Low-dose ticagrelor yields an antiplatelet efficacy similar to that of standard-dose ticagrelor in healthy subjects: an open-label randomized controlled trial

Pan Li, Ying Gu, Yawei Yang, Lizhi Chen, Junmei Liu, Lihong Gao, Yongwen Qin, Quancai Cai, Xianxian Zhao, Zhuo Wang, Liping Ma, Pan Li, Ying Gu, Yawei Yang, Lizhi Chen, Junmei Liu, Lihong Gao, Yongwen Qin, Quancai Cai, Xianxian Zhao, Zhuo Wang, Liping Ma

Abstract

Ticagrelor has a greater antiplatelet efficacy than clopidogrel but may be accompanied by an increased risk of bleeding. This study evaluated the antiplatelet effect and pharmacokinetic profile of low-dose ticagrelor in healthy Chinese volunteers. Thirty healthy subjects were randomized to receive standard-dose ticagrelor (180-mg loading dose, 90-mg twice daily [bid] [n = 10]), low-dose ticagrelor (90-mg loading dose, 45-mg bid [n = 10]), or clopidogrel (600-mg loading dose, 75-mg once daily [n = 10]). Platelet reactivity was assessed by using the VerifyNow P2Y12 assay at baseline and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours post-dosing. The ticagrelor and AR-C124910XX concentrations were measured for pharmacokinetic analysis. The percentage inhibition of P2Y12 reaction units was higher in the low-dose and standard-dose ticagrelor group than in the clopidogrel group at 0.5, 1, 2, 4, 8, and 48 hours post-dosing (P < 0.05 for all), but did not differ significantly between the two ticagrelor doses at any time-point (P > 0.05). The plasma ticagrelor and ARC124910XX concentrations were approximately 2-fold higher with standard-dose versus low-dose ticagrelor. No serious adverse events were reported. In conclusion, low-dose ticagrelor achieved faster and higher inhibition of platelet functions in healthy Chinese subjects than did clopidogrel, with an antiplatelet efficacy similar to that of standard-dose ticagrelor.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. Flow chart. LD, loading dose;…
Figure 1. Flow chart. LD, loading dose; BID, twice daily; QD, once daily.
Figure 2. Platelet reactivity as assessed by…
Figure 2. Platelet reactivity as assessed by the VerifyNow P2Y12 assay across time points.
(A) Mean % inhibition of PRU after LD and MD of standard-dose ticagrelor, low-dose ticagrelor or clopidogrel. †P < 0.001, *P < 0.05, low-dose ticagrelor vs clopidogrel. (B) The individual PRU values at all time points. LD, loading dose; BID, twice daily; PRU, P2Y12 reaction units.
Figure 3
Figure 3
Mean plasma concentrations of ticagrelor (A) and AR-C124910XX (B) across time points.
Figure 4. Ticagrelor plasma concentration versus %…
Figure 4. Ticagrelor plasma concentration versus % inhibition of PRU.
PRU, P2Y12 reaction units.

References

    1. Levine G. N. et al.. Expert consensus document: World Heart Federation expert consensus statement to antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 11, 597–606 (2014).
    1. Amsterdam E. A. 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. J Am Coll Cardiol 64, e139–228 (2014).
    1. Windecker S. et al.. 2014 ESC/ EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 35, 2541–2619 (2014).
    1. Levine G. N. et al.. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: Executive summary. 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. J Am Coll Cardiol 58, e44–122 (2011).
    1. Ferri N., Corsini A. & Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: Insights on pharmacokinetic and pharmacodynamic properties. Drugs 73, 1681–1709 (2013).
    1. Gurbel P. A. et al.. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 120, 2577–2585 (2009).
    1. Müller I. et al.. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 89, 783–787 (2003).
    1. Angiolillo D. J. et al.. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49, 1505–1516 (2007).
    1. Husted S. et al.. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 27, 1038–1047 (2006).
    1. Teng R., Oliver S., Hayes M. A. & Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 38, 1514–1521 (2010).
    1. Zhou D., Andersson T. B. & Grimm S. W. In vitro evaluation of potential drug–drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction and differential kinetics. Drug Metab Dispos 39, 703–710 (2011).
    1. van Giezen J. J. & Humphries R. G. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 31, 195–204 (2005).
    1. Butler K. & Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 70, 65–77 (2010).
    1. Wallentin L. et al.. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361, 1045–1057 (2009).
    1. Teng R. & Butler K. Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther 52, 478–491 (2014).
    1. Li P. et al.. Ticagrelor overcomes high platelet reactivity in patients with acute myocardial infarction or coronary artery in-stent restenosis: a randomized controlled trial. Sci Rep 5, 13789, doi: 10.1038/srep13789 (2015).
    1. Li H., Butler K., Yang L., Yang Z. & Teng R. Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single-centre study. Clin Drug Investig 32, 87–97 (2012).
    1. Hasan M. S., Basri H. B., Hin L. P. & Stanslas J. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Int J Neurosci 123, 143–154 (2013).
    1. Bonaca M. P. et al.. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med 372, 1791–1800 (2015).
    1. Shen A. Y., Yao J. F., Brar S. S., Jorgensen M. B. & Chen W. Racial ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 50, 309–315 (2007).
    1. Mak K. H. et al.. Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study. Am Heart J 157, 658–665 (2009).
    1. Wang T. Y. et al.. Comparison of baseline characteristics, treatment patterns, and in-hospital outcomes of Asian versus non-Asian white Americans with non-ST-segment elevation acute coronary syndromes from the CRUSADE quality improvement initiative. Am J Cardiol 100, 391–396 (2007).
    1. Butler K. & Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 70, 65–77 (2010).
    1. Husted S. et al.. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 27, 1038–1047 (2006).
    1. Storey R. F. et al.. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 50, 1852–1856 (2007).
    1. Storey R. F. et al.. Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol 67, 1145–1154 (2016).
    1. Guo L. Z. et al.. Comparison of pharmacodynamics between low dose ticagrelor and clopidogrel after loading and maintenance doses in healthy Korean subjects. Platelets 26, 563–569 (2015).
    1. Hiasa Y., Teng R. & Emanuelsson H. Pharmacodynamics, pharmacokinetics and safety of ticagrelor in Asian patients with stable coronary artery disease. Cardiovasc Interv Ther 29, 324–333 (2014).
    1. Cattaneo M., Schulz R. & Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 63, 2503–2509 (2014).
    1. Small D. S. et al.. Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese and white volunteers: an open-label trial. Clin Ther 32, 365–379 (2010).
    1. Storey R. F. et al.. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 32, 2945–2953 (2011).
    1. Cannon C. P. et al.. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 50, 1844–1851 (2007).
    1. Teng R. & Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 66, 487–496 (2010).
    1. Lordkipanidzé M. et al.. Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients. Eur Heart J 29, 2877–2885 (2008).
    1. Jeong Y. H. et al.. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J 164, 35–42 (2012).
    1. Breet N. J. et al.. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 303, 754–762 (2010).

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