≥70% platelet aggregation) received an increased dose of clopidogrel (150-300 mg/d) or switched to ticlopidine (500-1000 mg/d) under adenosine diphosphate test guidance. The primary end point was a composite of cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow-up. Secondary end points were stent thrombosis and each component of the primary end point. The primary end point event rate was 14.6% (36/247) in patients with HRPR and 8.7% (132/1525) in patients with low residual platelet reactivity (absolute risk increase, 5.9%; 95% CI, 1.6%-11.1%; P = .003). Stent thrombosis was higher in the HRPR group compared with the low residual platelet reactivity group (6.1% [15/247] vs 2.9% [44/1525]; absolute risk increase, 3.2%; 95% CI, 0.4%-6.7%; P = .01). By multivariable analysis, HRPR was independently associated with the primary end point (hazard ratio, 1.49; 95% CI, 1.08-2.05; P = .02) and with cardiac mortality (hazard ratio, 1.81; 95% CI, 1.18-2.76; P = .006). Among patients receiving platelet reactivity-guided antithrombotic medication after PCI, HRPR status was significantly associated with increased risk of ischemic events at short- and long-term follow-up. clinicaltrials.gov Identifier: NCT01231035.
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              The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts.

              P2Y12, a G protein-coupled receptor that plays a central role in platelet activation has been recently identified as the receptor targeted by the antithrombotic drug, clopidogrel. In this study, we further deciphered the mechanism of action of clopidogrel and of its active metabolite (Act-Met) on P2Y12 receptors. Using biochemical approaches, we demonstrated the existence of homooligomeric complexes of P2Y12 receptors at the surface of mammalian cells and in freshly isolated platelets. In vitro treatment with Act-Met or in vivo oral administration to rats with clopidogrel induced the breakdown of these oligomers into dimeric and monomeric entities in P2Y12 expressing HEK293 and platelets respectively. In addition, we showed the predominant association of P2Y12 oligomers to cell membrane lipid rafts and the partitioning of P2Y12 out of rafts in response to clopidogrel and Act-Met. The raft-associated P2Y12 oligomers represented the functional form of the receptor, as demonstrated by binding and signal transduction studies. Finally, using a series of receptors individually mutated at each cysteine residue and a chimeric P2Y12/P2Y13 receptor, we pointed out the involvement of cysteine 97 within the first extracellular loop of P2Y12 in the mechanism of action of Act-Met.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                20 October 2016
                : 10
                : 3435-3448
                [1 ]Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing
                [2 ]Department of Cardiology, Taixing People’s Hospital, Yangzhou University, Taizhou
                [3 ]Department of Cardiology, Nanjing Heart Center, Nanjing, People’s Republic of China
                Author notes
                Correspondence: Nai-Liang Tian, Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No 68 Changle Road, Nanjing 210006, People’s Republic of China, Tel/fax +86 25 5220 8048, Email tiannailiang@ 123456163.com

                These authors contributed equally to this work

                © 2016 Fan et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                triple antiplatelet treatment,dual antiplatelet treatment,stent implantation,complex lesions,acute coronary syndrome


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