Thromb Haemost 2016; 116(06): 1060-1069
DOI: 10.1160/TH16-05-0377
Cellular Haemostasis and Platelets
Schattauer Publishers Schattauer

Impact of timing from blood sampling to pharmacodynamic assessment on measures of platelet reactivity in patients treated with P2Y12 receptor inhibitors

Fabiana Rollini
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Francesco Franchi
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Kamaldeep Singh
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Jung Rae Cho
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Mona Bhatti
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Christopher DeGroat
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Jenny Hu
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Niti Aggarwal
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Zeina Alobaidi
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Estela Thano
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Elisabetta Ferrante
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Martin M. Zenni
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Theodore A. Bass
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
,
Dominick J. Angiolillo
1   University of Florida College of Medicine – Jacksonville, Jacksonville, Florida, USA
› Author Affiliations
Further Information

Publication History

Received: 16 May 2016

Accepted after major revision: 11 July 2016

Publication Date:
09 March 2018 (online)

Summary

Several platelet function tests (PFT) are available to assess the pharmacodynamic (PD) effects of P2Y12 inhibitors. However, there are technical variances between PFT, and P2Y12 inhibitors differ in pharmacological properties. Manufactures of PFT recommend a time-frame within which assessments needs to be executed. However, if the timing from blood sampling to processing affects PD results is unknown. We conducted a prospective study assessing the impact of timing from blood sampling to processing on PD measures using three different PFT. We studied 60 aspirin-treated patients with coronary artery disease (CAD) on maintenance P2Y12 inhibiting therapy [clopidogrel 75 mg/day (n=20), prasugrel 10 mg/day (n=20) and ticagrelor 90 mg bid (n=20)]. PD assessments (trough levels) were performed by VerifyNow P2Y12 (VN), light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) at 30 minutes, 2 and 4 hours post-sampling; VASP was also performed at 24 hours. P2Y12 reaction units (PRU) by VN significantly decreased over time with all P2Y12 inhibitors (clopidogrel p<0.001; prasugrel p=0.016; ticagrelor p<0.001). PRU at 30 minutes and 2 hours were similar, but decreased at 4 hours. LTA showed consistent findings with VN. Conversely, PD measures as assessed by VASP were stable over time (p>0.1 for all P2Y12 inhibitors). In conclusion, in CAD patients on maintenance therapy with P2Y12 inhibitors, timing from blood sampling to processing significantly influences PD measures as assessed by VN and LTA, but not by VASP.

 
  • References

  • 1 Angiolillo DJ. The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs 2012; 72: 2087-2116.
  • 2 Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015; 12: 30-47.
  • 3 Levine GN, Bates ER, Blankenship JC. et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011; 124: e574-651.
  • 4 O’Gara PT, Kushner FG, Ascheim DD. et al. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127: 529-555.
  • 5 Amsterdam EA, Wenger NK, Brindis RG. et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130: e344-426.
  • 6 Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet 2015; 386: 281-291.
  • 7 Franchi F, Rollini F, Cho JR. et al. Platelet function testing in contemporary clinical and interventional practice. Curr Treat Options Cardiovasc Med 2014; 16: 300.
  • 8 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.
  • 9 Aradi D, Kirtane A, Bonello L. et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36: 1762-1771.
  • 10 Michelson AD. Methods for the measurement of platelet function. Am J Cardiol 2009; Feb 2 103 (Suppl. 03) 20A-26A.
  • 11 Harrison P, Frelinger 3rd AL, Furman MI. et al. Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007; 120: 323-336.
  • 12 VerifyNow P2Y12 package insert. Available at: http://www.accriva.com/products/verifynow-system-platelet-reactivity-test Accessed April 22, 2016
  • 13 LTA package insert. Available at: http://www.practical-haemostasis.com/Platelets/platelet_function_testing_lta.html Accessed April 22, 2016
  • 14 Cattaneo M, Cerletti C, Harrison P. et al. Recommendations for the Standardization of Light Transmission Aggregometry: A Consensus of the Working Party from the Platelet Physiology Subcommittee of SSC/ISTH. J Thromb Haemost 2013; 11: 1183-1189.
  • 15 VASP package insert. Available at: http://search.cosmobio.co.jp/cosmo_search_p/search_gate2/docs/BCT_/7014.20110309.pdf Accessed April 22, 2016
  • 16 Rollini F, Franchi F, Cho JR. et al. A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study. Eur Heart J 2016 in press.
  • 17 Aleil B, Ravanat C, Cazenave JP. 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.
  • 18 Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 2004; 10: 307-312.
  • 19 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.
  • 20 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505-1516.
  • 21 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
  • 22 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59: 2159-2164.
  • 23 Collet JP, Cuisset T, Rangé G. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
  • 24 Varenhorst C, James S, Erlinge D. et al. Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin. Am Heart J 2009; 157: 562 e1-9.
  • 25 Bouman HJ, Parlak E, van Werkum JW. et al. Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel. J Thromb Haemost 2010; 08: 482-488.
  • 26 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.
  • 27 Judge HM, Buckland RJ, Sugidachi A. et al. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function. Thromb Haemost 2010; 103: 1210-1217.
  • 28 Bal Dit Sollier C, Berge N, Boval B. et al. Differential sensitivity and kinetics of response of different ex vivo tests monitoring functional variability of platelet response to clopidogrel. Thromb Haemost 2010; 104: 571-581.
  • 29 Brar SS, ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative metaanalysis of individual participant data. J Am Coll Cardiol 2011; 58: 1945-1954.
  • 30 Bonello L, Mancini J, Pansieri M. et al. Relationship between posttreatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel. J Thromb Haemost 2012; 10: 1999-2005.
  • 31 Germanovich K, Femia EA, Cheng CY. et al. Effects of pH and concentration of sodium citrate anticoagulant on platelet aggregation measured by light transmission aggregometry induced by adenosine diphosphate. J Thromb Haemost 2015; 13: 656.
  • 32 Erlinge D, Gurbel PA, James S. et al. Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in no-nelderly patients: the GENERATIONS trial, a pharmacodynamic and pharma-cokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 2013; 62: 577-583.
  • 33 Erlinge D, Ten Berg J, Foley D. et al. Reduction in platelet reactivity with prasu-grel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial. J Am Coll Car-diol 2012; 60: 2032-2040.
  • 34 Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016; 13: 11-27.
  • 35 Rollini F, Franchi F, Hu J. et al. Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. J Am Coll Cardiol 2016; 67: 1994-2004.
  • 36 Parodi G, Xanthopoulou I, Bellandi B. et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol 2015; 65: 511-512.
  • 37 Schneider DJ, Tracy PB, Mann KG. et al. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; 96: 2877-2883.
  • 38 Labarthe B, Théroux P, Angioï M. et al. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 2005; 46: 638-645.