Interaction Between Diabetes Mellitus and Platelet Reactivity in Determining Long-Term Outcomes Following Percutaneous Coronary Intervention

  • Fabio MangiacapraEmail author
  • Edoardo Bressi
  • Iginio Colaiori
  • Elisabetta Ricottini
  • Ilaria Cavallari
  • Marialessia Capuano
  • Michele Matia Viscusi
  • Silvia Spoto
  • Emanuele Barbato
  • Germano Di Sciascio
Original Article


Diabetes mellitus (DM) is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). We investigated the interaction between DM and high platelet reactivity (HPR) in determining long-term clinical outcomes after percutaneous coronary intervention (PCI). We enrolled 500 patients who were divided based on the presence of DM and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. Patients with both DM and HPR showed the highest estimates of MACE (37.9%, log-rank p < 0.001), all-cause death (15.5%, log-rank p = 0.022), and non-fatal myocardial infarction (25.9%, log-rank p < 0.001). At Cox proportional hazard analysis, the coexistence of DM and HPR was an independent predictor of MACE (HR 3.46, 95% CI 1.67–6.06, p < 0.001). Among patients with stable CAD undergoing elective PCI and treated with aspirin and clopidogrel, the combination of DM and HPR identifies a cohort of patients with the highest risk of MACE at 5 years.


Coronary artery disease Diabetes mellitus Percutaneous coronary intervention Platelet function 



coronary artery disease


diabetes mellitus


high platelet reactivity


percutaneous coronary intervention


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts 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.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Neumann, F. J., Sousa-Uva, M., Ahlsson, A., Alfonso, F., Banning, A. P., Benedetto, U., et al. (2019). 2018 ESC/EACTS Guidelines on myocardial revascularization. European Heart Journal, 40, 87–165.CrossRefGoogle Scholar
  2. 2.
    Redfors, B., Ben-Yehuda, O., Lin, S. H., Furer, A., Kirtane, A. J., Witzenbichler, B., et al. (2017). Quantifying ischemic risk after percutaneous coronary intervention attributable to high platelet reactivity on Clopidogrel (from the assessment of dual antiplatelet therapy with drug-eluting stents study). The American Journal of Cardiology, 120, 917–923.CrossRefGoogle Scholar
  3. 3.
    Mangiacapra, F., Colaiori, I., Ricottini, E., Creta, A., Di Gioia, G., Cavallari, I., et al. (2018). Impact of platelet reactivity on 5-year clinical outcomes following percutaneous coronary intervention: A landmark analysis. Journal of Thrombosis and Thrombolysis, 45, 496–503.CrossRefGoogle Scholar
  4. 4.
    Malmberg, K., Yusuf, S., Gerstein, H. C., Brown, J., Zhao, F., Hunt, D., et al. (2000). Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: Results of the OASIS (organization to assess strategies for ischemic syndromes) registry. Circulation, 102, 1014–1019.CrossRefGoogle Scholar
  5. 5.
    Rivas Rios, J. R., Franchi, F., Rollini, F., & Angiolillo, D. J. (2018). Diabetes and antiplatelet therapy: From bench to bedside. Cardiovasc Diagn Ther, 8, 594–609.CrossRefGoogle Scholar
  6. 6.
    Angiolillo, D. J., Jakubowski, J. A., Ferreiro, J. L., Tello-Montoliu, A., Rollini, F., Franchi, F., et al. (2014). Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease. Journal of the American College of Cardiology, 64, 1005–1014.CrossRefGoogle Scholar
  7. 7.
    Mangiacapra, F., Peace, A., Barbato, E., Patti, G., Gatto, L., Ricottini, E., et al. (2014). Thresholds for platelet reactivity to predict clinical events after coronary intervention are different in patients with and without diabetes mellitus. Platelets, 25, 348–356.CrossRefGoogle Scholar
  8. 8.
    Sweeny, J. M., Angiolillo, D. J., Franchi, F., Rollini, F., Waksman, R., Raveendran, G., et al. (2017). Impact of diabetes mellitus on the Pharmacodynamic effects of Ticagrelor versus Clopidogrel in troponin-negative acute coronary syndrome patients undergoing ad hoc percutaneous coronary intervention. Journal of the American Heart Association, 6.Google Scholar
  9. 9.
    Mangiacapra, F., Patti, G., Peace, A., Gatto, L., Vizzi, V., Ricottini, E., et al. (2010). Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. The American Journal of Cardiology, 106, 619–623.CrossRefGoogle Scholar
  10. 10.
    Genuth, S., Alberti, K. G., Bennett, P., Buse, J., Defronzo, R., Kahn, R., et al. (2003). Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care, 26, 3160–3167.CrossRefGoogle Scholar
  11. 11.
    Mangiacapra, F., Patti, G., Barbato, E., Peace, A. J., Ricottini, E., Vizzi, V., et al. (2012). A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: Results of the ARMYDA-PROVE (antiplatelet therapy for reduction of MYocardial damage during angioplasty-platelet reactivity for outcome validation effort) study. JACC. Cardiovascular Interventions, 5, 281–289.CrossRefGoogle Scholar
  12. 12.
    Thygesen, K., Alpert, J. S., Jaffe, A. S., Chaitman, B. R., Bax, J. J., Morrow, D. A., et al. (2018). Fourth universal definition of myocardial infarction (2018). Journal of the American College of Cardiology, 72, 2231–2264.CrossRefGoogle Scholar
  13. 13.
    Cutlip, D. E., Windecker, S., Mehran, R., Boam, A., Cohen, D. J., van Es, G. A., et al. (2007). Clinical end points in coronary stent trials: A case for standardized definitions. Circulation, 115, 2344–2351.CrossRefGoogle Scholar
  14. 14.
    Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., et al. (2015). 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: A report of the American College of Cardiology/American Heart Association task force on clinical data standards (writing committee to develop cardiovascular endpoints data standards). Journal of the American College of Cardiology, 66, 403–469.CrossRefGoogle Scholar
  15. 15.
    Rao, A. K., Pratt, C., Berke, A., Jaffe, A., Ockene, I., Schreiber, T. L., et al. (1988). Thrombolysis in myocardial infarction (TIMI) trial--phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. Journal of the American College of Cardiology, 11, 1–11.CrossRefGoogle Scholar
  16. 16.
    Beckman, J. A., Creager, M. A., & Libby, P. (2002). Diabetes and atherosclerosis: Epidemiology, pathophysiology, and management. JAMA, 287, 2570–2581.CrossRefGoogle Scholar
  17. 17.
    Pi, S. H., Rhee, T. M., Lee, J. M., Hwang, D., Park, J., Park, T. K., et al. (2018). Outcomes in patients with diabetes mellitus according to insulin treatment after percutaneous coronary intervention in the second-generation drug-eluting stent era. The American Journal of Cardiology, 121, 1505–1511.CrossRefGoogle Scholar
  18. 18.
    Angiolillo, D. J., 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, 2430–2435.CrossRefGoogle Scholar
  19. 19.
    Angiolillo, D. J., Bernardo, E., Ramírez, C., Costa, M. A., Sabaté, M., Jimenez-Quevedo, P., et al. (2006). Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. Journal of the American College of Cardiology, 48, 298–304.CrossRefGoogle Scholar
  20. 20.
    Farkouh, M. E., Domanski, M., Dangas, G. D., Godoy, L. C., Mack, M. J., Siami, F. S., et al. (2019). Long-term survival following multivessel revascularization in patients with diabetes: The FREEDOM follow-on study. Journal of the American College of Cardiology, 73, 629–638.CrossRefGoogle Scholar
  21. 21.
    Le Bras, A. (2019). Long-term mortality benefit of CABG surgery over PCI in patients with diabetes mellitus. Nature Reviews. Cardiology, 16, 3.PubMedGoogle Scholar
  22. 22.
    Cavalcante, R., Sotomi, Y., Mancone, M., Whan Lee, C., Ahn, J. M., Onuma, Y., et al. (2017). Impact of the SYNTAX scores I and II in patients with diabetes and multivessel coronary disease: A pooled analysis of patient level data from the SYNTAX, PRECOMBAT, and BEST trials. European Heart Journal, 38, 1969–1977.CrossRefGoogle Scholar
  23. 23.
    De Servi, S., Crimi, G., Calabrò, P., Piscione, F., Cattaneo, M., Maffeo, D., et al. (2016). Relationship between diabetes, platelet reactivity, and the SYNTAX score to one-year clinical outcome in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention. EuroIntervention, 12, 312–318.CrossRefGoogle Scholar
  24. 24.
    Kedhi, E., Généreux, P., Palmerini, T., McAndrew, T. C., Parise, H., Mehran, R., et al. (2014). Impact of coronary lesion complexity on drug-eluting stent outcomes in patients with and without diabetes mellitus: Analysis from 18 pooled randomized trials. Journal of the American College of Cardiology, 63, 2111–2118.CrossRefGoogle Scholar
  25. 25.
    Mangiacapra, F., Peace, A. J., Wijns, W., & Barbato, E. (2011). Lack of correlation between platelet reactivity and glycaemic control in type 2 diabetes mellitus patients treated with aspirin and clopidogrel. Journal of Thrombosis and Thrombolysis, 32, 54–58.CrossRefGoogle Scholar
  26. 26.
    Carreras, E. T., Hochholzer, W., Frelinger, A. L., Nordio, F., O’Donoghue, M. L., Wiviott, S. D., et al. (2016). Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel. Insights from the ELEVATE-TIMI 56 trial. Thrombosis and Haemostasis, 116, 69–77.CrossRefGoogle Scholar
  27. 27.
    Palmerini, T., Calabrò, P., Piscione, F., De Servi, S., Cattaneo, M., Maffeo, D., et al. (2014). Impact of gene polymorphisms, platelet reactivity, and the SYNTAX score on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention: The GEPRESS study. JACC. Cardiovascular Interventions, 7, 1117–1127.CrossRefGoogle Scholar
  28. 28.
    Fabris, E., Van’t Hof, A., Hamm, C. W., Lapostolle, F., Lassen, J. F., Goodman, S. G., et al. (2019). Pre-hospital administration of ticagrelor in diabetic patients with ST-elevation myocardial infarction undergoing primary angioplasty: A sub-analysis of the ATLANTIC trial. Catheterization and Cardiovascular Interventions, 93, E369–E377.CrossRefGoogle Scholar
  29. 29.
    Faggioni, M., Baber, U., Chandrasekhar, J., Sartori, S., Claessen, B. E., Rao, S. V., et al. (2019). Use of prasugrel vs clopidogrel and outcomes in patients with and without diabetes mellitus presenting with acute coronary syndrome undergoing percutaneous coronary intervention. International Journal of Cardiology, 275, 31–35.CrossRefGoogle Scholar
  30. 30.
    Mangiacapra, F., Panaioli, E., Colaiori, I., Ricottini, E., Lauria Pantano, A., Pozzilli, P., et al. (2016). Clopidogrel versus Ticagrelor for antiplatelet maintenance in diabetic patients treated with percutaneous coronary intervention: Results of the CLOTILDIA study (Clopidogrel high dose versus Ticagrelor for antiplatelet maintenance in diabetic patients). Circulation, 134, 835–837.CrossRefGoogle Scholar
  31. 31.
    Mangiacapra, F., Di Gioia, G., Pellicano, M., Di Serafino, L., Bressi, E., Peace, A. J., et al. (2016). Effects of Prasugrel versus Clopidogrel on coronary microvascular function in patients undergoing elective PCI. Journal of the American College of Cardiology, 68, 235–237.CrossRefGoogle Scholar
  32. 32.
    Mangiacapra, F., Pellicano, M., Di Serafino, L., Bressi, E., Peace, A. J., Di Gioia, G., et al. (2018). Platelet reactivity and coronary microvascular impairment after percutaneous revascularization in stable patients receiving clopidogrel or prasugrel. Atherosclerosis, 278, 23–28.CrossRefGoogle Scholar
  33. 33.
    Chin, K. L., Ofori-Asenso, R., Hopper, I., von Lueder, T. G., Reid, C. M., Zoungas, S., et al. (2019). Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: A systematic review of data from preclinical studies. Cardiovascular Research, 115, 266–276.CrossRefGoogle Scholar
  34. 34.
    Das, S. R., Everett, B. M., Birtcher, K. K., Brown, J. M., Cefalu, W. T., Januzzi, J. L., et al. (2018). 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: A report of the American College of Cardiology Task Force on expert consensus decision pathways. Journal of the American College of Cardiology, 72, 3200–3223.CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Fabio Mangiacapra
    • 1
    Email author
  • Edoardo Bressi
    • 1
  • Iginio Colaiori
    • 1
  • Elisabetta Ricottini
    • 1
  • Ilaria Cavallari
    • 1
  • Marialessia Capuano
    • 1
  • Michele Matia Viscusi
    • 1
  • Silvia Spoto
    • 2
  • Emanuele Barbato
    • 3
  • Germano Di Sciascio
    • 1
  1. 1.Unit of Cardiovascular Science, Department of MedicineCampus Bio-Medico UniversityRomeItaly
  2. 2.Unit of Internal Medicine, Department of MedicineCampus Bio-Medico UniversityRomeItaly
  3. 3.Department of Advanced Biomedical SciencesUniversity of Naples Federico IINaplesItaly

Personalised recommendations