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Journal of Thrombosis and Thrombolysis

, Volume 48, Issue 3, pp 413–421 | Cite as

Impact of aging on platelet reactivity in diabetic patients receiving dual antiplatelet therapy

  • Monica Verdoia
  • Patrizia Pergolini
  • Matteo Nardin
  • Roberta Rolla
  • Francesco Tonon
  • Elvin Kedhi
  • Harry Suryapranata
  • Alessandro Carriero
  • Giuseppe De LucaEmail author
  • on behalf of the Novara Atherosclerosis Study Group (NAS)
Article

Abstract

Advanced age and diabetes represent summative conditions in the determination of cardiovascular risk, and especially for the management of dual antiplatelet therapy (DAPT), often requiring balancing between bleeding and thrombotic complications. However, few studies have so far evaluated the impact of age on platelet reactivity and suboptimal platelet inhibition (high-on treatment platelet reactivity-HRPR) on DAPT among diabetic patients, that was, therefore the aim of the present study. In diabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor) platelet reactivity was assessed at 30–90 days post-discharge for an acute coronary syndrome or elective PCI. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). Elderly patients were considered ≥ 75 years of age. We included 462 patients, among them 149 (32.2%) were ≥ 75 years. Elderly patients were more often females (p = 0.006), with lower body size (p = 0.04), acute coronary syndrome at presentation and renal failure (p < 0.001), non-smokers (p = 0.002), in therapy with insulin (p = 0.02) and diuretics (p < 0.001) and lower rate of betablockers (p = 0.02). Age directly related with C reactive protein (p = 0.01), creatinine levels and inversely with hemoglobin (p < 0.001) and triglycerides (p = 0.003). No association was found at linear regression analysis for platelet reactivity and age with different activating stimuli, but for ASPI test (r = 0.12; p = 0.03). No significant difference in HAPR was found in elderly patients (2.4 vs. 3.2%, p = 0.76, OR[95% CI] = 0.45[0.1–2.11], p = 0.31). HRPR for ADP antagonists was similarly not affected by age (30.1% vs. 35.7%, p = 0.28, adjusted OR[95% CI] = 0.78[0.47–1.29], p = 0.33). Comparable results were obtained when considering separately the DAPT strategies with clopidogrel or ticagrelor, or when adjusting our results according to propensity score values. Among diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, age does not affect platelet reactivity or the rate of high-on treatment platelet reactivity. Similar results were obtained for ASA and clopidogrel or ticagrelor.

Keywords

Diabetes mellitus Aging Platelet aggregation Dual antiplatelet therapy 

Notes

Acknowledgements

This research had the financial support of the Università del Piemonte Orientale.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

References

  1. 1.
    De Luca G, Gibson CM, Bellandi F, Noc M, Dudek D, Zeymer U et al (2009) Diabetes mellitus is associated with distal embolization, impaired myocardial perfusion, and higher mortality in patients with ST-segment elevation myocardial infarction treated with primary angioplasty and glycoprotein IIb-IIIa inhibitors. Atherosclerosis 207:181–185CrossRefGoogle Scholar
  2. 2.
    De Luca G, Dirksen MT, Spaulding C, Kelbæk H, Schalij M, Thuesen L, van der Hoeven B, Vink MA, Kaiser C, Musto C, Chechi T, Spaziani G, de la Llera LSD, Pasceri V, Di Lorenzo E, Violini R, Suryapranata H, Stone GW, DESERT cooperation (2013) Impact of age on long-term outcome after primary angioplasty with bare-metal or drug-eluting stent. Am J Cardiol 112:181–186CrossRefGoogle Scholar
  3. 3.
    De Luca L, Tomai F, Verdoia M, De Luca G (2010) Evaluation and management of special subgroups after primary percutaneous coronary intervention. Am Heart J 160(6 Suppl):S22-7aGoogle Scholar
  4. 4.
    De Luca G, Suryapranata H (2015) Recent advances in optimal adjunctive antithrombotic therapy in STEMI patients undergoing primary angioplasty: an overview. Curr Vasc Pharmacol 13(5):594–615CrossRefGoogle Scholar
  5. 5.
    De Luca G, van’t Hof AW, Huber K, Gibson CM, Bellandi F, Arntz HR, Maioli M, Noc M, Zorman S, Secco GG, Zeymer U, Gabriel HM, Emre A, Cutlip D, Rakowski T, Gyongyosi M, Dudek D (2014) Impact of advanced age on myocardial perfusion, distal embolization, and mortality patients with ST-segment elevation myocardial infarction treated by primary angioplasty and glycoprotein IIb-IIIa inhibitors. Heart Vessels 29(1):15–20CrossRefGoogle Scholar
  6. 6.
    Verdoia M, Schaffer A, Barbieri L, Cassetti E, Piccolo R, Galasso G, Marino P, Sinigaglia F, De Luca G (2014) Benefits from new ADP antagonists as compared with clopidogrel in patients with stable angina or acute coronary syndrome undergoing invasive management: a meta-analysis of randomized trials. J Cardiovasc Pharmacol 63(4):339–350CrossRefGoogle Scholar
  7. 7.
    Gurbel PA, Tantry US (2011) Clopidogrel response variability and the advent of personalised antiplatelet therapy. A bench to bedside journey. Thromb Haemost 106(2):265–271Google Scholar
  8. 8.
    Alexopoulos D, Xanthopoulou I, Storey RF, Bliden KP, Tantry US, Angiolillo DJ, Gurbel PA (2014) Platelet reactivity during ticagrelor maintenance therapy: a patient-level data meta-analysis. Am Heart J 168(4):530–536CrossRefGoogle Scholar
  9. 9.
    Amsallem M, Manzo-Silberman S, Dillinger JG, Sideris G, Voicu S, Bal dit Sollier C, Drouet L, Henry P (2015) Predictors of high on-aspirin platelet reactivity in high-risk vascular patients treated with single or dual antiplatelet therapy. Am J Cardiol 115(9):1305–1310CrossRefGoogle Scholar
  10. 10.
    Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW (2010) Adenosine diphosphate-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. J Thromb Haemost 8(1):37–42CrossRefGoogle Scholar
  11. 11.
    Cayla G, Cuisset T, Silvain J, ANTARCTIC investigators et al (2016) Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 388:2015–2022CrossRefGoogle Scholar
  12. 12.
    Erlinge D, Gurbel PA, James S et al (2013) Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 62:577–583CrossRefGoogle Scholar
  13. 13.
    Matteau A, Yeh RW, Camenzind E, Steg PG, Wijns W, Mills J, Gershlick A, de Belder M, Ducrocq G, Mauri L (2015) Balancing long-term risks of ischemic and bleeding complications after percutaneous coronary intervention with drug-eluting stents. Am J Cardiol 116(5):686–693CrossRefGoogle Scholar
  14. 14.
    Ferreiro JL, Gómez-Hospital JA, Angiolillo DJ (2010) Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res 7(4):251–259CrossRefGoogle Scholar
  15. 15.
    Verdoia M, Schaffer A, Sartori C, Barbieri L, Cassetti E, Marino P et al (2014) Vitamin D deficiency is independently associated with the extent of coronary artery disease. Eur J Clin Invest 44:634–642CrossRefGoogle Scholar
  16. 16.
    Verdoia M, Pergolini P, Nardin M, Rolla R, Barbieri L, Schaffer A, Marino P, Bellomo G, Suryapranata H, De Luca G (2016) Impact of diabetes on immature platelets fraction and its relationship with platelet reactivity in patients receiving dual antiplatelet therapy. J Thromb Thrombolysis 42(2):245–253CrossRefGoogle Scholar
  17. 17.
    Vidali M, Rolla R, Parrella M, Cassani C, Manzini M, Portalupi MR, Serino R, Prando MD, Bellomo G, Pergolini P (2012) Role of the laboratory in monitoring patients receiving dual antiplatelet therapy. Int J Lab Hematol 34:484–494CrossRefGoogle Scholar
  18. 18.
    Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA, Working Group on High On-Treatment Platelet Reactivity (2010) Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933CrossRefGoogle Scholar
  19. 19.
    Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, ESC Scientific Document Group (2018) 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 39(2):119–177CrossRefGoogle Scholar
  20. 20.
    Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, Goodman SG, Corbalan R, Purdy DA, Murphy SA, McCabe CH, Antman EM, TRITON-TIMI 38 Investigators (2008) 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 118(16):1626–1636CrossRefGoogle Scholar
  21. 21.
    Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsén M, PLATO Investigators (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057CrossRefGoogle Scholar
  22. 22.
    De Luca G, Michael Gibson C, Bellandi F, Murphy S, Maioli M, Noc M, Zeymer U, Dudek D, Arntz HR, Zorman S, Gabriel HM, Emre A, Cutlip D, Rakowski T, Gyongyosi M, Huber K, Van’t Hof AW (2009) Benefits of pharmacological facilitation with glycoprotein IIb-IIIa inhibitors in diabetic patients undergoing primary angioplasty for STEMI A subanalysis of the EGYPT cooperation. J Thromb Thrombolysis 28(3):288–298CrossRefGoogle Scholar
  23. 23.
    Baber U, Mehran R, Kirtane AJ, Gurbel PA, Christodoulidis G, Maehara A, Witzenbichler B, Weisz G, Rinaldi MJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri EL Jr, Xu K, Parise H, Brodie BR, Stuckey TD, Stone GW (2015) Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the assessment of dual antiplatelet therapy with drug-eluting stents registry. Circ Cardiovasc Interv 8:e001683Google Scholar
  24. 24.
    Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, ten Berg J, Kirtane A, Siller-Matula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, Trenk D, Sibbing D, Gurbel PA, Working Group on On-Treatment Platelet Reactivity (2013) Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 62(24):2261–2273CrossRefGoogle Scholar
  25. 25.
    Beijers HJ, Ferreira I, Spronk HM, Bravenboer B, Dekker JM, Nijpels G, ten Cate H, Stehouwer CD (2012) Impaired glucose metabolism and type 2 diabetes are associated with hypercoagulability: potential role of central adiposity and low-grade inflammation–the Hoorn Study. Thromb Res 129(5):557–562CrossRefGoogle Scholar
  26. 26.
    Nardin M, Verdoia M, Sartori C, Pergolini P, Rolla R, Barbieri L, Schaffer A, Bellomo G, Suryapranata H, De Luca G, Novara Atherosclerosis Study Group (NAS) (2016) Diabetes mellitus, glucose control parameters and platelet reactivity in ticagrelor treated patients. Thromb Res 143:45–49CrossRefGoogle Scholar
  27. 27.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Jimenez-Quevedo P et al (2005) Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 54(8):2430–2435CrossRefGoogle Scholar
  28. 28.
    Silvain J, Cayla G, Hulot JS et al (2012) High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur Heart J 33:1241–1249CrossRefGoogle Scholar
  29. 29.
    Verdoia M, Pergolini P, Rolla R, Nardin M, Schaffer A, Barbieri L, Marino P, Bellomo G, Suryapranata H, De Luca G (2016) Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. J Thromb Haemost 14(1):57–64CrossRefGoogle Scholar
  30. 30.
    Ferlini M, Musumeci G, Grieco N, Rossini R, Servi S, Mafrici A, Sponzilli C, Demarchi A, Assanelli EM, Camisasca P, Chizzola G, Corrada E, Farina A, Pedrinazzi C, Lettieri C, Oltrona Visconti L (2018) The paradox of clopidogrel use in patients with acute coronary syndromes and diabetes: insight from the Diabetes and Acute Coronary Syndrome Registry. Coron Artery Dis 29:309–315CrossRefGoogle Scholar
  31. 31.
    Andreotti F, Rocca B, Husted S, Ajjan RA, ten Berg J, Cattaneo M, Collet JP, De Caterina R, Fox KA, Halvorsen S, Huber K, Hylek EM, Lip GY, Montalescot G, Morais J, Patrono C, Verheugt FW, Wallentin L, Weiss TW, Storey RF, ESC Thrombosis Working Group (2015) Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 36(46):3238–3249Google Scholar
  32. 32.
    Burlacu A, Genovesi S, Goldsmith D, Rossignol P, Ortiz A, Kalra PA, Małyszko J, Banach M, Kanbay M, Covic A (2017) Bleeding in advanced CKD patients on antithrombotic medication—a critical appraisal. Pharmacol Res 129:535–543CrossRefGoogle Scholar
  33. 33.
    Verdoia M, Schaffer A, Barbieri L, Bellomo G, Marino P, Sinigaglia F, Suryapranata H, De Luca G, on behalf of the Novara Atherosclerosis Study (2015) Impact of age on mean platelet volume and its relationship with coronary artery disease: a single-centre cohort study. Exp Gerontol 62C:32–36CrossRefGoogle Scholar
  34. 34.
    Verdoia M, Pergolini P, Nardin M, Rolla R, Barbieri L, Schaffer A, Marino P, Bellomo G, Suryapranata H, De Luca G (2016) Impact of diabetes on immature platelets fraction and its relationship with platelet reactivity in patients receiving dual antiplatelet therapy. J Thromb Thrombolysis 42(2):245–253CrossRefGoogle Scholar
  35. 35.
    Larsen SB, Grove EL, Hvas AM, Kristensen SD (2014) Platelet turnover in stable coronary artery disease—influence of thrombopoietin and low-grade inflammation. PLoS ONE 9:e85566CrossRefGoogle Scholar
  36. 36.
    Lee EY, Kim SJ, Song YJ, Choi SJ, Song J (2013) Immature platelet fraction in diabetes mellitus and metabolic syndrome. Thromb Res 132:692–695CrossRefGoogle Scholar
  37. 37.
    Mijovic R, Kovacevic N, Zarkov M, Stosic Z, Cabarkapa V, Mitic G (2015) Reticulated platelets and antiplatelet therapy response in diabetic patients. J Thromb Thrombolysis 40:203–210CrossRefGoogle Scholar
  38. 38.
    Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Jüni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN, ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies (2018) 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 39(3):213–260CrossRefGoogle Scholar
  39. 39.
    Genovese S, De Berardis G, Nicolucci A, Mannucci E, Evangelista V, Totani L et al (2013) Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes. Adv Ther 30:190–202CrossRefGoogle Scholar
  40. 40.
    Paniccia R, Antonucci E, Maggini N, Romano E, Gori AM, Marcucci R et al (2009) Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy. Am J Clin Pathol 131:834–842CrossRefGoogle Scholar
  41. 41.
    Siller-Matula JM, Gruber C, Francesconi M, Dechant C, Jilma B, Delle-Karth G, Grohs K, Podczeck-Schweighofer A, Christ G (2015) The net clinical benefit of personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention. Clin Sci (Lond). 128(2):121–130CrossRefGoogle Scholar
  42. 42.
    Rocca B, Fox KAA, Ajjan RA, Andreotti F, Baigent C, Collet JP, Grove EL, Halvorsen S, Huber K, Morais J, Patrono C, Rubboli A, Seljeflot I, Sibbing D, Siegbahn A, ten Berg J, Vilahur G, Verheugt FWA, Wallentin L, Weiss TW, Wojta J, Storey RF (2018) Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J 39(19):1672–1686fCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Monica Verdoia
    • 1
  • Patrizia Pergolini
    • 2
  • Matteo Nardin
    • 1
  • Roberta Rolla
    • 2
  • Francesco Tonon
    • 1
  • Elvin Kedhi
    • 3
  • Harry Suryapranata
    • 4
  • Alessandro Carriero
    • 5
  • Giuseppe De Luca
    • 1
    Email author
  • on behalf of the Novara Atherosclerosis Study Group (NAS)
  1. 1.Division of CardiologyAzienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont UniversityNovaraItaly
  2. 2.Clinical ChemistryAzienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont UniversityNovaraItaly
  3. 3.Department of CardiologyISALA HospitalZwolleThe Netherlands
  4. 4.Department of CardiologyUMC St RadboudNijmegenThe Netherlands
  5. 5.Division of RadiologyAzienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont UniversityNovaraItaly

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