Download PDF
Thromb Haemost 2012; 108(05): 937-945
DOI: 10.1160/TH12-06-0408
Platelets and Blood Cells
Schattauer GmbH

Thrombus and antiplatelet therapy in type 2 diabetes mellitus

A prospective study after non-ST elevation acute coronary syndrome and a randomised, blinded, placebo-controlled study in stable angina
Girish N. Viswanathan
1   Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
,
Sally M. Marshall
1   Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
,
Clyde B. Schechter
2   Albert Einstein College of Medicine, New York, New York, USA
,
Karthik Balasubramaniam
1   Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
,
José J. Badimon
3   Atherothrombosis Research Unit, Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
,
Azfar G. Zaman
1   Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
4   Freeman Hospital, Newcastle upon Tyne Hospitals NHS TRust, Newcastle upon Tyne, UK
› Author Affiliations Financial support: This study was supported by the British Heart Foundation (BHF/033/07) and The Northumberland, Tyne and Wear Comprehensive Local Research Network (CLRN) (UKCRN 5159 and 7338).
Further Information

Publication History

Received: 18 June 2012

Accepted after minor revision: 07 August 2012

Publication Date:
29 November 2017 (online)

    Permissions and Reprints

Summary

Type 2 diabetes mellitus (T2DM) is associated with higher rates of thrombotic complications in patients with coronary artery disease (CAD) despite optimal medical therapy. Thrombus area was measured in T2DM and non-diabetic patients receiving aspirin and clopidogrel 7–10 days after troponin positive Non ST-elevation acute coronary syndrome (NSTE-ACS). Secondly, we assessed response to clopidogrel in naive patients with T2DM and stable CAD in a randomised controlled trial. Thrombus area was measured by Badimon chamber and platelet reactivity by VerifyNow®. In T2DM patients presenting with NSTE-ACS, thrombus area was greater compared to non-diabetic patients (mean ± SD, 20,512 ± 12,567 [n=40] vs. 14,769 ± 8,531 [n=40] μm2/mm, p=0.02) Clopidogrel decreased thrombus area among stable CAD patients with T2DM (mean ± SD, Clopidogrel [n=45]: 13,978 ± 5,502 to 11,192 ± 3,764 μm2/mm vs. placebo [n=45]: 13,959 ± 7,038 to 14,201 ± 6,780 μm2/mm, p<0.001, delta values: clopidogrel vs. placebo, mean ± SD, 2,786 ± 4,561 vs. –249 ± 2,478, p<0.0005). Only 44% of patients with CAD and T2DM responded to clopidogrel as per VerifyNow® (cut-off PRUz value of ≥240). Importantly, no correlation was observed between thrombus area and VerifyNow® values (rho 0.08, p=0.49). Thrombus area values were similar among hypo-responders and good responders to clopidogrel (mean thrombus area ± SD: 12,186 ± 4,294 vs. 10,438 ± 3,401; p=0.17). Type 2 diabetes mellitus is associated with an increased blood thrombogenicity among NSTE-ACS patients on currently recommended medical therapy. Thrombus area was significantly reduced in all stable CAD patients independently of their response to clopidogrel therapy.

Keywords

Type 2 diabetes mellitus - acute coronary syndrome - stable coronary artery disease - thrombus - antiplatelet therapy
 

  • References

  • 1 Unger RH. Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. J Am Med Assoc 2008; 299: 1185-1187.
    CrossrefPubMedGoogle Scholar
  • 2 Boucher JL, Hurrell DG. Cardiovascular Disease and Diabetes. Diabetes Spectrum 2008; 21: 154-155.
    CrossrefPubMedGoogle Scholar
  • 3 Donahoe SM. et al. Diabetes and Mortality Following Acute Coronary Syndromes. J Am Med Assoc 2007; 298: 765-775.
    CrossrefPubMedGoogle Scholar
  • 4 Preis SR. et al. Trends in All-Cause and Cardiovascular Disease Mortality Among Women and Men With and Without Diabetes Mellitus in the Framingham Heart Study, 1950 to 2005. Circulation 2009; 119: 1728-1735.
    CrossrefPubMedGoogle Scholar
  • 5 Krempf M. et al. Cardiovascular event rates in diabetic and nondiabetic individuals with and without established atherothrombosis (from the REduction of Atherothrombosis for Continued Health [REACH] Registry). Am J Cardiol 2010; 5: 667-671.
    PubMedGoogle Scholar
  • 6 Fox CS. et al. Increasing Cardiovascular Disease Burden Due to Diabetes Mellitus: The Framingham Heart Study. Circulation 2007; 115: 1544-1550.
    CrossrefPubMedGoogle Scholar
  • 7 Seshasai SR. et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364: 829-841.
    CrossrefPubMedGoogle Scholar
  • 8 Anderson JL. et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50: e1-e157.
    CrossrefPubMedGoogle Scholar
  • 9 Badimon JJ. et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-1787.
    CrossrefPubMedGoogle Scholar
  • 10 Badimon L. et al. Platelet thrombus formation on collagen type I. A model of deep vessel injury. Influence of blood rheology, von Willebrand factor, and blood coagulation. Circulation 1988; 78: 1431-1442.
    CrossrefPubMedGoogle Scholar
  • 11 Natarajan A. et al. The presence of coronary artery disease increases platelet-dependent thrombosis in patients with type 2 diabetes mellitus. J Thromb Haemost 2008; 6: 2210-2213.
    CrossrefPubMedGoogle Scholar
  • 12 Osende JI. et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol 2001; 38: 1307-1312.
    CrossrefPubMedGoogle Scholar
  • 13 Marcucci R. et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237-242.
    CrossrefPubMedGoogle Scholar
  • 14 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
    CrossrefPubMedGoogle Scholar
  • 15 Alzahrani SH, Ajjan RA. Review article: Coagulation and fibrinolysis in diabetes. Diabetes Vasc Dis Res 2010; 7: 260-273.
    CrossrefPubMedGoogle Scholar
  • 16 Natarajan A. et al. Platelet hyperactivity in type 2 diabetes: role of antiplatelet agents. Diabetes Vasc Dis Res 2008; 5: 138-144.
    CrossrefPubMedGoogle Scholar
  • 17 Bassand J-P. et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598-1660.
    CrossrefPubMedGoogle Scholar
  • 18 Wiviott SD. et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2007; 357: 2001-2015.
    CrossrefPubMedGoogle Scholar
  • 19 James S. 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: 3006-3016.
    CrossrefPubMedGoogle Scholar
  • 20 Wiviott SD. 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.
    CrossrefPubMedGoogle Scholar
  • 21 Skyler JS. et al. Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A Position Statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009; 53: 298-304.
    CrossrefPubMedGoogle Scholar
  • 22 Bhatt DL. et al. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. N Engl J Med 2006; 354: 1706-1717.
    CrossrefPubMedGoogle Scholar
  • 23 Bhatt DL. 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.
    CrossrefPubMedGoogle Scholar
  • 24 Angiolillo DJ. et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011; 32: 838-846.
    CrossrefPubMedGoogle Scholar
  • 25 Cairns JA, Eikelboom J. The Pursuit of Clinically Relevant Measures of Platelet Function After Antiplatelet Drug Therapy. J Am Coll Cardiol 2008; 52: 1978-1980.
    CrossrefPubMedGoogle Scholar
  • 26 Price MJ. 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: 1132-1137.
    CrossrefPubMedGoogle Scholar
  • 27 Kannel WB. et al. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J 1990; 120: 672-676.
    CrossrefPubMedGoogle Scholar
  • 28 Haffner SM. Coronary Heart Disease in Patients with Diabetes. N Engl J Med 2000; 342: 1040-1042.
    CrossrefPubMedGoogle Scholar
  • 29 Bulugahapitiya U. et al. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med 2009; 26: 142-148.
    CrossrefPubMedGoogle Scholar
  • 30 World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. WHO 2006 Available at: http://whqlibdoc.who.int/publications/2006/9241594934_eng.pdf
    PubMedGoogle Scholar