Use of the VerifyNow point of care assay to assess the pharmacodynamic effects of loading and maintenance dose regimens of prasugrel and ticagrelor

Dominick J Angiolillo, Latonya Been, Marc Rubinstein, Michael Martin, Fabiana Rollini, Francesco Franchi, Dominick J Angiolillo, Latonya Been, Marc Rubinstein, Michael Martin, Fabiana Rollini, Francesco Franchi

Abstract

Prasugrel and ticagrelor are potent oral platelet P2Y12 inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y12 inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y12 inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1-179 vs. 2-128) and ticagrelor (1-196 vs. 1-177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registration http://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.

Keywords: Platelet function; Prasugrel; Ticagrelor.

Figures

Fig. 1
Fig. 1
Platelet activation mediated by platelet P2Y1 and P2Y12 receptors. Illustration of the differences between P2Y1 and P2Y12 mediated signaling and the selective nature of the VerifyNow test in defining the effects of P2Y12 inhibitors Adapted with permission from Nicholas RA (2001) Identification of the P2Y12 receptor: a novel member of the P2Y family of receptors activated by extracellular nucleotides. Mol Pharmacol, 60(3):416–420
Fig. 2
Fig. 2
Distribution of on treatment PRUTest values among prasugrel treated patients. Box Whisker plot of the minimum, median, maximum, interquartile range and outliers of PRUTest values in prasugrel treated patients
Fig. 3
Fig. 3
Distribution of on treatment PRUTest values among ticagrelor treated patients. Box Whisker plot of the minimum, median, maximum, interquartile range and outliers of PRUTest values in ticagrelor treated patients

References

    1. Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. J Am Coll Cardiol. 2018;72(23 Pt A):2915–2931. doi: 10.1016/j.jacc.2018.09.057.
    1. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol. 2015;12:30–47. doi: 10.1038/nrcardio.2014.156.
    1. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49:1505–1516. doi: 10.1016/j.jacc.2006.11.044.
    1. Sibbing D, Aradi D, Alexopoulos D, Ten Berg J, Bhatt DL, Bonello L, Collet JP, Cuisset T, Franchi F, Gross L, Gurbel P, Jeong YH, Mehran R, Moliterno DJ, Neumann FJ, Pereira NL, Price MJ, Sabatine MS, So DYF, Stone GW, Storey RF, Tantry U, Trenk D, Valgimigli M, Waksman R, Angiolillo DJ. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019;12:1521–1537. doi: 10.1016/j.jcin.2019.03.034.
    1. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015. doi: 10.1056/NEJMoa0706482.
    1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. doi: 10.1056/NEJMoa0904327.
    1. Michelson AD. Methods for the measurement of platelet function. Am J Cardiol. 2009;103:20A–26A. doi: 10.1016/j.amjcard.2008.11.019.
    1. Malinin A, Pokov A, Spergling M, Defranco A, Schwartz K, Schwartz D, Mahmud E, Atar D, Serebruany V. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res. 2007;119:277–284. doi: 10.1016/j.thromres.2006.01.019.
    1. VerifyNow PRUTest - Platelet Reactivity Test Device Package Insert
    1. Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des. 2006;12:1255–1259. doi: 10.2174/138161206776361318.
    1. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline, CLSI document EP28-A3, Clinical and Laboratory Standards Institute (CLSI)
    1. Bae JP, Candrilli SD, Fortenberry J, Meyers JL, Jakubowski JA, Drenning D. Point-of-care platelet reactivity determination with VerifyNow-P2Y12 following administration of clopidogrel or prasugrel: data from a real-world, clinical care inpatient setting. Hosp Pract. 2014;42:7–15. doi: 10.3810/hp.2014.10.1139.
    1. Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, Tanguay JF, Cannon CP, Topol EJ. 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. doi: 10.1161/CIRCULATIONAHA.111.029165.
    1. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614–623. doi: 10.1016/S0140-6736(13)61170-8.
    1. Michelson AD, Frelinger AL, Braunwald E, Downey WE, Angiolillo DJ, Xenopoulos NP, Jakubowski JA, Li Y, Murphy SA, Qin J, McCabe CH, Antman EM, Wiviott SD. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J. 2009;30:1753–1763. doi: 10.1093/eurheartj/ehp159.
    1. Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, Emanuelsson H, Cannon CP, Becker RC, Wallentin L. 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. doi: 10.1016/j.jacc.2010.03.100.
    1. Angiolillo DJ, Schneider DJ, Bhatt DL, French WJ, Price MJ, Saucedo JF, Shaburishvili T, Huber K, Prats J, Liu T, Harrington RA, Becker RC. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombol. 2012;34:44–55. doi: 10.1007/s11239-012-0737-3.
    1. Rollini F, Franchi F, Thano E, Faz G, Park Y, Kureti M, Cho JR, Been L, Bass TA, Angiolillo DJ. In vitro pharmacodynamic effects of cangrelor on platelet P2Y(12) receptor-mediated signaling in ticagrelor-treated patients. JACC Cardiovasc Interv. 2017;10:1374–1375. doi: 10.1016/j.jcin.2017.04.027.
    1. Rollini F, Franchi F, Tello-Montoliu A, Patel R, Darlington A, Ferreiro JL, Cho JR, Muñiz-Lozano A, Desai B, Zenni MM, Guzman LA, Bass TA, Angiolillo DJ. Pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in prasugrel-treated patients. JACC Cardiovasc Interv. 2014;7:426–434. doi: 10.1016/j.jcin.2013.11.019.
    1. Franchi F, Rollini F, Rivas A, Wali M, Briceno M, Agarwal M, Shaikh Z, Nawaz A, Silva G, Been L, Smairat R, Kaufman M, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Bass TA, Angiolillo DJ. Platelet inhibition with cangrelor and crushed ticagrelor in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2019;139:1661–1670. doi: 10.1161/CIRCULATIONAHA.118.038317.
    1. Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006;27:1166–1173. doi: 10.1093/eurheartj/ehi877.
    1. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation. 2011;123:798–813. doi: 10.1161/CIRCULATIONAHA.109.913376.
    1. Capodanno D, Angiolillo DJ. Antithrombotic therapy for atherosclerotic cardiovascular disease risk mitigation in patients with coronary artery disease and diabetes mellitus. Circulation. 2020;142:2172–2188. doi: 10.1161/CIRCULATIONAHA.120.045465.
    1. Rollini F, Franchi F, Cho JR, DeGroat C, Bhatti M, Muniz-Lozano A, Singh K, Ferrante E, Wilson RE, Dunn EC, Zenni MM, Guzman LA, Bass TA, Angiolillo DJ. 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;37:2722–2730. doi: 10.1093/eurheartj/ehv744.
    1. Franchi F, Rollini F, Aggarwal N, Hu J, Kureti M, Durairaj A, Duarte VE, Cho JR, Been L, Zenni MM, Bass TA, Angiolillo DJ. Pharmacodynamic comparison of prasugrel 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. doi: 10.1161/CIRCULATIONAHA.116.023402.
    1. Franchi F, Rollini F, Angiolillo DJ. Antithrombotic therapy for patients with STEMI undergoing primary PCI. Nat Rev Cardiol. 2017;14:361–379. doi: 10.1038/nrcardio.2017.18.
    1. Franchi F, Rollini F, Park Y, Hu J, Kureti M, Rivas Rios J, Faz G, Yaranov D, Been L, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Bass TA, Angiolillo DJ. Effects of methylnaltrexone on ticagrelor-induced antiplatelet effects in coronary artery disease patients treated with morphine. JACC Cardiovasc Interv. 2019;12:1538–1549. doi: 10.1016/j.jcin.2019.05.028.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner