Download PDF
Thromb Haemost 2017; 117(05): 940-947
DOI: 10.1160/TH16-09-0703
Cellular Haemostasis and Platelets
Schattauer GmbH

Consistent platelet inhibition with ticagrelor 60 mg twice-daily following myocardial infarction regardless of diabetes status

Mark R. Thomas
1   Cardiovascular Research Unit, Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
,
Dominick J. Angiolillo
2   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA
,
Marc P. Bonaca
3   TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
,
Ramzi A. Ajjan
4   Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
,
Heather M. Judge
1   Cardiovascular Research Unit, Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
,
Fabiana Rollini
2   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA
,
Francesco Franchi
2   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA
,
Arif J. Ahsan
5   Trent Cardiac Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
,
Deepak L. Bhatt
3   TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
,
Julia F. Kuder
3   TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
,
Philippe Gabriel Steg
6   INSERM-Unité 1148, Assistance Publique- Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, and Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France
,
Marc Cohen
7   Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School, Newark, New Jersey, USA
,
Rangasamy Muthusamy
8   Rotherham NHS Foundation Trust, Rotherham, UK
,
Marc S. Sabatine
3   TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
,
Robert F. Storey
1   Cardiovascular Research Unit, Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
› Author Affiliations
Further Information

Publication History

Received: 13 September 2016

Accepted after major revision: 09 February 2017

Publication Date:
28 November 2017 (online)

    Permissions and Reprints

Summary

Diabetes increases cardiovascular risk and reduces pharmacodynamic response to some oral antiplatelet drugs. This study aimed to determine whether ticagrelor 60 mg twice daily (bid) provided potent and consistent platelet inhibition in patients with vs without diabetes in the PEGASUS-TIMI 54 platelet function substudy. Out of 180 patients studied, 58 patients were randomised to and had received at least four weeks of ticagrelor 60 mg bid, with 20 (34 %) having diabetes, 58 patients received ticagrelor 90 mg bid, with 12 (21 %) having diabetes, and 64 patients received placebo, with 18 (28 %) having diabetes. Blood was sampled pre- and 2 hours post-maintenance dose. In patients treated with ticagrelor 60 mg bid, on-treatment platelet reactivity to ADP, as determined by light transmission aggregometry (LTA), VerifyNow and VASP, was similar in patients with vs without diabetes (LTA post-dose, ADP 20 ?M: 29 ± 14 vs 34 ± 10 %, respectively; p = 0.19). A consistent inhibitory effect of ticagrelor 60 mg bid was observed pre- and post-dose regardless of diabetes status, even in insulin-treated patients. Patients with diabetes did not have an increased incidence of high platelet reactivity in either ticagrelor group. Platelet reactivity was similar in patients with diabetes treated with ticagrelor 60 mg vs 90 mg bid. Pharmacokinetics of ticagrelor were not affected by diabetes status. In conclusion, ticagrelor 60 mg bid is equally effective at reducing platelet reactivity in patients with and without diabetes, yielding a consistently high level of platelet inhibition regardless of diabetes status.

Keywords

Coronary artery disease - acute coronary syndromes - pharmacology - pharmacodynamics

 

  • References

  • 1 Donahoe SM, Stewart GC, McCabe CH. et al. Diabetes and mortality following acute coronary syndromes.. J Am Med Assoc 2007; 298: 765-775
    CrossrefPubMedGoogle Scholar
  • 2 Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome.. Circulation 2011; 123: 798-813
    CrossrefPubMedGoogle Scholar
  • 3 Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome.. Nat Rev Cardiol 2014; 12: 30-47
    CrossrefPubMedGoogle Scholar
  • 4 Bonaca MP, Bhatt DL, Cohen M. et al. Long-term use of ticagrelor in patients with prior myocardial infarction.. N Engl J Med 2015; 372: 1791-1800
    CrossrefPubMedGoogle Scholar
  • 5 Udell JA, Bonaca MP, Collet J-P. et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials.. Eur Heart J 2016; 37: 390-399
    PubMedGoogle Scholar
  • 6 Capodanno D, Patel A, Dharmashankar K. et al. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease.. Circulation: Cardiovascular Interventions 2011; 04: 180-187
    CrossrefPubMedGoogle Scholar
  • 7 Mortensen SB, Larsen SB, Grove EL. et al. Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus.. Thromb Res 2010; 126: e318-322
    CrossrefPubMedGoogle Scholar
  • 8 Christensen KH, Grove EL, Würtz M. et al. Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes.. Platelets 2014; 26: 230-235
    PubMedGoogle Scholar
  • 9 Angiolillo DJ, Jakubowski JA, Ferreiro JL. 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: 1005-1014
    CrossrefPubMedGoogle Scholar
  • 10 Carreras ET, Hochholzer W, Frelinger AL III. et al. Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel.. Thromb Haemost 2016; 116: 1-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Clavijo LC, Maya J, Carlson G. et al. Platelet inhibition with ticagrelor versus clopidogrel in Hispanic patients with stable coronary artery disease with or without diabetes mellitus.. Cardiovasc Revasc Med 2015; 16: 450-454
    CrossrefPubMedGoogle Scholar
  • 12 Price MJ. Diabetes mellitus and clopidogrel response variability.. J Am Coll Car-diol 2014; 64: 1015-1018
    CrossrefPubMedGoogle Scholar
  • 13 Bhatt DL, Bonaca MP, Bansilal S. et al. Reduction in Ischemic Events With Ti-cagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS-TIMI 54.. J Am Coll Cardiol 2016; 67: 2732-2740
    CrossrefPubMedGoogle Scholar
  • 14 Storey RF, Angiolillo DJ, Bonaca MP. et al. Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial.. J Am Coll Cardiol 2016; 67: 1145-1154
    PubMedGoogle Scholar
  • 15 Storey RF, Angiolillo DJ, Patil SB. et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy.. J Am Coll Cardiol 2010; 56: 1456-1462
    CrossrefPubMedGoogle Scholar
  • 16 Tantry US, Bonello L, Aradi D. et al. Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding.. J Am Coll Cardiol 2013; 62: 2261-2273
    CrossrefPubMedGoogle Scholar
  • 17 Aradi D, Storey RF, Komócsi A. et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention.. Eur Heart J 2013; 35: 209-215
    PubMedGoogle Scholar
  • 18 Bonello L, Tantry US, Marcucci R. et al. Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphos-phate.. J Am Coll Cardiol 2010; 56: 919-933
    CrossrefPubMedGoogle Scholar
  • 19 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.. J Am Coll Cardiol 2003; 41: 961-965
    CrossrefPubMedGoogle Scholar
  • 20 Kazi DS, Leong TK, Chang TI. et al. Association of Spontaneous Bleeding and Myocardial Infarction With Long-Term Mortality After Percutaneous Coronary Intervention.. J Am Coll Cardiol 2015; 65: 1411-1420
    CrossrefPubMedGoogle Scholar
  • 21 Nardin M, Verdoia M, Sartori C. et al. Diabetes mellitus, glucose control parameters and platelet reactivity in ticagrelor treated patients.. Thromb Res 2016; 143: 45-49
    CrossrefPubMedGoogle Scholar
  • 22 Alexopoulos D, Vogiatzi C, Stavrou K. et al. Diabetes mellitus and platelet reactivity in patients under prasugrel or ticagrelor treatment: an observational study.. Cardiovasc Diabetol 2015; 14: 68.
    CrossrefPubMedGoogle Scholar
  • 23 Harmsze AM, Van Werkum JW, Moral F. et al. Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients.. Platelets 2010; 22: 98-102
    PubMedGoogle Scholar
  • 24 Franchi F, Rollini F, Aggarwal N. et al. Pharmacodynamic Comparison of Prasu-grel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study.. Circulation 2016; 134: 780-792
    CrossrefPubMedGoogle Scholar
  • 25 Tamminen M, Lassila R, Westerbacka J. et al. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects.. Int J Obes Relat Metab Disord 2003; 27: 907-911
    CrossrefPubMedGoogle Scholar
  • 26 Neergaard-Petersen S, Hvas AM, Kristensen SD. et al. The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease.. Thromb Haemost 2014; 112: 1142-1150
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 King R, Tiede C, Simmons K. et al. Inhibition of complement C3 and fibrinogen interaction: a potential novel therapeutic target to reduce cardiovascular disease in diabetes.. Lancet 2015; 385 (Suppl. 01) S57.
    CrossrefPubMedGoogle Scholar
  • 28 Rollini F, Tello-Montoliu A, Patel R. et al. Pharmacodynamic effects of EV-077 in patients with diabetes mellitus and coronary artery disease on aspirin or clopidogrel monotherapy: results of an in vitro pilot investigation.. J Thromb Thrombolysis 2014; 37: 131-138
    CrossrefPubMedGoogle Scholar
  • 29 Cattaneo M, Schulz R, Nylander S.. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance.. J Am Coll Cardiol 2014; 63: 2503-2509
    CrossrefPubMedGoogle Scholar
  • 30 Bonello L, Laine M, Kipson N. et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome.. J Am Coll Cardiol 2014; 63: 872-877
    CrossrefPubMedGoogle Scholar