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Thromb Haemost 2020; 120(08): 1221-1229
DOI: 10.1055/s-0040-1713375
Atherosclerosis and Ischaemic Disease

Platelet Inhibition with Ticagrelor versus Clopidogrel in Diabetic Patients after Percutaneous Coronary Intervention for Chronic Coronary Syndromes

Zhenyu Liu
1   Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Ran Tian
1   Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Yang Wang
2   Medical Research and Biometrics Center, Fu-Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Qian Chen
3   Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Jingyi Li
1   Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Lihong Xu
4   Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
,
Shuyang Zhang
1   Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
› Institutsangaben Funding This study was an investigator-initiated study funded by AstraZeneca (ESR-14–10403).
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Abstract

Background Clopidogrel is currently the only P2Y12 inhibitor with class I recommendation in patients after percutaneous coronary intervention (PCI) for chronic coronary syndromes (CCS). Diabetic patients have reduced therapeutic response to clopidogrel.

Purpose This study assessed the antiplatelet effect of ticagrelor versus clopidogrel in diabetic patients after recent PCI for CCS.

Methods Eligible patients were randomly assigned to receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily, in addition to aspirin 100 mg once daily for 15 days. P2Y12 reaction unit (PRU) and percent inhibition were measured by VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HOPR) was defined as PRU > 208. Bleeding was assessed by the Platelet Inhibition and Patient Outcomes criteria. Cardiac ischemic events were evaluated as adverse events.

Results The baseline characteristics of the patients (n = 39) were well balanced between the two groups. Both before and 2 to 4 hours after the final study dose on day 15, PRU was lower (41.3 ± 35.8 vs. 192.6 ± 49.5, p < 0.001; 36.6 ± 25.8 vs. 187.6 ± 70.9, p < 0.001), percent inhibition was higher (83.0% [70.5%, 96.0%] vs. 16.0% [0%, 25.0%], p < 0.001; 85.0% [76.0%, 96.5%] vs. 25.0% [0%, 39.0%], p < 0.001), and HOPR occurred less frequently (0% [0/20] vs. 26.3% [5/19], p = 0.020; 0% [0/20] vs. 31.6% [6/19], p = 0.008) in the ticagrelor group (n = 20) compared with the clopidogrel group (n = 19). No major or minor bleeding, or serious adverse events occurred in both groups.

Conclusion Ticagrelor achieved greater peak and trough platelet inhibition than did clopidogrel in diabetic patients after recent PCI for CCS, which suggests the potential use of ticagrelor in this clinical setting.

Keywords

clopidogrel - coronary artery disease - diabetes mellitus - percutaneous coronary intervention - ticagrelor

Note

The authors are solely responsible for the design and conduct of the study, collection, analysis, and interpretation of the data, and writing, editing, and submitting of the manuscript. The study protocol was reviewed and approved by the ethics committee in Peking Union Medical College Hospital (Approval No. HS-873). Written informed consent was obtained from each study participant before initiation of any study procedure.


Trial Registration

The PLATIDE-PCI study was registered on ClinicalTrials.gov (NCT02748330) on April 19, 2016.


Authors' Contributions

Z.L. and S.Z. designed and conducted the study, analyzed and interpreted the data, and drafted the manuscript. Y.W. helped to design the study and to draft the manuscript, in particular the statistics section. R.T., J.L., and L.X. participated in the conduct of the study and the collection of the data, and helped to prepare the manuscript. Q.C. did the statistical analysis of the study and helped to prepare the manuscript. All authors revised the manuscript critically and gave the final approval of the manuscript submitted.


Supplementary Material



Publikationsverlauf

Eingereicht: 18. März 2020

Angenommen: 08. Mai 2020

Artikel online veröffentlicht:
15. Juli 2020

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Levine GN, Bates ER, Blankenship JC. , et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011; 58 (24) e44-e122
    CrossrefPubMedGoogle Scholar
  • 2 Levine GN, Bates ER, Bittl JA. , et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68 (10) 1082-1115
    CrossrefPubMedGoogle Scholar
  • 3 Valgimigli M, Bueno H, Byrne RA. , et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
    CrossrefPubMedGoogle Scholar
  • 4 Neumann FJ, Sousa-Uva M, Ahlsson A. , et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
    CrossrefPubMedGoogle Scholar
  • 5 Knuuti J, Wijns W, Saraste A. , et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
    CrossrefPubMedGoogle Scholar
  • 6 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. , et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49 (14) 1505-1516
    CrossrefPubMedGoogle Scholar
  • 7 Gurbel PA, Tantry US. Clopidogrel resistance?. Thromb Res 2007; 120 (03) 311-321
    CrossrefPubMedGoogle Scholar
  • 8 Husted S. Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents. Fundam Clin Pharmacol 2009; 23 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 9 Sibbing D, Braun S, Morath T. , et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53 (10) 849-856
    CrossrefPubMedGoogle Scholar
  • 10 Stone GW, Witzenbichler B, Weisz G. , et al; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013; 382 (9892): 614-623
    CrossrefPubMedGoogle Scholar
  • 11 Breet NJ, van Werkum JW, Bouman HJ. , et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010; 303 (08) 754-762
    CrossrefPubMedGoogle Scholar
  • 12 Parodi G, Marcucci R, Valenti R. , et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 2011; 306 (11) 1215-1223
    CrossrefPubMedGoogle Scholar
  • 13 Geisler T, Langer H, Wydymus M. , et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27 (20) 2420-2425
    CrossrefPubMedGoogle Scholar
  • 14 Hochholzer W, Trenk D, Bestehorn HP. , et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48 (09) 1742-1750
    CrossrefPubMedGoogle Scholar
  • 15 Angiolillo DJ, Bernardo E, Sabaté M. , et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50 (16) 1541-1547
    CrossrefPubMedGoogle Scholar
  • 16 Brar SS, ten Berg J, Marcucci R. , et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011; 58 (19) 1945-1954
    CrossrefPubMedGoogle Scholar
  • 17 Lüscher TF, Creager MA, Beckman JA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part II. Circulation 2003; 108 (13) 1655-1661
    CrossrefPubMedGoogle Scholar
  • 18 Sarwar N, Gao P, Seshasai SR. , et al; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375 (9733): 2215-2222
    CrossrefPubMedGoogle Scholar
  • 19 Elezi S, Kastrati A, Pache J. , et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998; 32 (07) 1866-1873
    CrossrefPubMedGoogle Scholar
  • 20 Abizaid A, Kornowski R, Mintz GS. , et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998; 32 (03) 584-589
    CrossrefPubMedGoogle Scholar
  • 21 Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 diabetes. Diabetes Care 2001; 24 (08) 1476-1485
    CrossrefPubMedGoogle Scholar
  • 22 Ferroni P, Basili S, Falco A, Davì G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2 (08) 1282-1291
    CrossrefPubMedGoogle Scholar
  • 23 Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003; 26 (07) 2181-2188
    CrossrefPubMedGoogle Scholar
  • 24 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. , et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005; 54 (08) 2430-2435
    CrossrefPubMedGoogle Scholar
  • 25 Angiolillo DJ, Bernardo E, Ramírez C. , et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006; 48 (02) 298-304
    CrossrefPubMedGoogle Scholar
  • 26 Storey RF, Husted S, Harrington RA. , et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50 (19) 1852-1856
    CrossrefPubMedGoogle Scholar
  • 27 Storey RF, Angiolillo DJ, Patil SB. , et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010; 56 (18) 1456-1462
    CrossrefPubMedGoogle Scholar
  • 28 Wallentin L, Becker RC, Budaj A. , et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
    CrossrefPubMedGoogle Scholar
  • 29 Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27 (09) 1038-1047
    CrossrefPubMedGoogle Scholar
  • 30 Gurbel PA, Bliden KP, Butler K. , et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120 (25) 2577-2585
    CrossrefPubMedGoogle Scholar
  • 31 Gurbel PA, Bliden KP, Butler K. , et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121 (10) 1188-1199
    CrossrefPubMedGoogle Scholar
  • 32 Clavijo LC, Maya J, Carlson G. , et al. Platelet inhibition with ticagrelor versus clopidogrel in Hispanic patients with stable coronary artery disease with or without diabetes mellitus. Cardiovasc Revasc Med 2015; 16 (08) 450-454
    CrossrefPubMedGoogle Scholar
  • 33 Orme RC, Parker WAE, Thomas MR. , et al. Study of two dose regimens of ticagrelor compared with clopidogrel in patients undergoing percutaneous coronary intervention for stable coronary artery disease (STEEL-PCI). Circulation 2018; 138 (13) 1290-1300
    CrossrefPubMedGoogle Scholar
  • 34 He M, Li D, Zhang Y. , et al. Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease. Platelets 2019; 30 (06) 752-761
    CrossrefPubMedGoogle Scholar
  • 35 Price MJ, Coleman JL, Steinhubl SR, Wong GB, Cannon CP, Teirstein PS. Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers. Am J Cardiol 2006; 98 (05) 681-684
    CrossrefPubMedGoogle Scholar
  • 36 Malinin A, Pokov A, Spergling M. , et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res 2007; 119 (03) 277-284
    CrossrefPubMedGoogle Scholar
  • 37 Price MJ, Endemann S, Gollapudi RR. , et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29 (08) 992-1000
    CrossrefPubMedGoogle Scholar
  • 38 Price MJ, Angiolillo DJ, Teirstein PS. , et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011; 124 (10) 1132-1137
    CrossrefPubMedGoogle Scholar
  • 39 Aradi D, Storey RF, Komócsi A. , et al; Working Group on Thrombosis of the European Society of Cardiology. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2014; 35 (04) 209-215
    CrossrefPubMedGoogle Scholar
  • 40 Tantry US, Bonello L, Aradi D. , et al; Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62 (24) 2261-2273
    CrossrefPubMedGoogle Scholar
  • 41 James S, Akerblom A, Cannon CP. , et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 2009; 157 (04) 599-605
    CrossrefPubMedGoogle Scholar
  • 42 Bonaca MP, Bhatt DL, Cohen M. , et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
    CrossrefPubMedGoogle Scholar
  • 43 Steg PG, Bhatt DL, Simon T. , et al; THEMIS Steering Committee and Investigators. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med 2019; 381 (14) 1309-1320
    CrossrefPubMedGoogle Scholar
  • 44 Bhatt DL, Steg PG, Mehta SR. , et al; THEMIS Steering Committee and Investigators. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet 2019; 394 (10204): 1169-1180
    CrossrefPubMedGoogle Scholar
  • 45 Angiolillo DJ, Capodanno D, Danchin N. , et al. Derivation, validation, and prognostic utility of a prediction rule for nonresponse to clopidogrel: the ABCD-GENE score. JACC Cardiovasc Interv 2020; 13 (05) 606-617
    CrossrefPubMedGoogle Scholar
  • 46 Levine GN, Jeong YH, Goto S. , et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014; 11 (10) 597-606
    CrossrefPubMedGoogle Scholar
  • 47 Kang J, Park KW, Palmerini T. , et al. Racial differences in ischaemia/bleeding risk trade-off during anti-platelet therapy: individual patient level landmark meta-analysis from seven RCTs. Thromb Haemost 2019; 119 (01) 149-162
    Artikel in Thieme ConnectPubMedGoogle Scholar