Molecular Diagnosis & Therapy

, Volume 22, Issue 6, pp 641–652 | Cite as

Value of a Hypothetical Pharmacogenomic Test for the Diagnosis of Statin-Induced Myopathy in Patients at High Cardiovascular Risk

  • Dominic Mitchell
  • Jason R. Guertin
  • Jacques LeLorierEmail author
Current Opinion


We recently conducted two economic evaluations of a hypothetical pharmacogenomic test for statin-induced myopathy (SIM) in patients at high cardiovascular risk. Although the models differed in modeling technique and data inputs, both yielded similar results. We believe our approach to assessing the economic value of a diagnostic test was highly advantageous as it characterized the complete range of false-negative and false-positive test outcomes. We used a broad interpretation of test parameters that reflected physician and patient behavioral responses to the test results and accounted for patient adherence to treatment. Both economic evaluations indicated that a highly accurate pharmacogenomic test for SIM would provide a positive incremental net monetary benefit (INMB) for a provincial payer in Canada. However, the value of the test would depend on its ability to accurately diagnose patients when they experience musculoskeletal pain symptoms and guide patients with a test result indicating no SIM to adhere to treatment. Interestingly, our results indicated that a highly inaccurate test would still yield a positive INMB. We found this surprising result was driven by the imbalance of the risk of cardiovascular events outweighing the risk of rhabdomyolysis in patients at high cardiovascular risk. A highly accurate pharmacogenomic test for SIM in patients at high cardiovascular risk would provide economic value for payers. However, the economic and clinical value of the test would depend on the credibility of the test results and their success in influencing patients without SIM to adhere to therapy.


Author contributions

DM contributed to the conception and design of the study, data acquisition, analysis and interpretation of data, drafting the article, and final approval. JRG and JL contributed to the conception and design of the study, analysis and interpretation of data, drafting the article, and final approval.

Compliance with Ethical Standards


This research was supported by Genome Canada and Genome Québec. Jason R. Guertin is a recipient of an establishment fund from the Centre de recherche du CHU de Québec - Université Laval and from the Fondation du CHU de Québec.

Conflict of interest

Dominic Mitchell, Jason R. Guertin, and Jacques LeLorier have no conflicts of interest that are directly relevant to the content of this review.

Supplementary material

40291_2018_356_MOESM1_ESM.docx (44 kb)
Supplementary material 1 (DOCX 44 kb)


  1. 1.
    Mohamad TN, All M, Faddah R. Primary and secondary prevention of coronary artery disease. In: Drugs and disease: cardiology. Medscape; 2017. Accessed 24 Feb 2018.
  2. 2.
    Anderson TJ, Gregoire J, Hegele RA, Couture P, Mancini GB, McPherson R, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013;29(2):151–67. Scholar
  3. 3.
    Catalan VS, LeLorier J. Predictors of long-term persistence on statins in a subsidized clinical population. Value Health. 2000;3(6):417–26. Scholar
  4. 4.
    Newby LK, LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER, et al. Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation. 2006;113(2):203–12. Scholar
  5. 5.
    Guertin JR, Rahme E, LeLorier J. Use of continuous exposure variables when examining dose-dependent pharmacological effects—application to the association between exposure to higher statin doses and the incidence of diabetes. J Popul Ther Clin Pharmacol. 2017;24(1):5–15. Scholar
  6. 6.
    Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J. 2016;37(11):908–16. Scholar
  7. 7.
    Statin benefits questioned for heart disease prevention: Cholesterol-lowering drugs heavily promoted to prevent strokes and heart attacks. CBC Radio Canada; 2013. Accessed 28 Feb 2018.
  8. 8.
    Rallidis LS, Fountoulaki K, Anastasiou-Nana M. Managing the underestimated risk of statin-associated myopathy. Int J Cardiol. 2012;159(3):169–76. Scholar
  9. 9.
    Mampuya WM, Frid D, Rocco M, Huang J, Brennan DM, Hazen SL, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J. 2013;166(3):597–603. Scholar
  10. 10.
    Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011;10(3):373–87. Scholar
  11. 11.
    Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014;168(1):6–15. Scholar
  12. 12.
    Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference. Can J Cardiol. 2011;27(5):635–62. Scholar
  13. 13.
    Mancini GBJ, Tashakkor AY, Baker S, Bergeron J, Fitchett D, Frohlich J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus Update. Can J Cardiol. 2013;29(12):1553–68. Scholar
  14. 14.
    Mancini GBJ, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol. 2016;32(7):S35–65. Scholar
  15. 15.
    Di Stasi SL, MacLeod TD, Winters JD, Binder-Macleod SA. Effects of statins on skeletal muscle: a perspective for physical therapists. Phys Ther. 2010;90(10):1530–42. Scholar
  16. 16.
    Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40(3):567–72.CrossRefGoogle Scholar
  17. 17.
    Keltz E, Khan FY, Mann G. Rhabdomyolysis. The role of diagnostic and prognostic factors. Muscles Ligaments Tendons J. 2013;3(4):303–12.PubMedGoogle Scholar
  18. 18.
    Chai C, James H. Working out ’til you’re sick? Doctors warn of rhabdo, a deadly condition linked to over exercising. Montreal: Global News; 2014. Accessed 22 Nov 2017.
  19. 19.
    Swankhuizen M, Regier L. Statin intolerance—Management considerations. Saskatoon: RxFiles; 2013. Accessed 24 Oct 2017.
  20. 20.
    Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, et al. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008;359(8):789–99. Scholar
  21. 21.
    Carr DF, O’Meara H, Jorgensen AL, Campbell J, Hobbs M, McCann G, et al. SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink. Clin Pharmacol Ther. 2013;94(6):695–701. Scholar
  22. 22.
    Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54(17):1609–16. Scholar
  23. 23.
    Wilke RA, Ramsey LB, Johnson SG, Maxwell WD, McLeod HL, Voora D, et al. The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther. 2012;92(1):112–7. Scholar
  24. 24.
    Stewart A. SLCO1B1 polymorphisms and statin-induced myopathy. PLoS Curr. 2013. Scholar
  25. 25.
    Regence. Medical policy manual: genetic testing for statin-induced myopathy. Portland: Regence; 2018.Google Scholar
  26. 26.
    Génome Canada. Personalized medicine strategies for molecular diagnostics and targeted therapeutics of cardiovascular disease. Ottawa: Génome Canada; 2018. Accessed 17 Jan 2018.
  27. 27.
    Génome Québec. Personalized medicine strategies for molecular diagnostics and targeted therapeutics of cardiovascular disease. Montreal: Génome Québec; 2018. Accessed 17 Jan 2018.
  28. 28.
    Mitchell D, Guertin JR, Iliza AC, Fanton-Aita F, LeLorier J. Economic evaluation of a pharmacogenomics test for statin-induced myopathy in cardiovascular high-risk patients initiating a statin. Mol Diagn Ther. 2017;21(1):95–105. Scholar
  29. 29.
    Mitchell D, Guertin JR, Dubois A, Dubé MP, Tardif JC, Iliza AC, et al. A discrete event simulation model to assess the economic value of a hypothetical pharmacogenomics test for statin-induced myopathy in patients initiating a statin in secondary cardiovascular prevention. Mol Diagn Ther. 2018. Scholar
  30. 30.
    Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman O, Faergeman G, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. Atheroscler Suppl. 2004;5(3):81–7. Scholar
  31. 31.
    Jones SB, Sen S, Lakshminarayan K, Rosamond WD. Poststroke outcomes vary by pathogenic stroke subtype in the Atherosclerosis Risk in Communities Study. Stroke. 2013;44(8):2307–10. Scholar
  32. 32.
    Giacomini M. How good is good enough? Standards in policy decisions to cover new health technologies. Healthc Policy. 2007;3(2):91–101.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Caro JJ, Briggs AH, Siebert U, Kuntz KM. Modeling good research practices—overview: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-1. Value Health. 2012;15(6):796–803. Scholar
  34. 34.
    Siebert U, Alagoz O, Bayoumi AM, Jahn B, Owens DK, Cohen DJ, et al. State-transition modeling: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-3. Value Health. 2012;15(6):812–20. Scholar
  35. 35.
    Karnon J, Stahl J, Brennan A, Caro JJ, Mar J, Möller J. Modeling using discrete event simulation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-4. Value Health. 2012;15(6):821–7. Scholar
  36. 36.
    Annemans L, Redekop K, Payne K. Current methodological issues in the economic assessment of personalized medicine. Value Health. 2013;16(6 Suppl):S20–6. Scholar
  37. 37.
    Elkin EB, Marshall DA, Kulin NA, Ferrusi IL, Hassett MJ, Ladabaum U, et al. Economic evaluation of targeted cancer interventions: critical review and recommendations. Genet Med. 2011;13(10):853–60. Scholar
  38. 38.
    Thariani R, Veenstra DL, Carlson JJ, Garrison LP, Ramsey S. Paying for personalized care: cancer biomarkers and comparative effectiveness. Mol Oncol. 2012;6(2):260–6. Scholar
  39. 39.
    Epstein RS, Frueh FW, Geren D, Hummer D, McKibbin S, O’Connor S, et al. Payer perspectives on pharmacogenomics testing and drug development. Pharmacogenomics. 2009;10(1):149–51. Scholar
  40. 40.
    Irwin RJ, Irwin TC. A principled approach to setting optimal diagnostic thresholds: where ROC and indifference curves meet. Eur J Intern Med. 2011;22(3):230–4. Scholar
  41. 41.
    Felder S, Mayrhofer T. Medical decision making: a health economic primer. 2nd ed. Berlin: Springer; 2017.CrossRefGoogle Scholar
  42. 42.
    Habibzadeh F, Habibzadeh P, Yadollahie M. On determining the most appropriate test cut-off value: the case of tests with continuous results. Biochem Med. 2016;26(3):297–307. Scholar
  43. 43.
    Akobeng Anthony K. Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr. 2007;96(5):644–7. Scholar
  44. 44.
    Berm EJJ, de Looff M, Wilffert B, Boersma C, Annemans L, Vegter S, et al. Economic evaluations of pharmacogenetic and pharmacogenomic screening tests: a systematic review. second update of the literature. PLoS One. 2016;11(1):e0146262. Scholar
  45. 45.
    Paulden M, Franek J, Pham B, Bedard PL, Trudeau M, Krahn M. Cost-effectiveness of the 21-gene assay for guiding adjuvant chemotherapy decisions in early breast cancer. Value Health. 2013;16(5):729–39. Scholar
  46. 46.
    Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and adherence to long-term statin therapy? Curr Atheroscler Rep. 2013;15(1):291. Scholar
  47. 47.
    Cheng K, Ingram N, Keenan J, Choudhury RP. Evidence of poor adherence to secondary prevention after acute coronary syndromes: possible remedies through the application of new technologies. Open Heart. 2015;2(1):e000166.CrossRefGoogle Scholar
  48. 48.
    Wouters H, Van Dijk L, Geers HC, Winters NA, Van Geffen EC, Stiggelbout AM, et al. Understanding statin non-adherence: knowing which perceptions and experiences matter to different patients. PLoS One. 2016;11(1):e0146272. Scholar
  49. 49.
    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. Scholar
  50. 50.
    Laufs U, Scharnagl H, Halle M, Windler E, Endres M, März W. Treatment options for statin-associated muscle symptoms. Dtsch Ärzteblatt Int. 2015;112(44):748–55. Scholar
  51. 51.
    Fitchett DH, Hegele RA, Verma S. Statin intolerance. Circulation. 2015;131(13):e389.CrossRefGoogle Scholar
  52. 52.
    Patel J, Martin SS, Banach M. Expert opinion: the therapeutic challenges faced by statin intolerance. Expert Opin Pharmacother. 2016;17(11):1497–507. Scholar
  53. 53.
    Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et al. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012–22. Scholar
  54. 54.
    Kitzmiller JP, Binkley PF, Pandey SR, Suhy AM, Baldassarre D, Hartmann K. Statin pharmacogenomics: pursuing biomarkers for predicting clinical outcomes. Discov Med. 2013;16(86):45–51.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Gryn SE, Hegele RA. Pharmacogenomics, lipid disorders, and treatment options. Clin Pharmacol Ther. 2014;96(1):36–47. Scholar
  56. 56.
    Needham M, Mastaglia FL. Statin myotoxicity: a review of genetic susceptibility factors [Review]. Neuromuscul Disord. 2014;24(1):4–15.CrossRefGoogle Scholar
  57. 57.
    Patel J, Superko HR, Martin SS, Blumenthal RS, Christopher-Stine L. Genetic and immunologic susceptibility to statin-related myopathy. Atherosclerosis. 2015;240(1):260–71. Scholar
  58. 58.
    Anderson TJ, Grégoire J, Pearson GJ, Barry AR, Couture P, Dawes M, et al. 2016 Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2016;32(11):1263–82. Scholar
  59. 59.
    Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol. 2017;9(2):76–91. Scholar
  60. 60.
    Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. Scholar
  61. 61.
    Descamps OS, Fraass U, Dent R, Marz W, Gouni-Berthold I. Anti-PCSK9 antibodies for hypercholesterolaemia: overview of clinical data and implications for primary care. Int J Clin Pract. 2017;71(8):e12979. Scholar
  62. 62.
    Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99. Scholar
  63. 63.
    Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9. Scholar
  64. 64.
    B.C. PharmaCare. B.C. PharmaCare Drug Information Sheet for alirocumab (PRALUENT). Victoria: PharmaCare. Ministry of Health; 2016.Google Scholar
  65. 65.
    Sanofi-aventis Canada Inc. Praluent: product monograph including patient medication information, Laval; 2017.Google Scholar
  66. 66.
    Amgen Canada Inc. Repatha (evolocumab): product monograph including patient medication information, Mississauga; 2016.Google Scholar
  67. 67.
    CADTH. Guidelines for the economic evaluation of health technologies: Canada. 3rd ed. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2006.Google Scholar
  68. 68.
    CADTH. Guidelines for the Economic Evaluation of Health Technologies: Canada. 4th ed. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2017.Google Scholar
  69. 69.
    van Kempen BJ, Spronk S, Koller MT, Elias-Smale SE, Fleischmann KE, Ikram MA, et al. Comparative effectiveness and cost-effectiveness of computed tomography screening for coronary artery calcium in asymptomatic individuals. J Am Coll Cardiol. 2011;58(16):1690–701. Scholar
  70. 70.
    Sullivan PW, Lawrence WF, Ghushchyan V. A national catalog of preference-based scores for chronic conditions in the United States. Med Care. 2005;43(7):736–49.CrossRefGoogle Scholar
  71. 71.
    Gorodetskaya I, Zenios S, McCulloch CE, Bostrom A, Hsu CY, Bindman AB, et al. Health-related quality of life and estimates of utility in chronic kidney disease. Kidney Int. 2005;68(6):2801–8. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Dominic Mitchell
    • 1
    • 2
  • Jason R. Guertin
    • 3
    • 4
  • Jacques LeLorier
    • 1
    • 2
    Email author
  1. 1.Faculté de MédecineUniversité de MontréalMontréalCanada
  2. 2.Centre de Recherche du Centre Hospitalier de l’Université de MontréalMontréalCanada
  3. 3.Département de Médecine Sociale et Préventive, Faculté de MédecineUniversité LavalQuébecCanada
  4. 4.Centre de recherche du CHU de QuébecUniversité LavalQuébecCanada

Personalised recommendations