Skip to main content
Top
Published in: Cardiovascular Diabetology 1/2023

Open Access 01-12-2023 | Diabetes | Research

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium

Authors: Ki-Hyun Jeon, Young-Hoon Jeong, In-Ho Chae, Byeong-Keuk Kim, Hyung Joon Joo, Kiyuk Chang, Yongwhi Park, Young Bin Song, Sung Gyun Ahn, Sang Yeub Lee, Jung Rae Cho, Ae-Young Her, Hyo-Soo Kim, Moo Hyun Kim, Do-Sun Lim, Eun-Seok Shin, Jung-Won Suh, On Behalf of the PTRG-DES Consortium Investigators

Published in: Cardiovascular Diabetology | Issue 1/2023

Login to get access

Abstract

Background

Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients.

Methods

The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke.

Results

Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869–1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193–1.902; P < 0.001).

Conclusion

The levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients.

Clinical trial registration

URL: https://​www.​clinicaltrials.​gov. Unique identifier: NCT04734028.
Appendix
Available only for authorised users
Literature
1.
go back to reference Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.CrossRefPubMed Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.CrossRefPubMed
2.
go back to reference Schramm TK, Gislason GH, Kober L, Rasmussen S, Rasmussen JN, Abildstrom SZ, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 2008;117:1945–54.CrossRefPubMed Schramm TK, Gislason GH, Kober L, Rasmussen S, Rasmussen JN, Abildstrom SZ, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 2008;117:1945–54.CrossRefPubMed
3.
go back to reference American Diabetes A. 9. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41:S86-S104. American Diabetes A. 9. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41:S86-S104.
4.
go back to reference O’Keefe JH, Bell DS. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol. 2007;100:899–904.CrossRefPubMed O’Keefe JH, Bell DS. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol. 2007;100:899–904.CrossRefPubMed
5.
go back to reference DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009 Diabetologia. 2010;53:1270–87. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009 Diabetologia. 2010;53:1270–87.
6.
go back to reference Intensive blood-glucose. Control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK prospective diabetes study (UKPDS) Group. Lancet. 1998;352:837–53.CrossRef Intensive blood-glucose. Control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK prospective diabetes study (UKPDS) Group. Lancet. 1998;352:837–53.CrossRef
8.
go back to reference Gariani K, Mavrakanas T, Combescure C, Perrier A, Marti C. Is diabetes mellitus a risk factor for venous thromboembolism? A systematic review and meta-analysis of case-control and cohort studies. Eur J Intern Med. 2016;28:52–8.CrossRefPubMed Gariani K, Mavrakanas T, Combescure C, Perrier A, Marti C. Is diabetes mellitus a risk factor for venous thromboembolism? A systematic review and meta-analysis of case-control and cohort studies. Eur J Intern Med. 2016;28:52–8.CrossRefPubMed
9.
go back to reference Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care. 2003;26:2181–8.CrossRefPubMed Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care. 2003;26:2181–8.CrossRefPubMed
10.
go back to reference Boden G, Vaidyula VR, Homko C, Cheung P, Rao AK. Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose. J Clin Endocrinol Metab. 2007;92:4352–8.CrossRefPubMed Boden G, Vaidyula VR, Homko C, Cheung P, Rao AK. Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose. J Clin Endocrinol Metab. 2007;92:4352–8.CrossRefPubMed
11.
go back to reference Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol. 2005;46:1827–32.CrossRefPubMed Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol. 2005;46:1827–32.CrossRefPubMed
12.
go back to reference Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, 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;124:1132–7.CrossRefPubMed Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, 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;124:1132–7.CrossRefPubMed
13.
go back to reference Park KW, Jeon KH, Kang SH, Oh IY, Cho HJ, Lee HY, et al. Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study). Am J Cardiol. 2011;108:1556–63.CrossRefPubMed Park KW, Jeon KH, Kang SH, Oh IY, Cho HJ, Lee HY, et al. Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study). Am J Cardiol. 2011;108:1556–63.CrossRefPubMed
14.
go back to reference Winocour PD, Watala C, Kinglough-Rathbone RL. Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ratio in isolated platelet membranes from diabetic and control subjects. Thromb Haemost. 1992;67:567–71.CrossRefPubMed Winocour PD, Watala C, Kinglough-Rathbone RL. Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ratio in isolated platelet membranes from diabetic and control subjects. Thromb Haemost. 1992;67:567–71.CrossRefPubMed
15.
go back to reference Westerbacka J, Yki-Jarvinen H, Turpeinen A, Rissanen A, Vehkavaara S, Syrjala M, et al. Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol. 2002;22:167–72.CrossRefPubMed Westerbacka J, Yki-Jarvinen H, Turpeinen A, Rissanen A, Vehkavaara S, Syrjala M, et al. Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol. 2002;22:167–72.CrossRefPubMed
16.
go back to reference Spinetti G, Kraenkel N, Emanueli C, Madeddu P. Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies. Cardiovasc Res. 2008;78:265–73.CrossRefPubMed Spinetti G, Kraenkel N, Emanueli C, Madeddu P. Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies. Cardiovasc Res. 2008;78:265–73.CrossRefPubMed
17.
go back to reference Schafer A, Bauersachs J. Endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation in diabetes and atherosclerosis. Curr Vasc Pharmacol. 2008;6:52–60.CrossRefPubMed Schafer A, Bauersachs J. Endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation in diabetes and atherosclerosis. Curr Vasc Pharmacol. 2008;6:52–60.CrossRefPubMed
19.
go back to reference Angiolillo DJ, Bernardo E, Sabate M, Jimenez-Quevedo P, Costa MA, Palazuelos J, 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;50:1541–7.CrossRefPubMed Angiolillo DJ, Bernardo E, Sabate M, Jimenez-Quevedo P, Costa MA, Palazuelos J, 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;50:1541–7.CrossRefPubMed
20.
go back to reference Her AY, Jeong YH, Kim BK, Joo HJ, Chang K, Park Y, et al. Platelet function and genotype after DES Implantation in East Asian Patients: Rationale and characteristics of the PTRG-DES Consortium. Yonsei Med J. 2022;63:413–21.CrossRefPubMedPubMedCentral Her AY, Jeong YH, Kim BK, Joo HJ, Chang K, Park Y, et al. Platelet function and genotype after DES Implantation in East Asian Patients: Rationale and characteristics of the PTRG-DES Consortium. Yonsei Med J. 2022;63:413–21.CrossRefPubMedPubMedCentral
21.
go back to reference ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 2. Classification and diagnosis of diabetes: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46:19–S40.CrossRef ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 2. Classification and diagnosis of diabetes: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46:19–S40.CrossRef
22.
go back to reference Sibbing D, Aradi D, Alexopoulos D, Ten Berg J, Bhatt DL, Bonello L, et al. Updated Expert Consensus Statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019;12:1521–37.CrossRefPubMed Sibbing D, Aradi D, Alexopoulos D, Ten Berg J, Bhatt DL, Bonello L, et al. Updated Expert Consensus Statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019;12:1521–37.CrossRefPubMed
23.
go back to reference Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J. 2012;164:35–42.CrossRefPubMed Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J. 2012;164:35–42.CrossRefPubMed
24.
go back to reference Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding Academic Research Consortium. Circulation. 2011;123:2736–47.CrossRefPubMed Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding Academic Research Consortium. Circulation. 2011;123:2736–47.CrossRefPubMed
25.
go back to reference Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Executive Group on behalf of the joint european Society of Cardiology /American College of Cardiology /American Heart Association /World Heart Federation Task Force for the Universal Definition of Myocardial I. Fourth Universal Definition of myocardial infarction (2018). J Am Coll Cardiol. 2018;72:2231–64.CrossRefPubMed Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Executive Group on behalf of the joint european Society of Cardiology /American College of Cardiology /American Heart Association /World Heart Federation Task Force for the Universal Definition of Myocardial I. Fourth Universal Definition of myocardial infarction (2018). J Am Coll Cardiol. 2018;72:2231–64.CrossRefPubMed
26.
27.
go back to reference Schaeffer G, Wascher TC, Kostner GM, Graier WF. Alterations in platelet Ca2 + signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production. Diabetologia. 1999;42:167–76.CrossRefPubMed Schaeffer G, Wascher TC, Kostner GM, Graier WF. Alterations in platelet Ca2 + signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production. Diabetologia. 1999;42:167–76.CrossRefPubMed
28.
go back to reference Freedman JE. Oxidative stress and platelets. Arterioscler Thromb Vasc Biol. 2008;28:11–6.CrossRef Freedman JE. Oxidative stress and platelets. Arterioscler Thromb Vasc Biol. 2008;28:11–6.CrossRef
29.
go back to reference Angiolillo DJ, Jakubowski JA, Ferreiro JL, Tello-Montoliu A, Rollini F, Franchi F, et al. Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease. J Am Coll Cardiol. 2014;64:1005–14.CrossRefPubMed Angiolillo DJ, Jakubowski JA, Ferreiro JL, Tello-Montoliu A, Rollini F, Franchi F, et al. Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease. J Am Coll Cardiol. 2014;64:1005–14.CrossRefPubMed
30.
go back to reference Angiolillo DJ, Bernardo E, Ramirez C, Costa MA, Sabate M, Jimenez-Quevedo P, 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;48:298–304.CrossRefPubMed Angiolillo DJ, Bernardo E, Ramirez C, Costa MA, Sabate M, Jimenez-Quevedo P, 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;48:298–304.CrossRefPubMed
31.
go back to reference Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614–23.CrossRefPubMed Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614–23.CrossRefPubMed
32.
go back to reference Brar SS, ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS, 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;58:1945–54.CrossRefPubMed Brar SS, ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS, 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;58:1945–54.CrossRefPubMed
33.
go back to reference Suh JW, Lee SP, Park KW, Lee HY, Kang HJ, Koo BK, et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol. 2011;57:280–9.CrossRefPubMed Suh JW, Lee SP, Park KW, Lee HY, Kang HJ, Koo BK, et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol. 2011;57:280–9.CrossRefPubMed
34.
go back to reference Kang J, Park KW, Palmerini T, Stone GW, Lee MS, Colombo A, 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;119:149–62.CrossRefPubMed Kang J, Park KW, Palmerini T, Stone GW, Lee MS, Colombo A, 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;119:149–62.CrossRefPubMed
35.
go back to reference Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Circulation. 2008;118:1626–36.CrossRefPubMed Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Circulation. 2008;118:1626–36.CrossRefPubMed
36.
go back to reference James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient outcomes (PLATO) trial. Eur Heart J. 2010;31:3006–16.CrossRefPubMedPubMedCentral James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient outcomes (PLATO) trial. Eur Heart J. 2010;31:3006–16.CrossRefPubMedPubMedCentral
Metadata
Title
Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium
Authors
Ki-Hyun Jeon
Young-Hoon Jeong
In-Ho Chae
Byeong-Keuk Kim
Hyung Joon Joo
Kiyuk Chang
Yongwhi Park
Young Bin Song
Sung Gyun Ahn
Sang Yeub Lee
Jung Rae Cho
Ae-Young Her
Hyo-Soo Kim
Moo Hyun Kim
Do-Sun Lim
Eun-Seok Shin
Jung-Won Suh
On Behalf of the PTRG-DES Consortium Investigators
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-023-01976-4

Other articles of this Issue 1/2023

Cardiovascular Diabetology 1/2023 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine