Skip to main content
Log in

Cost Effectiveness of Genotype-Guided Antiplatelet Therapy in Asian Ischemic Stroke Patients: Ticagrelor as an Alternative to Clopidogrel in Patients with CYP2C19 Loss of Function Mutations

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 25 November 2020

Abstract

Background

Patients with ischemic stroke are often treated with clopidogrel monotherapy as part of secondary stroke prevention. The prevalence of loss of function (LOF) mutations in the CYP2C19 gene is higher in Asians than in Western populations. Patients with loss of function (LOF) mutations are at risk for poorer secondary outcomes when prescribed clopidogrel.

Objective

We aimed to determine the cost effectiveness of genotype-guided antiplatelet therapy in an Asian population with the aim of prescribing ticagrelor as an alternative to patients with LOF mutations.

Methods

Markov models were developed to look at the cost effectiveness of genetic testing of CYP2C19, with patients who screened positive for LOF alleles being switched to ticagrelor compared to universal clopidogrel treatment. Effect ratios were obtained from the literature and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. Lifetime costs and quality-adjusted life-years (QALYs) were calculated. The primary endpoints were the incremental cost-effectiveness ratios (ICERs).

Results

The prevalence of the LOF mutations was 61% in the population, with 65% of ethnic Chinese, 60% of ethnic Indian, and 53% of ethnic Malay patients having LOF mutations. Based on this prevalence, the overall ICER of genetic testing was S$33,839/QALY with ICERS of S$30,755/QALY, S$33,177/QALY, and S$41,470/QALY for Chinese, Indians, and Malays, respectively.

Conclusion

This study suggests that it is cost effective to screen for LOF mutations in the CYP2C19 gene in ischemic stroke populations, with ticagrelor as a substitute for clopidogrel in those with LOF mutations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kernan WN, Ovbiagele B, Black HR, et al (2014) Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline for healthcare professionals from the American Heart Association/American Stroke Association.

  2. CAPRIE Steering committee. A randomized blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996;348:1329–39.

    Article  Google Scholar 

  3. Sangkuhl K, Klein TE, Altman RB (2010) Clopidogrel pathway. Pharmacogenet. Genomics.

  4. Goh LL, Lim CW, Sim WC, et al. Analysis of genetic variation in CYP450 genes for clinical implementation. PLoS One. 2017. https://doi.org/10.1371/journal.pone.0169233.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Aw JWX, Tan DSY, Goh LL (2018) Letter by Aw et al Regarding Article, Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. Circ. Genomic Precis. Med.

  6. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016. https://doi.org/10.1056/NEJMoa1603060.

    Article  PubMed  Google Scholar 

  7. Evaluation, Institute for Health Metrics and; Epidemiology & Disease Control Division MoH S (2019) The Burden of Disease in Singapore, 1990–2017: An overview of the Global Burden of Disease Study 2017 results. Seattle.

  8. NRoD O (2018) Singapore Stroke Registry Annual Report 2016.

  9. Department of Statistics MoTI R of S (2018) Complete Life Tables for Singapore Resident Population, 2017–2018.

  10. Sun W, Li Y, Li J, et al. Variant recurrent risk among stroke patients with different CYP2C19 phenotypes and treated with clopidogrel. Platelets. 2015. https://doi.org/10.3109/09537104.2014.953044.

    Article  PubMed  Google Scholar 

  11. Amarenco P, Albers GW, Denison H, et al. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet Neurol. 2017. https://doi.org/10.1016/S1474-4422(17)30038-8.

    Article  PubMed  Google Scholar 

  12. Putaala J. Long-term mortality after first-ever and recurrent stroke in young adults. Stroke. 2014. https://doi.org/10.1161/STROKEAHA.114.005648.

    Article  PubMed  Google Scholar 

  13. Wallentin L, James S, Storey RF, et al. 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. https://doi.org/10.1016/S0140-6736(10)61274-3.

    Article  PubMed  Google Scholar 

  14. Guzauskas GF, Boudreau DM, Villa KF, et al. The cost-effectiveness of primary stroke centers for acute stroke care. Stroke. 2012. https://doi.org/10.1161/STROKEAHA.111.648238.

    Article  PubMed  Google Scholar 

  15. Daly TM, Dumaual CM, Miao X, et al. Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport. Clin Chem. 2007. https://doi.org/10.1373/clinchem.2007.086348.

    Article  PubMed  Google Scholar 

  16. Dumaual C, Miao X, Daly TM, et al (2007) Comprehensive assesment of metabolic enzyme and transporter genes using the affymetrix® targeted genotyping system. Pharmacogenomics.

  17. WHO (World Health Organization) Cost effectiveness and strategic planning (WHO-CHOICE). https://www.who.int/choice/cost-effectiveness/methods/en/. Accessed 27 Aug 2020.

  18. Bertram MY, Lauer JA, De Joncheere K, et al. Cost-effectiveness thresholds: Pros and cons. Bull World Health Organ. 2016. https://doi.org/10.2471/BLT.15.164418.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sorich MJ, Horowitz JD, Sorich W, et al. Cost-effectiveness of using CYP2C19 genotype to guide selection of clopidogrel or ticagrelor in Australia. Pharmacogenomics. 2013. https://doi.org/10.2217/pgs.13.164.

    Article  PubMed  Google Scholar 

  20. Chin CT, Mellstrom C, Chua TSJ, Matchar DB (2013) Lifetime cost-effectiveness analysis of ticagrelor in patients with acute coronary syndromes based on the PLATO trial: A Singapore healthcare perspective. Singapore Med J. https://doi.org/10.11622/smedj.2013045.

  21. Patel V, Lin F-J, 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. 2014. https://doi.org/10.4321/s1886-36552014000300007.

    Article  Google Scholar 

  22. Lala A, Berger JS, Sharma G, et al. Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A cost-effectiveness analysis. J Thromb Haemost. 2013. https://doi.org/10.1111/jth.12059.

    Article  PubMed  Google Scholar 

  23. Kim K, Touchette DR, Cavallari LH, et al. Cost-Effectiveness of Strategies to Personalize the Selection of P2Y12 Inhibitors in Patients with Acute Coronary Syndrome. Cardiovasc Drugs Ther. 2019. https://doi.org/10.1007/s10557-019-06896-8.

    Article  PubMed  Google Scholar 

  24. Xie HG, Stein CM, Kim RB, et al. Allelic, genotypic and phenotypic distributions of S-mephenytoin 4’-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics. 1999. https://doi.org/10.1097/00008571-199910000-00001.

    Article  PubMed  Google Scholar 

  25. Tang XF, Wang J, Zhang JH, et al. Effect of the CYP2C19*2 and*3 genotypes, ABCB1 C3435T and PON1 Q192R alleles on the pharmacodynamics and adverse clinical events of clopidogrel in Chinese people after percutaneous coronary intervention. Eur J Clin Pharmacol. 2013. https://doi.org/10.1007/s00228-012-1446-8.

    Article  PubMed  Google Scholar 

  26. Shetkar SS, Ramakrishnan S, Seth S, et al. CYP 450 2C19 polymorphisms in Indian patients with coronary artery disease. Indian Heart J. 2014. https://doi.org/10.1016/j.ihj.2013.10.001.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lamba JK, Dhiman RK, Kohli KK. CΥP2C19 genetic mutation in North Indians. Clin Pharmacol Ther. 2000. https://doi.org/10.1067/mcp.2000.109365.

    Article  PubMed  Google Scholar 

  28. Kimura M, Ieiri I, Mamiya K, et al. Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population. Ther Drug Monit. 1998. https://doi.org/10.1097/00007691-199806000-00001.

    Article  PubMed  Google Scholar 

  29. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013. https://doi.org/10.1056/NEJMoa1215340.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Claiborne Johnston S, Donald Easton J, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018. https://doi.org/10.1056/NEJMoa1800410.

    Article  PubMed  Google Scholar 

  31. Chi NF, Wen CP, Liu CH, et al. Comparison between aspirin and clopidogrel in secondary stroke prevention based on real-world data. J Am Heart Assoc. 2018. https://doi.org/10.1161/JAHA.118.009856.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wang Y, Zhao X, Lin J, et al. Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. J Am Med Assoc. 2016. https://doi.org/10.1001/jama.2016.8662.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kaavya Narasimhalu.

Ethics declarations

Funding

This study was not funded.

Conflict of interest

The authors report no conflicts of interest or disclosures.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

All authors consent to publish.

Availability of data and material

Can be made available on reasonable request to the corresponding author.

Code availability

Not applicable.

Authors’ contributions

Kaavya Narasimhalu—conceptualised the idea and wrote the manuscript. Yoong Kwei Ang—Statistical analyses and critical revision of the manuscript. Doreen Su Yin Tan, Deidre Anne De Silva, Kelvin Bryan Tan—conceptualised the manuscript and critical revision of manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Narasimhalu, K., Ang, Y.K., Tan, D.S.Y. et al. Cost Effectiveness of Genotype-Guided Antiplatelet Therapy in Asian Ischemic Stroke Patients: Ticagrelor as an Alternative to Clopidogrel in Patients with CYP2C19 Loss of Function Mutations. Clin Drug Investig 40, 1063–1070 (2020). https://doi.org/10.1007/s40261-020-00970-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-020-00970-y

Navigation