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

  • Dominic Mitchell
  • Jason R. Guertin
  • Anick Dubois
  • Marie-Pierre Dubé
  • Jean-Claude Tardif
  • Ange Christelle Iliza
  • Fiorella Fanton-Aita
  • Alexis Matteau
  • Jacques LeLorier
Original Research Article
  • 30 Downloads

Abstract

Background

Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown.

Methods

We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters.

Results

Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations.

Conclusion

We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

Notes

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, AD, MPD, JCT, ACI, FFA, AM, 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

Conflict of interest

Dominic Mitchell, Jason R. Guertin, Anick Dubois, Marie-Pierre Dubé, Jean-Claude Tardif, Ange Christelle Iliza, Fiorella Fanton-Aita, Alexis Matteau, and Jacques LeLorier declare that they have no conflicts of interest that are directly relevant to the content of this review.

Open Access

This article is distributed under the terms of the Creative Commons Attribution–NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Supplementary material

40291_2018_323_MOESM1_ESM.pdf (1 mb)
Supplementary material 1 (PDF 1074 kb)

References

  1. 1.
    Statistics Canada. Cholesterol levels of adults, 2012 to 2013. Statistics Canada, Ottawa, Canada. http://www.statcan.gc.ca/pub/82-625-x/2014001/article/14122-eng.htm. Accessed 6 Oct 2017.
  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.  https://doi.org/10.1016/j.cjca.2012.11.032.CrossRefPubMedGoogle Scholar
  3. 3.
    Morgan S, Smolina K, Mooney D, Raymond C, Bowen ML, Gorczynski C, et al. The Canadian Rx atlas, 3rd edition (The Canadian prescription drug atlas). Vancouver: Centre for Health Services and Policy Research; 2013.Google Scholar
  4. 4.
    Talameh JA, Kitzmiller JP. Pharmacogenetics of statin-induced myopathy: a focused review of the clinical translation of pharmacokinetic genetic variants. J Pharmacogenom Pharmacoproteomics. 2014;5(2):128.  https://doi.org/10.4172/2153-0645.1000128.Google Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    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.  https://doi.org/10.2522/ptj.20090251.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rallidis LS, Fountoulaki K, Anastasiou-Nana M. Managing the underestimated risk of statin-associated myopathy. Int J Cardiol. 2012;159(3):169–76.  https://doi.org/10.1016/j.ijcard.2011.07.048.CrossRefPubMedGoogle Scholar
  8. 8.
    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.  https://doi.org/10.1016/j.ahj.2013.06.004.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011;10(3):373–87.  https://doi.org/10.1517/14740338.2011.540568.CrossRefPubMedGoogle Scholar
  10. 10.
    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.  https://doi.org/10.1016/j.ahj.2014.03.019.CrossRefPubMedGoogle Scholar
  11. 11.
    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
  12. 12.
    Chai C, James H. Working out ’til you’re sick? Doctors warn of rhabdo, a deadly condition linked to over exercising. Global news, Canada, Montreal. 2014. http://globalnews.ca/news/1082282/doctors-warn-of-rhabdo-a-deadly-condition-linked-to-over-exercising/. Accessed 22 Nov 2017.
  13. 13.
    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.  https://doi.org/10.1016/j.cjca.2016.01.003.CrossRefPubMedGoogle Scholar
  14. 14.
    Swankhuizen M, Regier L. Statin intolerance ‐ management considerations. RxFiles, Saskatoon, Canada. 2013. http://www.rxfiles.ca/rxfiles/uploads/documents/Lipid-Statin-Intolerance.pdf. Accessed 24 Oct 2017.
  15. 15.
    Hovingh GK, Gandra SR, McKendrick J, Dent R, Wieffer H, Catapano AL, et al. Identification and management of patients with statin-associated symptoms in clinical practice: a clinician survey. Atherosclerosis. 2016;245:111–7.  https://doi.org/10.1016/j.atherosclerosis.2015.12.015.CrossRefPubMedGoogle Scholar
  16. 16.
    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.  https://doi.org/10.1016/j.cjca.2016.07.510.CrossRefPubMedGoogle Scholar
  17. 17.
    Jansen ME, Rigter T, Rodenburg W, Fleur TMC, Houwink EJF, Weda M, et al. Review of the reported measures of clinical validity and clinical utility as arguments for the implementation of pharmacogenetic testing: a case study of statin-induced muscle toxicity. Front Pharmacol. 2017;8:555.  https://doi.org/10.3389/fphar.2017.00555.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pharmacogenomics Research Network. Pharmacogenomics of Statin Therapy Center. 2017. http://www.pgrn.org/pgx-of-statin-therapy.html. Accessed 9 Oct 2017.
  19. 19.
    Canada G. Personalized medicine strategies for molecular diagnostics and targeted therapeutics of cardiovascular disease. Ottawa: Génome Canada; 2018. https://www.genomecanada.ca/en/personalized-medicine-strategies-molecular-diagnostics-and-targeted-therapeutics-cardiovascular. Accessed 17 Jan 2018.
  20. 20.
    Québec G. Personalized medicine strategies for molecular diagnostics and targeted therapeutics of cardiovascular disease. Génome Québec, Montreal. 2018. http://www.genomequebec.com/159-en/project/personalized-medicine-strategies-for-molecular-diagnostics-and-targeted-therapeutics-of-cardiovascular-diseases.html. Accessed 17 Jan 2018.
  21. 21.
    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.  https://doi.org/10.1007/s40291-016-0238-8.CrossRefPubMedGoogle Scholar
  22. 22.
    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.  https://doi.org/10.1016/j.atherosclerosissup.2004.08.027.CrossRefPubMedGoogle Scholar
  23. 23.
    Caro JJ, Möller J, Karnon J, Stahl J, Ishak J. Discrete event simulation for health technology assessment. Boca Raton: CRC Press; 2016.Google Scholar
  24. 24.
    Standfield L, Comans T, Scuffham P. Markov modeling and discrete event simulation in health care: a systematic comparison. Int J Technol Assess Health Care. 2014;30(2):165–72.  https://doi.org/10.1017/s0266462314000117.CrossRefPubMedGoogle Scholar
  25. 25.
    Ambapkar SN, Shetty N, Dwivedy A, Malve HO. Statin-induced rhabdomyolysis in patient with renal failure and underlying undiagnosed hypothyroidism. Indian J Crit Care Med. 2016;20(5):305–7.  https://doi.org/10.4103/0972-5229.182210.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Smolina K, Wright FL, Rayner M, Goldacre MJ. Long-term survival and recurrence after acute myocardial infarction in England, 2004 to 2010. Circ Cardiovasc Qual Outcomes. 2012;5(4):532–40.  https://doi.org/10.1161/circoutcomes.111.964700.CrossRefPubMedGoogle Scholar
  27. 27.
    Asanin MR, Vasiljevic ZM, Matic MD, Mrdovic IB, Perunicic JP, Matic DP, et al. The long-term risk of stroke in patients with acute myocardial infarction complicated with new-onset atrial fibrillation. Clin Cardiol. 2009;32(8):467–70.  https://doi.org/10.1002/clc.20603.CrossRefPubMedGoogle Scholar
  28. 28.
    Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology. 2006;66(5):641–6.  https://doi.org/10.1212/01.wnl.0000201253.93811.f6.CrossRefPubMedGoogle Scholar
  29. 29.
    Smolina K, Wright FL, Rayner M, Goldacre MJ. Incidence and 30-day case fatality for acute myocardial infarction in England in 2010: national-linked database study. Eur J Public Health. 2012;22(6):848–53.  https://doi.org/10.1093/eurpub/ckr196.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Canadian Institute for Health Information. 30-Day stroke in-hospital mortality. In: Health Indicators Interactive Tool. Ottawa: Canadian Institute for Health Information. 2017. http://indicatorlibrary.cihi.ca/display/HSPIL/30-Day+Stroke+In-Hospital+Mortality. Accessed 15 Sep 2017.
  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.  https://doi.org/10.1161/strokeaha.113.000830.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Aarnio K, Haapaniemi E, Melkas S, Kaste M, Tatlisumak T, Putaala J. Long-term mortality after first-ever and recurrent stroke in young adults. Stroke. 2014;45(9):2670–6.  https://doi.org/10.1161/strokeaha.114.005648.CrossRefPubMedGoogle Scholar
  33. 33.
    Statistics Canada. Life tables, Canada, provinces and territories—2010 to 2012. Ottawa (Ontario); Statistics Canada; 2016. Cat No.: 84-537-XIE.Google Scholar
  34. 34.
    Statistique Canada. Indice des prix à la consommation, aperçu historique (1997 à 2016). 2017. http://www.statcan.gc.ca/tables-tableaux/sum-som/l02/cst01/econ46a-fra.htm. Accessed 15 Mar 2017.
  35. 35.
    Mihaylova B, Briggs A, O’Hagan A, Thompson SG. Review of statistical methods for analysing healthcare resources and costs. Health Econ. 2011;20(8):897–916.  https://doi.org/10.1002/hec.1653.CrossRefPubMedGoogle Scholar
  36. 36.
    Régie de l’assurance-maladie du Québec. Manuel des médecins omnipraticiens: rémunération à l’acte. Québec: RAMQ; 2017.Google Scholar
  37. 37.
    Régie de l’assurance-maladie du Québec. Liste des médicaments: dernière mise à jour le 3 mai 2017. Québec: RAMQ; 2017.Google Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    Hauber AB, McCirnk L, Garcia-Cebrian A, Maas G, Das Gupta R, Le T. Population health-state utilities for fibromyalgia in the United Kingdom. Value Health. 2008;11(6):A353.CrossRefGoogle Scholar
  40. 40.
    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.  https://doi.org/10.1111/j.1523-1755.2005.00752.x.CrossRefPubMedGoogle Scholar
  41. 41.
    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
  42. 42.
    Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292(21):2585–90.  https://doi.org/10.1001/jama.292.21.2585.CrossRefPubMedGoogle Scholar
  43. 43.
    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.  https://doi.org/10.1016/j.jacc.2012.12.034.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Cardinal H, Monfared AA, Dorais M, Lelorier J. The concept of the ‘percent wasted patients’ in preventive health strategies. Pharmacoepidemiol Drug Saf. 2006;15(1):57–61.  https://doi.org/10.1002/pds.1148.CrossRefPubMedGoogle Scholar
  45. 45.
    Catalan VS, LeLorier J. Predictors of long-term persistence on statins in a subsidized clinical population. Value Health. 2000;3(6):417–26.  https://doi.org/10.1046/j.1524-4733.2000.36006.x.CrossRefPubMedGoogle Scholar
  46. 46.
    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.  https://doi.org/10.22374/1710-6222.24.1.1.
  47. 47.
    Dorais M, Chirovsky D, Ambegaonkar B, Sazonov V, Davies G, Grant S, et al. Utilization patterns of extended-release niacin in Canada: analysis of an administrative claims database. Can J Cardiol. 2010;26(7):e229–35.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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.  https://doi.org/10.1007/s11883-012-0291-7.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    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.  https://doi.org/10.1371/journal.pone.0146272.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Public Health Agency of Canada. Tracking heart disease and stroke in Canada 2009. Ottawa: Public Health Agency of Canada; 2009.Google Scholar
  51. 51.
    Ontario Case Costing: OCC Costing Analysis Tool [online database]. Ministry of Health and Long Term Care. 2015. https://hsimi.ca/occp/occpreports/. Accessed 10 Apr 2015.
  52. 52.
    Smolderen KG, Bell A, Lei Y, Cohen EA, Steg PG, Bhatt DL, et al. One-year costs associated with cardiovascular disease in Canada: insights from the REduction of Atherothrombosis for Continued Health (REACH) registry. Can J Cardiol. 2010;26(8):297–305.CrossRefPubMedGoogle Scholar
  53. 53.
    Conly J, Clement F, Tonelli M, Hemmelgarn B, Klarenbach S, Lloyd A, et al. Cost-effectiveness of the use of low- and high-potency statins in people at low cardiovascular risk. CMAJ. 2011;183(16):E1180–8.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ghali WA, Knudtson ML. Overview of the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease. On behalf of the APPROACH investigators. Can J Cardiol. 2000;16(10):1225–30.PubMedGoogle Scholar
  55. 55.
    Skrabal MZ, Stading JA, Cannella CA, Monaghan MS. Two cases of rhabdomyolysis associated with high-dose simvastatin. Am J Health Syst Pharm. 2003;60(6):578–81.PubMedGoogle Scholar
  56. 56.
    CADTH. Guidelines for the economic evaluation of health technologies: Canada, 4th ed. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2017.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Dominic Mitchell
    • 1
    • 2
  • Jason R. Guertin
    • 3
    • 4
  • Anick Dubois
    • 1
    • 5
    • 6
  • Marie-Pierre Dubé
    • 1
    • 5
    • 6
  • Jean-Claude Tardif
    • 1
    • 5
    • 6
  • Ange Christelle Iliza
    • 1
    • 2
  • Fiorella Fanton-Aita
    • 1
    • 2
  • Alexis Matteau
    • 1
    • 2
    • 7
  • Jacques LeLorier
    • 1
    • 2
  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 Médecine, Université LavalQuébec CityCanada
  4. 4.Centre de Recherche du CHU de Québec, Université LavalQuébec CityCanada
  5. 5.Institut de Cardiologie de MontréalMontréalCanada
  6. 6.Centre de Pharmacogénomique Beaulieu-Saucier de l’Université de MontréalMontréalCanada
  7. 7.Cardiology DivisionCentre Hospitalier de l’Université de MontréalMontréalCanada

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