Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention

  • Vardhaman Patel
  • Fang-Ju Lin
  • Olaitan Ojo
  • Sapna Rao
  • Shengsheng Yu
  • Lin Zhan
  • Daniel R. Touchette
Keywords: Clopidogrel, Prasugrel, Acute Coronary Syndrome, Polymorphism, Genetic, Genetic Testing, Costs and Cost Analysis, United States


Background: Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients.

Objective: The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider’s perspective.

Methods: A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding) for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs) were calculated for the treatment strategies, with quality-adjusted life years (QALYs) as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed.

Results: Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs) and genotype-guided therapy (USD19,231, 10.05 QALYs). The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost-effective with <21% certainty at willingness-to-pay of >USD170,000/QALY.

Conclusions: Our modeling analyses suggest that genotype-guided therapy is a cost-effective strategy in patients with acute coronary syndrome undergoing planned percutaneous coronary intervention.


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Author Biographies

Vardhaman Patel

Graduate student

Department of Pharmacy Systems, Outcomes and Policy

Fang-Ju Lin
Outcomes Scientist
Olaitan Ojo

Lieutenant Commander

DoD Pharmacoeconomic Center

Sapna Rao

Graduate Student

Department of Epidemiology

Shengsheng Yu

Associate Director

Global Health Outcomes

Lin Zhan

Senior Manager

Global HTA

Daniel R. Touchette

Associate Professor

Department of Pharmacy Systems, Outcomes and Policy


1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Heart disease and stroke statistics--2014 update: a report from the american heart association. Circulation. 2014;129(3):e28-e292. doi: 10.1161/01.cir.0000441139.02102.80

2. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Alonso-Coello P, Akl EA, Lansberg MG, Guyatt GH, Spencer FA. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e637S-e668S. doi: 141/2_suppl/e637S

3. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354-362. doi: NEJMoa0809171

4. Mao L, Jian C, Changzhi L, Dan H, Suihua H, Wenyi T, Wei W. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects. Arch Cardiovasc Dis. 2013;106(10):517-527. doi: 10.1016/j.acvd.2013.06.055

5. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373(9660):309-317. doi: 10.1016/s0140-6736(08)61845-0

6. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Buonamici P, Antoniucci D, Abbate R, Gensini GF. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol. 2009;103(6):806-811. doi: 10.1016/j.amjcard.2008.11.048

7. Harmsze AM, van Werkum JW, Ten Berg JM, Zwart B, Bouman HJ, Breet NJ, van 't Hof AW, Ruven HJ, Hackeng CM, Klungel OH, de Boer A, Deneer VH. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J. 2010;31(24):3046-3053. doi: 10.1093/eurheartj/ehq321

8. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363-375. doi: 10.1056/NEJMoa0808227

9. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376(9749):1320-1328. doi: 10.1016/s0140-6736(10)61274-3

10. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ (Clinical research ed). 2011;343:d4588. doi: 10.1136/bmj.d4588

11. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328-332. doi: clpt2011132

12. Holmes DR, Jr., Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2010;56(4):321-341. doi: S0735-1097(10)01997-2

13. Plavix (clopidogrel bisulfate) [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011.

14. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317-323. doi: 10.1038/clpt.2013.105

15. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119(19):2553-2560. doi: CIRCULATIONAHA.109.851949

16. 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.

17. 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):323-332.

18. Mahoney EM, Wang K, Arnold SV, Proskorovsky I, Wiviott S, Antman E, Braunwald E, Cohen DJ. 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):71-79. doi: CIRCULATIONAHA.109.900704

19. 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(20):2001-2015. doi: NEJMoa0706482

20. Pinto DS, Stone GW, Shi C, Dunn ES, Reynolds MR, York M, Walczak J, Berezin RH, Mehran R, McLaurin BT, Cox DA, Ohman EM, Lincoff AM, Cohen DJ. Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes. J Am Coll Cardiol. 2008;52(22):1758-1768. doi: S0735-1097(08)02876-3

21. Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363. doi: S0140-6736(08)60422-5

22. Unger EF. Prasugrel for reduction of cardiovascular events in patients with acute coronary syndrome (ACS) Silver Spring, Maryland: U.S. Food and Drug Administration; 2009 [updated Feb 3 2009;]. Available from: (Accessed 7 November 2010).

23. Memtsoudis SG, Besculides MC, Gaber L, Liu S, Gonzalez Della Valle A. Risk factors for pulmonary embolism after hip and knee arthroplasty: a population-based study. International orthopaedics. 2009;33(6):1739-1745. doi: 10.1007/s00264-008-0659-z

24. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;41(12):913-958.

25. Eli Lilly and Company. A comparison of prasugrel (CS-747) and clopidogrel in acute coronary syndrome subjects who are to undergo percutaneous coronary intervention [ Identifier: NCT00097591] Bethesda, MD: Eli Lilly and Company; 2010. Available from: (Accessed 8 October 2012).

26. Consumer Price Index (CPI): Bureau of Labor Statistics; 2011. Available from: (Accessed 20 March 2012).

27. Red Book Online [Internet database, accessed through Micromedex 2.0]. Ann Arbor, MI: Truven Health Analytics; 2014.

28. Kadkol S. Personal communication (estimated UIC laboratory costs for genetic testing). 2012.

29. Physician fee schedule (PFS) relative value files Baltimore, MD: Center for Medicare & Medicaid Services; 2011. Available from: (Accessed 13 March 2012).

30. Etemad LR, McCollam PL. Total first-year costs of acute coronary syndrome in a managed care setting. J Manag Care Pharm. 2005;11(4):300-306.

31. Beck JR, Pauker SG, Gottlieb JE, Klein K, Kassirer JP. A convenient approximation of life expectancy (the "DEALE"). II. Use in medical decision-making. Am J Med. 1982;73(6):889-897.

32. Fryback DG, Dunham NC, Palta M, Hanmer J, Buechner J, Cherepanov D, Herrington SA, Hays RD, Kaplan RM, Ganiats TG, Feeny D, Kind P. US norms for six generic health-related quality-of-life indexes from the National Health Measurement study. Med Care. 2007;45(12):1162-1170. doi: 10.1097/MLR.0b013e31814848f1

33. 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):1677-1682. doi: 10.1161/strokeaha.108.538967

34. 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):618-628. doi: 10.1097/MLR.0b013e31803dce05

35. Tengs TO, Lin TH. A meta-analysis of quality-of-life estimates for stroke. PharmacoEconomics. 2003;21(3):191-200.

36. Healthcare Cost and Utilization Project (HCUP). Agency for Healthcare Research and Quality, Rockville, MD: HCUPnet; 2008. Available from: (Accessed 10 May 2011).

37. Guzauskas GF, Hughes DA, Bradley SM, Veenstra DL. A risk-benefit assessment of prasugrel, clopidogrel, and genotype-guided therapy in patients undergoing percutaneous coronary intervention. Clin Pharmacol Ther. 2012;91(5):829-837.

38. Mauskopf JA, Graham JB, Bae JP, Ramaswamy K, Zagar AJ, Magnuson EA, Cohen DJ, Meadows ES. Cost-effectiveness of prasugrel in a US managed care population. J Med Econ. 2012;15(1):166-174. doi: 10.3111/13696998.2011.637590

39. 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):2704-2714. doi: 10.1001/jama.2011.1880

40. Cattaneo M, Podda GM. State of the art of new P2Y12 antagonists. Intern Emerg Med. 2010;5(5):385-391. doi: 10.1007/s11739-010-0363-z

41. Wiviott SD, Desai N, Murphy SA, Musumeci G, Ragosta M, Antman EM, Braunwald E. Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies. Am J Cardiol. 2011;108(7):905-911. doi: S0002-9149(11)01906-0

42. Morrow DA, Wiviott SD, White HD, Nicolau JC, Bramucci E, Murphy SA, Bonaca MP, Ruff CT, Scirica BM, McCabe CH, Antman EM, Braunwald E. Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction. Circulation. 2009;119(21):2758-2764. doi: CIRCULATIONAHA.108.833665

43. Eisenberg MJ, Filion KB, Azoulay A, Brox AC, Haider S, Pilote L. Outcomes and cost of coronary artery bypass graft surgery in the United States and Canada. Arch Intern Med. 2005;165(13):1506-1513.

44. Nagle PC, Smith AW. Review of recent US cost estimates of revascularization. Am J Manag Care. 2004 Oct;10(11 Suppl):S370-S376.

45. O'Brien JA, Patrick AR, Caro J. Estimates of direct medical costs for microvascular and macrovascular complications resulting from type 2 diabetes mellitus in the United States in 2000. Clin Ther. 2003;25(3):1017-1038. doi: S0149291803801224

46. Sculpher MJ, Lozano-Ortega G, Sambrook J, Palmer S, Ormanidhi O, Bakhai A, Flather M, Steg PG, Mehta SR, Weintraub W. Fondaparinux versus Enoxaparin in non-ST-elevation acute coronary syndromes: short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am Heart J. 2009;157(5):845-52. doi: S0002-8703(09)00149-5

47. Agarwal S, Banerjee S, Tuzcu EM, Kapadia SR. Influence of age on revascularization related costs of hospitalization among patients of stable coronary artery disease. Am J Cardiol. 2010;105(11):1549-1554. doi: 10.1016/j.amjcard.2010.01.012

48. Reed SD, Blough DK, Meyer K, Jarvik JG. Inpatient costs, length of stay, and mortality for cerebrovascular events in community hospitals. Neurology. 2001;57(2):305-314.

49. Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27(9):1459-1466.

50. Amin M, Fergusson D, Aziz A, Wilson K, Coyle D, Hebert P. The cost of allogeneic red blood cells--a systematic review. Transfus Med. 2003;13(5):275-285.

51. Jefferies LC, Sachais BS, Young DS. Blood transfusion costs by diagnosis-related groups in 60 university hospitals in 1995. Transfusion. 2001;41(4):522-529.

52. Resnic FS, Arora N, Matheny M, Reynolds MR. A cost-minimization analysis of the angio-seal vascular closure device following percutaneous coronary intervention. Am J Cardiol. 2007;99(6):766-770. doi: S0002-9149(06)02363-0

53. Smith TL, Melfi CA, Kesterson JA, Sandmann BJ, Kotsanos JG. Direct medical charges associated with myocardial infarction in patients with and without diabetes. Med Care. 1999;37(4 Suppl Lilly):AS4-AS11.

54. Eisenstein EL, Shaw LK, Anstrom KJ, Nelson CL, Hakim Z, Hasselblad V, Mark DB. Assessing the clinical and economic burden of coronary artery disease: 1986-1998. Med Care. 2001;39(8):824-835.

55. Arias E. United States life tables, 2006. Natl Vital Stat Rep. 2010;58(21):1-40.
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