Cost-Effectiveness of Strategies to Personalize the Selection of P2Y12 Inhibitors in Patients with Acute Coronary Syndrome

  • Kibum Kim
  • Daniel R. Touchette
  • Larisa H. Cavallari
  • Amer K. Ardati
  • Robert J. DiDomenicoEmail author



Perform a cost-effectiveness analysis comparing strategies for selecting P2Y12 inhibitors in acute coronary syndrome (ACS).


Six strategies for selection of P2Y12 inhibitors in ACS were compared from the US healthcare system perspective: (1) clopidogrel for all (universal clopidogrel); (2) ticagrelor guided by platelet reactivity assay (PRA; clopidogrel + phenotype); (3) ticagrelor use only in CYP2C19 poor metabolizers (genotype + conservative ticagrelor); (4) ticagrelor use in both CYP2C19 intermediate and poor metabolizers (genotype + liberal ticagrelor); (5) ticagrelor use only in patients with CYP2C19 polymorphisms and clopidogrel nonresponse by PRA (genotype + phenotype); and (6) ticagrelor for all (universal ticagrelor). A decision model was developed to model major adverse cardiovascular events and bleeding during 1 year of treatment with a P2Y12 inhibitor. Model inputs were identified from the literature. Lifetime costs were adjusted to 2017 US dollars; quality-adjusted life-years (QALYs) were projected using a Markov model. The primary endpoint was the incremental cost-effectiveness compared to the next best option along the cost-effectiveness continuum. Sensitivity analyses were performed on all model inputs to assess their influence on the incremental cost-effectiveness.


In the base case analysis, incremental cost-effectiveness ratios (ICER) for the clopidogrel + phenotype, genotype + liberal ticagrelor, and universal ticagrelor strategies were $12,119/QALY, $29,412/QALY, and $142,456/QALY, respectively. Genotype + conservative ticagrelor and genotype + phenotype were not cost-effective due to second-order dominance. Genotype + liberal ticagrelor compared to clopidogrel + phenotype demonstrated the highest acceptance (97%) at a willingness to pay (WTP) threshold of $100,000/QALY.


Cost-effective strategies to personalize P2Y12 inhibition in ACS include clopidogrel +phenotype and genotype + liberal ticagrelor. Universal ticagrelor may be considered cost-effective at a higher WTP threshold ($150,000/QALY). Genotype + liberal ticagrelor exhibited the highest acceptability compared to clopidogrel + phenotype over the widest range of WTP thresholds and may be preferred.


Acute coronary syndrome Personalized medicine Ticagrelor Clopidogrel P2Y12 inhibitors Cost-effectiveness 



The authors would like to acknowledge and thank Marty Calabrese, PharmD for his assistance in collecting and analyzing background information on treatment trends and economics of cardiovascular diseases, including acute coronary syndrome.

Compliance with Ethical Standards

Conflict of Interest

Dr. DiDomenico received an honorarium from Amgen Inc. for preparation of a heart failure drug monograph for Pharmacy Practice News. He also served as an Otsuka America Pharmaceuticals, Inc. heart failure advisory board member. Dr. Touchette received an unrestricted grants from Cardinal Health, Sunovion Pharmaceuticals Inc. He has also served as a consultant to and Director of the American College of Clinical Pharmacy Practice-Based Research Network on a study funded by Pfizer Inc.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics−2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492.PubMedCrossRefGoogle Scholar
  2. 2.
    O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 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. J Am Coll Cardiol. 2013;61(4):e78–140.PubMedCrossRefGoogle Scholar
  3. 3.
    Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, 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. 2014;64(24):e139–228.PubMedCrossRefGoogle Scholar
  4. 4.
    Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2016;68(10):1082–115.PubMedCrossRefGoogle Scholar
  5. 5.
    Dayoub EJ, Seigerman M, Tuteja S, Kobayashi T, Kolansky DM, Giri J, et al. Trends in platelet adenosine diphosphate P2Y12 receptor inhibitor use and adherence among antiplatelet-naive patients after percutaneous coronary intervention, 2008-2016. JAMA Intern Med. 2018;178(7):943–50.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Kim K, Lee TA, Touchette DR, DiDomenico RJ, Ardati AK, Walton SM. Contemporary trends in oral antiplatelet agent use in patients treated with percutaneous coronary intervention for acute coronary syndrome. J Manag Care Spec Pharm. 2017;23(1):57–63.PubMedGoogle Scholar
  7. 7.
    Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317–23.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Jang JS, Cho KI, Jin HY, Seo JS, Yang TH, Kim DK, et al. Meta-analysis of cytochrome P450 2C19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel. Am J Cardiol. 2012;110(4):502–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821–30.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.PubMedCrossRefGoogle Scholar
  12. 12.
    FDA drug safety communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. U.S. Food & Drug Administration. 2010. Accessed 25 June 2019
  13. 13.
    Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff R, Duarte JD, Voora D, et al. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv. 2018;11(2):181–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Notarangelo FM, Maglietta G, Bevilacqua P, Cereda M, Merlini PA, Villani GQ, et al. Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary syndromes: the PHARMCLO trial. J Am Coll Cardiol. 2018;71(17):1869–77.PubMedCrossRefGoogle Scholar
  15. 15.
    Sanchez-Ramos J, Davila-Fajardo CL, Toledo Frias P, et al. Results of genotype-guided antiplatelet therapy in patients who undergone percutaneous coronary intervention with stent. Int J Cardiol. 2016;225:289–95.PubMedCrossRefGoogle Scholar
  16. 16.
    Shen DL, Wang B, Bai J, Han Q, Liu C, Huang XH, et al. Clinical value of CYP2C19 genetic testing for guiding the antiplatelet therapy in a Chinese population. J Cardiovasc Pharmacol. 2016;67(3):232–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Xie X, Ma YT, Yang YN, Li XM, Zheng YY, Ma X, et al. Personalized antiplatelet therapy according to CYP2C19 genotype after percutaneous coronary intervention: a randomized control trial. Int J Cardiol. 2013;168(4):3736–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Wang Y, Yan BP, Liew D, Lee VWY. Cost-effectiveness of cytochrome P450 2C19 *2 genotype-guided selection of clopidogrel or ticagrelor in Chinese patients with acute coronary syndrome. Pharm J. 2018;18(1):113–20.Google Scholar
  19. 19.
    Crespin DJ, Federspiel JJ, Biddle AK, Jonas DE, Rossi JS. Ticagrelor versus genotype-driven antiplatelet therapy for secondary prevention after acute coronary syndrome: a cost-effectiveness analysis. Value Health. 2011;14(4):483–91.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Jiang M, You JH. CYP2C19 LOF and GOF-guided antiplatelet therapy in patients with acute coronary syndrome: a cost-effectiveness analysis. Cardiovasc Drugs Ther. 2017;31(1):39–49.PubMedCrossRefGoogle Scholar
  21. 21.
    Kazi DS, Garber AM, Shah RU, Dudley RA, Mell MW, Rhee C, et al. Cost-effectiveness of genotype-guided and dual antiplatelet therapies in acute coronary syndrome. Ann Intern Med. 2014;160(4):221–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Lala A, Berger JS, Sharma G, Hochman JS, Scott Braithwaite R, Ladapo JA. Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost-effectiveness analysis. J Thromb Haemost. 2013;11(1):81–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Patel V, Lin FJ, Ojo O, et al. Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention. Pharm Pract (Granada). 2014;12(3):438.CrossRefGoogle Scholar
  24. 24.
    Reese ES, Daniel Mullins C, Beitelshees AL, Onukwugha E. Cost-effectiveness of cytochrome P450 2C19 genotype screening for selection of antiplatelet therapy with clopidogrel or prasugrel. Pharmacotherapy. 2012;32(4):323–32.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Empey PE, Stevenson JM, Tuteja S, Weitzel KW, Angiolillo DJ, Beitelshees AL, et al. Multisite investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy. Clin Pharmacol Ther. 2018;104(4):664–74.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet. 2016;388(10055):2015–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Komocsi A, Aradi D, Szuk T, et al. Comparison of platelet function guided versus unguided treatment with P2Y12 inhibitors in patients with acute myocardial infarction (from the Hungarian myocardial infarction registry). Am J Cardiol. 2018;121(10):1129–37.PubMedCrossRefGoogle Scholar
  28. 28.
    Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet. 2017;390(10104):1747–57.PubMedCrossRefGoogle Scholar
  29. 29.
    Coleman CI, Limone BL. Cost-effectiveness of universal and platelet reactivity assay-driven antiplatelet therapy in acute coronary syndrome. Am J Cardiol. 2013;112(3):355–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Straub N, Beivers A, Lenk E, Aradi D, Sibbing D. A model-based analysis of the clinical and economic impact of personalising P2Y12-receptor inhibition with platelet function testing in acute coronary syndrome patients. Thromb Haemost. 2014;111(2):290–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Jiang M, You JH. CYP2C19 genotype plus platelet reactivity-guided antiplatelet therapy in acute coronary syndrome patients: a decision analysis. Pharmacogenet Genomics. 2015;25(12):609–17.PubMedCrossRefGoogle Scholar
  32. 32.
    Mangiacapra F, Barbato E, Patti G, Gatto L, Vizzi V, Ricottini E, et al. Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention. JACC Cardiovasc Interv. 2010;3(3):318–23.PubMedCrossRefGoogle Scholar
  33. 33.
    Cavallari LH, Franchi F, Rollini F, et al. Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention. J Transl Med. 2018;16(1):92.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Effient prescribing information.: Indianapolis: Daiichi Sankyo, Inc. and Eli Lilly and Company, 2019.Google Scholar
  35. 35.
    Sanders GD, Neumann PJ, Basu A, Brock DW, Feeny D, Krahn M, et al. Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine. JAMA. 2016;316(10):1093–103.PubMedCrossRefGoogle Scholar
  36. 36.
    Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Cornel JH, et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient outcomes (PLATO) trial. Eur Heart J. 2011;32(23):2933–44.PubMedCrossRefGoogle Scholar
  37. 37.
    Hoyert DL, Xu J. Deaths: preliminary data for 2011. Center for Disease Control and Prevention: Atlanta; 2012.Google Scholar
  38. 38.
    Nikolic E, Janzon M, Hauch O, Wallentin L, Henriksson M. For the PLATO health economic substudy group. Cost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO study. Eur Heart J. 2013;34(3):220–8.PubMedCrossRefGoogle Scholar
  39. 39.
    RED BOOK Online. Chicago: Truven Health Analytics; 2017.Google Scholar
  40. 40.
    Mercaldi CJ, Siu K, Sander SD, Walker DR, Wu Y, Li Q, et al. Long-term costs of ischemic stroke and major bleeding events among Medicare patients with Nonvalvular atrial fibrillation. Cardiol Res Pract. 2012;2012:645469–13.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. 2012;379(9827):1705–11.PubMedCrossRefGoogle Scholar
  42. 42.
    Erickson KF, Japa S, Owens DK, Chertow GM, Garber AM, Goldhaber-Fiebert JD. Cost-effectiveness of statins for primary cardiovascular prevention in chronic kidney disease. J Am Coll Cardiol. 2013;61(12):1250–8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Clinical laboratory fee schedule, revised for January 2017. Baltimore: Centers for Medicare & Medicaid Services, 2017.Google Scholar
  44. 44.
    Godino C, Mendolicchio L, Figini F, Latib A, Sharp ASP, Cosgrave J, et al. Comparison of VerifyNow-P2Y12 test and flow cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy? Thromb J. 2009;7:4.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382(9892):614–23.PubMedCrossRefGoogle Scholar
  46. 46.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354–62.PubMedCrossRefGoogle Scholar
  47. 47.
    Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;306(24):2704–14.PubMedCrossRefGoogle Scholar
  48. 48.
    Fryback DG, Dunham NC, Palta M, Hanmer J, Buechner J, Cherepanov D, et al. US norms for six generic health-related quality-of-life indexes from the National Health Measurement study. Med Care. 2007;45(12):1162–70.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Mahoney EM, Wang K, Arnold SV, Proskorovsky I, Wiviott S, Antman E, et al. Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction TRITON-TIMI 38. Circulation. 2010;121(1):71–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Christensen MC, Mayer S, Ferran JM. Quality of life after intracerebral hemorrhage: results of the factor seven for acute hemorrhagic stroke (FAST) trial. Stroke. 2009;40(5):1677–82.PubMedCrossRefGoogle Scholar
  51. 51.
    Nyman JA, Barleen NA, Dowd BE, Russell DW, Coons SJ, Sullivan PW. Quality-of-life weights for the US population: self-reported health status and priority health conditions, by demographic characteristics. Med Care. 2007;45(7):618–28.PubMedCrossRefGoogle Scholar
  52. 52.
    Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, 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(2):237–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Tello-Montoliu A, Rivera J, Hernandez D, et al. Temporal changes in platelet response in acute coronary syndrome patients with Prasugrel and Clopidogrel after stent implantation. Circ J. 2018;82(2):353–60.PubMedCrossRefGoogle Scholar
  54. 54.
    HCUPnet: Healthcare cost and utilization project—free health care statistics. Agency for Healthcare Research and Quality, Rockville. Accessed Rockville: Agency for Healthcare Research and Quality. Available at Accessed December 16, 2017.
  55. 55.
    Jefferies LC, Sachais BS, Young DS. Blood transfusion costs by diagnosis-related groups in 60 university hospitals in 1995. Transfusion. 2001;41(4):522–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Consumer price index for medical care (CPI). Rockville: Health Resources and Services Administration2017.Google Scholar
  57. 57.
    Disutility [online]. (2016). York; York Health Economics Consortium; 2016. Accessed 25 June 2019
  58. 58.
    Kim K, Lee TA, Ardati AK, DiDomenico RJ, Touchette DR, Walton SM. Comparative effectiveness of oral antiplatelet agents in patients with acute coronary syndrome. Pharmacotherapy. 2017;37(8):877–87.PubMedCrossRefGoogle Scholar
  59. 59.
    Sahlen A, Varenhorst C, Lagerqvist B, et al. Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: experiences from SWEDEHEART registry. Eur Heart J. 2016;37(44):3335–42.PubMedCrossRefGoogle Scholar
  60. 60.
    Capranzano P, Capodanno D. Switching between P2Y12 inhibitors: rationale, methods, and expected consequences. Vasc Pharmacol. 2019;116:4–7.CrossRefGoogle Scholar
  61. 61.
    Nawarskas JJ, Montoya TN. Switching from Ticagrelor or Prasugrel to Clopidogrel. Cardiol Rev. 2018;26(2):107–11.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacotherapy and Pharmacotherapy Outcomes Research CenterUniversity of UtahSalt Lake CityUSA
  2. 2.Center for Pharmacoepidemiology and Pharmacoeconomic ResearchUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Department of Pharmacy Systems, Outcomes and PolicyUniversity of Illinois at ChicagoChicagoUSA
  4. 4.Department of Pharmacotherapy and Translational Research and Center for PharmacogenomicsUniversity of FloridaGainesvilleUSA
  5. 5.Division of CardiologyUniversity of Illinois at ChicagoChicagoUSA
  6. 6.Department of Pharmacy PracticeUniversity of Illinois at ChicagoChicagoUSA

Personalised recommendations