Clopidogrel Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients Treated With Percutaneous Coronary Intervention
2016; Lippincott Williams & Wilkins; Volume: 134; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.116.023743
ISSN1524-4539
AutoresFabio Mangiacapra, Elena Panaioli, Iginio Colaiori, Elisabetta Ricottini, Angelo Lauria Pantano, Paolo Pozzilli, Emanuele Barbato, Germano Di Sciascio,
Tópico(s)Coronary Interventions and Diagnostics
ResumoHomeCirculationVol. 134, No. 11Clopidogrel Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients Treated With Percutaneous Coronary Intervention Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBClopidogrel Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients Treated With Percutaneous Coronary InterventionResults of the CLOTILDIA Study (Clopidogrel High Dose Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients) Fabio Mangiacapra, MD, PhD, Elena Panaioli, MD, Iginio Colaiori, MD, Elisabetta Ricottini, MD, Angelo Lauria Pantano, MD, PhD, Paolo Pozzilli, MD, Emanuele Barbato, MD, PhD and Germano Di Sciascio, MD Fabio MangiacapraFabio Mangiacapra From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author , Elena PanaioliElena Panaioli From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author , Iginio ColaioriIginio Colaiori From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author , Elisabetta RicottiniElisabetta Ricottini From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author , Angelo Lauria PantanoAngelo Lauria Pantano From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author , Paolo PozzilliPaolo Pozzilli From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author , Emanuele BarbatoEmanuele Barbato From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author and Germano Di SciascioGermano Di Sciascio From Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (F.M., E.P., I.C., E.R., G.D.S.); Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy (A.L.P., P.P.); Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium (E.B.); and Departement of Advanced Biomedical Sciences, University of Naples Federico II, Italy (E.B.). Search for more papers by this author Originally published13 Sep 2016https://doi.org/10.1161/CIRCULATIONAHA.116.023743Circulation. 2016;134:835–837A large proportion of patients with coronary artery disease treated with elective percutaneous coronary intervention have high residual platelet reactivity1 and endothelial dysfunction, which might represent the link to the occurrence of ischemic events.2 This is even more the case for patients with diabetes mellitus, in whom more potent P2Y12 receptor inhibitors have been proposed with promising results in terms of reduced platelet reactivity.3 Nevertheless, whether this enhanced platelet inhibition alsomight be beneficial to the endothelial function is yet unknown.CLOTILDIA (Clopidogrel High Dose Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients)4 was a single-center, prospective, randomized, open label, crossover study, enrolling patients with type2 diabetes mellitus and stable coronary artery disease treated with percutaneous coronary intervention and drug-eluting stent implantation. Patients were recruited at least 1month after percutaneous coronary intervention (3.8±2.1 months), while they were still on dual-antiplatelet therapy with aspirin (100 mg/d) and clopidogrel (75 mg/d). At study entry (T0), with the use ofa computer-based randomization system, patients were assigned randomlyto receive either 90 mg ticagrelor twice daily or clopidogrel 150 mg once daily for 14 days. On day 15 (T1), a crossover was performed to the alternate therapy for an additional 14 days (until T2). At each time point (T0, T1, and T2), all patients underwent ultrasound-based measurement of brachial artery reactivity (including flow-mediated dilation [FMD] and nitroglycerin-mediated dilation [NMD]), and platelet function testing using the VerifyNow P2Y12 assay (Accumetrics).A total of 42 patients were enrolled in this study;21 wereassigned randomlyto receive ticagrelor, and 21 wereassigned randomlyto receive high-dose clopidogrel. Baseline characteristics were similar in the 2groups. Values of FMD and NMD at the 3 study time points are shown in the Figure. At T0, no significant differences in FMD and NMD were observed between the 2groups (FMD,10.0±4.2% versus 9.7±3.4%, P=0.867; NMD, 12.3±3.3% versus 12.3±3.5%, P=0.968). From T0 to T1, both study groups showed a significant increase in FMD (ticagrelor,P<0.001; high-dose clopidogrel,P=0.049) and NMD (ticagrelor,P<0.001; high-dose clopidogrel,P=0.034). Yet, at T1 patients who received ticagrelor had significantly higher values of both FMD and NMD values than patients who received high-dose clopidogrel (FMD,16.0±4.4% versus 12.0±3.6%, P=0.009; NMD, 18.8±3.8% versus 15.1±4.5%, P=0.043). From T1 to T2, althougha significant decrease was observed in brachial artery reactivity indexes switching from ticagrelor to high-dose clopidogrel (FMD,P<0.001; NMD,P=0.003), a significant further increase was observed crossing over from high-dose clopidogrel to ticagrelor in both FMD (P<0.001) and NMD (0.009). At T2, patients who received ticagrelor incomparisonwith patients who received high-dose clopidogrel showed significantly higher values of FMD (17.2±5.4% versus 11.2±4.4%, P<0.001) and NMD (18.6±6.4% versus 13.5±5.9%, P=0.020). At the end of the study drug assignment period, both FMD and NMD values were significantly higher with ticagrelor incomparisonwith high-dose clopidogrel (FMD,16.6±4.8% versus 11.6±3.9%, P<0.001; NMD, 18.7±5.2% versus 14.8±4.5%, P=0.007). On the other hand, ticagrelor resulted overall in significantly lower platelet reactivity (28±31 versus 116±58 P2Y12 reaction units, P<0.001) and higher platelet inhibition (87±15% versus 51±22, P<0.001) incomparisonwith high-dose clopidogrel.Download figureDownload PowerPointFigure. Study end points. Flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), P2Y12 reaction units (PRU), and platelet inhibition (PI) in the 2treatment groups at the 3time points. Values are reported as mean and standard deviation.The interaction between platelets and endothelium is well established, and so is the potential benefit that antiplatelet drugs exert on the arterial wall, independent of platelet inhibition.2 Clopidogrel, a thienopyridine irreversibly blocking ADP P2Y12 receptor, is able to increase the endothelial cell production of nitric oxide, with an attendant dose-dependent improvement in endothelial function. Ticagrelor is an allosteric antagonist of ADP and, contrary to clopidogrel, reversibly blocks P2Y12 receptor. Torngren et al5 observed that, in patients with a previous acute coronary syndrome, those treated with ticagrelor had significantly better endothelial function than patients on clopidogrel or prasugrel. A possible mechanistic explanation for the improved vasoreactivity achieved with ticagrelor might relate to the increased adenosine availability obtained through the inhibition of adenosine cell uptake and the increased ATP release from human red blood cells.6 Both mediators are in fact able to induce vasodilation: adenosine mediates relaxation of smooth muscular cells, whereas ATP promotes the release of nitric oxide, endothelial hyperpolarization factor, and prostacyclins from the endothelium. Moreover, it has been shown that ticagrelor is able to enhance vasodilation response to adenosine. Finally, another possible mechanism for these off-target effects of ticagrelor could relate to the expression of P2Y12 receptors on vascular smooth muscle cells.Despite limitations including relatively small sample size, short duration, no washout period between different study phases, and uncertain clinical correlation of changes in these arterial measures, the results of the CLOTILDIA study suggest for the first time that, in patients with type2 diabetes mellitus and stable coronary artery disease treated with percutaneous coronary intervention, antiplatelet therapy with ticagrelor versus high-dose clopidogrel, in addition to aspirin, is able to provide, besides more profound platelet inhibition, a significant improvement in endothelial function and endothelium-independent brachial artery reactivity. Additionalstudies are warranted to explore the clinical impact of these findings and weigh the opportunity to extend the use of ticagrelor also to patients withstable coronary artery disease who areat high risk, such as those with diabetes mellitus.Fabio Mangiacapra, MD, PhDElena Panaioli, MDIginio Colaiori, MDElisabetta Ricottini, MDAngelo Lauria Pantano, MD, PhDPaolo Pozzilli, MDEmanuele Barbato, MD, PhDGermano Di Sciascio, MDDisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Fabio Mangiacapra, MD, PhD, Unit of Cardiovascular Science, Department of Medicine, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo, 200-00128 Rome, Italy. E-mail [email protected]References1. Mangiacapra F, De Bruyne B, Muller O, Trana C, Ntalianis A, Bartunek J, Heyndrickx G, Di Sciascio G, Wijns W, Barbato E. High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention.JACC Cardiovasc Interv. 2010; 3:35–40. doi: 10.1016/j.jcin.2009.10.024.CrossrefMedlineGoogle Scholar2. Hamilos M, Muller O, Ntalianis A, Trana C, Bartunek J, Sarno G, Mangiacapra F, Dierickx K, Meeus P, Cuisset T, De Bruyne B, Wijns W, Barbato E. Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel.J Thromb Thrombolysis. 2011; 32:64–71. doi: 10.1007/s11239-011-0557-x.CrossrefMedlineGoogle Scholar3. Angiolillo DJ, Badimon JJ, Saucedo JF, Frelinger AL, Michelson AD, Jakubowski JA, Zhu B, Ojeh CK, Baker BA, Effron MB. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial.Eur Heart J. 2011; 32:838–846. doi: 10.1093/eurheartj/ehq494.CrossrefMedlineGoogle Scholar4. Clopidogrel High Dose Versus Ticagrelor for Antiplatelet Maintenance in Diabetic Patients. ClincialTrials.gov Identifier: NCT02742987.http://www.clinicaltrials.gov. Accessed August 4, 2016.Google Scholar5. Torngren K, Ohman J, Salmi H, Larsson J, Erlinge D. Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome.Cardiology. 2013; 124:252–258. doi: 10.1159/000347122.CrossrefMedlineGoogle Scholar6. van Giezen JJ, Sidaway J, Glaves P, Kirk I, Björkman JA. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model.J Cardiovasc Pharmacol Ther. 2012; 17:164–172. doi: 10.1177/1074248411410883.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Cabou C and Martinez L (2022) The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology, International Journal of Molecular Sciences, 10.3390/ijms23115883, 23:11, (5883) Guan B, Zhao L, Ma D, Fan Y, Zhang H, Wang A and Xu H (2022) The Effect of Ticagrelor on Endothelial Function Compared to Prasugrel, Clopidogrel, and Placebo: A Systematic Review and Meta-Analysis, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.820604, 8 Akkaif M, Ng M, SK Abdul Kader M, Daud N, Sha’aban A and Ibrahim B (2021) A review of the effects of ticagrelor on adenosine concentration and its clinical significance, Pharmacological Reports, 10.1007/s43440-021-00309-0, 73:6, (1551-1564), Online publication date: 1-Dec-2021. 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Alemayehu M, Kim R, Lavi R, Gong I, D’Alfonso S, Mansell S, Wall S and Lavi S (2017) Effect of Ticagrelor Versus Clopidogrel on Vascular Reactivity, Journal of the American College of Cardiology, 10.1016/j.jacc.2017.02.048, 69:17, (2246-2248), Online publication date: 1-May-2017. September 13, 2016Vol 134, Issue 11 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.023743PMID: 27619717 Originally publishedSeptember 13, 2016 Keywordsplatelet aggregation inhibitorsendotheliumdiabetes mellitusPDF download Advertisement SubjectsPercutaneous Coronary InterventionPharmacology
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