Thromb Haemost 2012; 108(02): 338-348
DOI: 10.1160/TH11-12-0876
Platelets and Blood Cells
Schattauer GmbH

The extent of P2Y12 inhibition by clopidogrel in diabetes mellitus patients with acute coronary syndrome is not related to glycaemic control: Roles of white blood cell count and body weight

Olivier Morel
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
3   U. 770 INSERM, Le Kremlin Bicêtre, France
,
Soraya El Ghannudi
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
,
Sebastien Hess
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
,
Antje Reydel
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
,
Ulun Crimizade
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
,
Laurence Jesel
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
,
Bogdan Radulescu
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
,
Marie L. Wiesel
2   UMR_S 949 INSERM-Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France
,
Christian Gachet
2   UMR_S 949 INSERM-Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France
,
Patrick Ohlmann
1   Pôle d'activité médico-chirurgicale Cardiovasculaire, Nouvel Hôpital Civil, Université de Strasbourg, France
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 22. Dezember 2011

Accepted after major revision: 11. Mai 2012

Publikationsdatum:
25. November 2017 (online)

Summary

It was the study objective to determine whether glycaemic control affects the extent of platelet inhibition by thienopyridines as assessed by vasodilator-stimulated phosphoprotein flow cytometry (VASP-FCT) in patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) during acute coronary syndrome (ACS). Although the proportion of high on-treatment residual platelet reactivity is higher in DM, the contributions of glycaemic control and other factors associated with DM, such as excess body weight and inflammation, to this impaired platelet inhibition by thienopyridines have not yet been fully characterised. In this study, the extent of P2Y12 ADP receptor pathway inhibition was evaluated by the VASP-FCT. Platelet activation was expressed as the platelet reactivity index (PRI). Low response to clopidogrel (LR) was defined as a PRI of >61%. Four hundred forty-five consecutive ACS patients (DM = 160, NDM = 285) were enrolled. The proportion of LR was higher in DM patients (50 vs. 37.5%). In DM, PRI was not correlated with glycosylated haemoglobin (HbA1c) or glycaemia. In a univariate analysis, LR was associated with age, male sex, overweight, and white blood cell count (WBC). In a multivariate analysis, WBC >10,000 and body weight >80 kg were the sole independent predictors of LR to clopidogrel (hazard ratio (HR) 3.02 [1.36–6.68], p=0.006 and HR 2.47 [1.14–5.35], p = 0.021, respectively). Conversely, in non-DM patients, ST-elevation myocardial infarction was the sole independent predictor of LR. In conclusion, in ACS DM patients undergoing PCI, the extent of P2Y12 inhibition by clopidogrel is not related to glycaemic control but is related to body weight and inflammatory status as assessed by the WBC.

 
  • References

  • 1 Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care 2009; 32: 531-540.
  • 2 Angiolillo DJ, Bernardo E, Sabate 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: 1541-1547.
  • 3 El Ghannudi S, Ohlmann P, Jesel L. et al. Impaired inhibition of P2Y(12) by clopidogrel is a major determinant of cardiac death in diabetes mellitus patients treated by percutaneous coronary intervention. Atherosclerosis 2011; 217: 465-472.
  • 4 Geisler T, Mueller K, Aichele S. et al. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after PCI: prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol 2010; 99: 743-752.
  • 5 Geisler T, Anders N, Paterok M. et al. Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care 2007; 30: 372-374.
  • 6 Morel O, Kessler L, Ohlmann P, Bareiss P. Diabetes and the platelet: toward new therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis 2010; 212: 367-376.
  • 7 Ferreira IA, Mocking AI, Feijge MA. et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417-422.
  • 8 Erlinge D, Varenhorst C, Braun OO. et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 2008; 52: 1968-1977.
  • 9 Freynhofer MK, Bruno V, Willheim M. et al. Vasodilator-stimulated phosphoprotein-phosphorylation assay in patients on clopidogrel: Does standardisation matter?. Thromb Haemost 2012; 107: 538-544.
  • 10 Aleil B, Ravanat C, Cazenave J P. et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005; 03: 85-92.
  • 11 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
  • 12 El Ghannudi S, Ohlmann P, Meyer N. et al. Impact of P2Y12 inhibition by clopidogrel on cardiovascular mortality in unselected patients treated by percutaneous coronary angioplasty: a prospective registry. JACC Cardiovasc Interv 2010; 03: 648-656.
  • 13 Freynhofer MK, Brozovic I, Bruno V. et al. Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. Thromb Haemost 2011; 106: 230-239.
  • 14 Morel O, El Ghannudi S, Jesel L. et al. Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel. J Am Coll Cardiol 2011; 57: 399-408.
  • 15 Angiolillo DJ, Bernardo E, Ramirez 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: 298-304.
  • 16 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: 2430-2435.
  • 17 Mangiacapra F, Patti G, Peace A. et al. Comparison of platelet reactivity and peri-procedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010; 106: 619-623.
  • 18 Serebruany V, Pokov I, Kuliczkowski W. et al. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 2008; 100: 76-82.
  • 19 Ferreira IA, Eybrechts KL, Mocking AI, Kroner C, Akkerman JW. IRS-1 mediates inhibition of Ca2+ mobilization by insulin via the inhibitory G-protein Gi. J Biol Chem 2004; 279: 3254-3264.
  • 20 Singla A, Antonino MJ, Bliden KP. et al. The relation between platelet reactivity and glycemic control in diabetic patients with cardiovascular disease on maintenance aspirin and clopidogrel therapy. Am Heart J. 2009 158. 784 e1-6.
  • 21 Vivas D, Garcia-Rubira JC, Bernardo E. et al. Effects of intensive glucose control on platelet reactivity in patients with acute coronary syndromes. Results of the CHIPS Study (“Control de Hiperglucemia y Actividad Plaquetaria en Pacientes con Sindrome Coronario Agudo”). Heart 2011; 97: 803-809.
  • 22 Gaborit B, Frere C, Cuisset T. et al. Enhanced post-clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control. J Thromb Haemost 2009; 07: 1939-1941.
  • 23 Cuisset T, Frere C, Quilici J. et al. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 2009; 123: 597-603.
  • 24 Sibbing D, von Beckerath O, Schomig A. et al. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. Am J Cardiol 2007; 100: 203-205.
  • 25 Diehl P, Olivier C, Halscheid C. et al. Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes. Basic Res Cardiol 2010; 105: 379-387.
  • 26 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted?. J Invasive Cardiol 2004; 16: 169-174.
  • 27 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: 1742-1750.
  • 28 Mak KH, Bhatt DL, Shao M. et al. The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease. Eur Heart J 2009; 30: 857-865.
  • 29 Bhatt DL. What makes platelets angry: diabetes, fibrinogen, obesity, and impaired response to antiplatelet therapy?. J Am Coll Cardiol 2008; 52: 1060-1061.
  • 30 Morel O, Luca F, Grunebaum L. et al. Shor t-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles. Int J Obes 2011; 35: 1479-1486.
  • 31 Ang L, Palakodeti V, Khalid A. et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol 2008; 52: 1052-1059.
  • 32 Breet NJ, van Werkum JW, Bouman HJ. et al. The relationship between platelet reactivity and infarct-related artery patency in patients presenting with a ST-elevation myocardial infarction. Thromb Haemost 2011; 106: 331-336.
  • 33 Hermann A, Rauch BH, Braun M. et al. Platelet CD40 ligand (CD40L)--subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 2001; 12: 74-82.
  • 34 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006; 55: 780-784.
  • 35 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
  • 36 Grau AJ, Boddy AW, Dukovic DA. et al. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke 2004; 35: 1147-1152.
  • 37 O'Donoghue M, Morrow DA, Cannon CP. et al. Association between baseline neutrophil count, clopidogrel therapy, and clinical and angiographic outcomes in patients with ST-elevation myocardial infarction receiving fibrinolytic therapy. Eur Heart J 2008; 29: 984-991.
  • 38 Bhatt DL, Flather MD, Hacke W. et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49: 1982-1988.
  • 39 Weber M, Bhatt DL, Brennan DM. et al. High-sensitivity C-reactive protein and clopidogrel treatment in patients at high risk of cardiovascular events: a substudy from the CHARISMA trial. Heart 2011; 97: 626-631.
  • 40 Wiviott SD, Braunwald E, Angiolillo DJ. 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: 1626-1636.
  • 41 Dangas G, Mehran R, Guagliumi G. et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009; 54: 1438-1446.
  • 42 Heestermans AA, van Werkum JW, Taubert D. et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res 2008; 122: 776-781.
  • 43 Patti G, Barczi G, Orlic D. et al. Outcome comparison of 600– and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results from the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. J Am Coll Cardiol 2011; 58: 1592-1599.
  • 44 Patti G, Grieco D, Dicuonzo G. et al. High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of myocardial damage during angioplasty) randomized study. J Am Coll Cardiol 2011; 57: 771-778.
  • 45 Dorler J, Edlinger M, Alber HF. et al. Clopidogrel pre-treatment is associated with reduced in-hospital mortality in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. Eur Heart J 2011; 32: 2954-2961.