Platelet Inhibition with Ticagrelor versus Clopidogrel in Diabetic Patients after Percutaneous Coronary Intervention for Chronic Coronary SyndromesFunding This study was an investigator-initiated study funded by AstraZeneca (ESR-14–10403).
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.
Keywordsclopidogrel - coronary artery disease - diabetes mellitus - percutaneous coronary intervention - ticagrelor
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.
The PLATIDE-PCI study was registered on ClinicalTrials.gov (NCT02748330) on April 19, 2016.
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.
Received: 18 March 2020
Accepted: 08 May 2020
15 July 2020 (online)
Georg Thieme Verlag KG
Stuttgart · New York
- 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
- 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
- 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
- 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
- 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
- 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
- 7 Gurbel PA, Tantry US. Clopidogrel resistance?. Thromb Res 2007; 120 (03) 311-321
- 8 Husted S. Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents. Fundam Clin Pharmacol 2009; 23 (01) 1-9
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 21 Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 diabetes. Diabetes Care 2001; 24 (08) 1476-1485
- 22 Ferroni P, Basili S, Falco A, Davì G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2 (08) 1282-1291
- 23 Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003; 26 (07) 2181-2188
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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