Skip to main content
Editorial
Originally Published 3 April 2018
Free Access

Implementation of Genotype-Guided Antiplatelet Therapy: Feasible but Not Without Obstacles

Circulation: Genomic and Precision Medicine
See Article by Lee et al
Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is a cornerstone for prevention of recurrent cardiovascular events in patients with acute coronary syndromes or undergoing percutaneous coronary intervention (PCI). Although clopidogrel remains the most commonly used P2Y12 receptor inhibitor and is generally effective, a large body of retrospective evidence suggests that a subset of patients do not respond adequately to this medication resulting in increased on-treatment platelet reactivity and rates of atherothrombotic events. A major determinant of variable clopidogrel efficacy includes loss-of-function (LOF) genetic variation in the CYP2C19 gene, most notably CYP2C19*2 and *3. CYP2C19 is responsible, in part, for converting the clopidogrel prodrug into a biologically active thiol metabolite that irreversibly binds to the P2Y12 receptor thus inhibiting ADP-induced platelet aggregation.
In recent years, alternative P2Y12 receptor inhibitors (ie, prasugrel and ticagrelor) have been developed and are approved for use for most clinical indications in which clopidogrel is prescribed. Although large-scale trials have shown that these agents are superior to clopidogrel in terms of platelet inhibition and reduction of major adverse cardiovascular events, clopidogrel continues to be the most widely used agent because of its cost and lower propensity to cause pathological bleeding.1,2 Importantly, however, genetic variation in CYP2C19 does not alter the pharmacokinetics or antiplatelet potential of prasugrel and ticagrelor thereby providing a modality for more personalized antiplatelet therapy approaches. Indeed, the US Food and Drug Administration updated the clopidogrel label in 2010 advising clinicians to be aware that poor metabolizers of clopidogrel (eg, those that carry CYP2C19 LOF alleles) exhibit high cardiovascular event rates and that alternative therapy should be considered in these individuals. In addition, current American College of Cardiology Foundation/American Heart Association PCI guidelines state that genetic testing and alternative therapy might be considered in high-risk patients, but at the present time, the evidence base is insufficient to recommend routine genetic testing in patients undergoing PCI.3
Although the medical community awaits the findings from large, randomized clinical trials assessing genotype-directed antiplatelet therapy over standard of care, there has been a great deal of confusion about whether to perform genetic testing and to what extent genotyping can aid in determining therapeutic strategy. Pharmacogenetic algorithms have been developed to help clinicians better understand how available genetic information can be used to optimize treatment but do not offer guidance whether testing should be performed.4 More recently, investigators of the IGNITE network (Implementing Genomics in Practice) have evaluated the use of CYP2C19 genotype–guided antiplatelet therapy on clinical outcomes using a pragmatic design and showed that PCI patients who carry CYP2C19 LOF alleles have significantly increased risk of experiencing major adverse cardiovascular events when treated with clopidogrel compared with those who received prasugrel or ticagrelor.5 These data are consistent with the results of prospective studies conducted in China and Spain showing that PCI patients who carry either the CYP2C19*2 or *3 alleles have significantly fewer cardiovascular events when treated with alternative P2Y12 receptor inhibitors compared with clopidogrel.68
Accumulating evidence about the potential benefit of genetic testing has resulted in several institutions integrating CYP2C19 genotyping into routine care despite the fact that limited data exist concerning the implementation of such approaches in real-world clinical settings. In this issue of Circulation: Genomic and Precision Medicine, Lee et al9 provide interesting and timely data pertaining to the feasibility, sustainability, and clinical impact of CYP2C19 genotype–guided antiplatelet therapy in 1193 high-risk patients that underwent PCI at the University of North Carolina Cardiac Catheterization Laboratory. Specifically, the authors evaluated the fidelity of genotype-directed antiplatelet therapy algorithm use over time, determined the factors that influenced CYP2C19 testing and physician prescribing decision, and investigated the impact of prasugrel/ticagrelor versus clopidogrel use on cardiovascular end points in genetically compromised patients. Primary implementation end points included frequency of genetic testing as well as alternative therapy selection. Secondary analyses were performed to determine the effect of genotype and antiplatelet agent choice on clinical outcomes including moderate to life-threatening bleeding as well as major adverse cardiovascular and cerebrovascular events.
In this single academic medical center, Lee et al9 showed that CYP2C19 genetic testing was routinely ordered and results were regularly used to guide prescribing decisions indicating that implementation of such tests is feasible in real-world settings. Moreover, the clinical factors that were most predictive of genetic test ordering and P2Y12 inhibitor selection were the presentation of high-risk phenotypes (eg, acute coronary syndrome indication for PCI, stent placement in left anterior descending or left main coronary artery, etc) and CYP2C19 metabolizer status, respectively suggesting that the clinician’s choice was generally reactive. However, several factors seemed to influence the decision to genotype or to prescribe alternative therapy including prior P2Y12 inhibitor use, indication for PCI, and risk of bleeding, illustrating that genetic test results were just one of multiple factors used to guide clinical care.
Although the authors demonstrated that CYP2C19 genotype–guided antiplatelet therapy was feasible, fidelity, and sustainability of such approaches warrant further investigation. The overall frequency of genetic testing (73%) and use of alternative therapy in genetically compromised patients (71%) was adequate; however, these percentages fluctuated significantly over the course of the investigation. Although the specific factors that contributed to this variability over time were beyond the scope of the current investigation, the authors speculate that lack of automated clinical decision support within the electronic health records and recurrent clinician education may, in part, contribute to reduced sustainability of algorithm implementation over time. These findings are particularly important if one considers the use of genotype-guided strategies in medical centers without the means or institutional infrastructure afforded to the current research team. As the authors rightly pointed out, several factors minimized logistical barriers and allowed for successful implementation of genetic testing in the current study including in-house genotyping services (median turnaround time was ≈1 day), electronic health record support, and appropriate education and access to clinical pharmacologists and nurses. It is not difficult to imagine that medical centers without these benefits, as well as the support of their governing bodies, would have a significantly more difficult time implementing genotype-guided approaches in their day-to-day practices.
With regards to clinical end points, Lee et al9 observed that patients who were heterozygous or homozygous for CYP2C19 LOF alleles were more likely to experience major adverse cardiovascular and cerebrovascular events when treated with clopidogrel compared with alternative P2Y12 inhibitors (adjusted hazard ratio, 4.65; 95% confidence interval, 2.2–10.0; P<0.001). This effect was more pronounced in patients with an acute coronary syndrome indication (adjusted hazard ratio, 10.0; 95% confidence interval, 3.97–27.7; P<0.001), consistent with prior reports that suggest that those who are at higher risk of experiencing a recurrent event (ie, PCI and acute coronary syndrome patients) may benefit more from alternative therapy compared with those in lower risk categories.10,11 In patients who did not carry CYP2C19 LOF alleles, no difference in major adverse cardiovascular and cerebrovascular events risk was observed between those who were administered clopidogrel compared with ticagrelor/prasugrel. Similarly, no association with moderate to life-threatening bleeding was observed by CYP2C19 genotype nor medication group; however, it should be noted that analyses pertaining to bleeding risk likely had low statistical power based on the total number of events (n=31) and therefore should be interpreted with some degree of caution.
Through completion of this study, Lee et al9 furthers our understanding of the challenges in implementing genotype-directed approaches and provides additional support that high-risk PCI patients who carry CYP2C19 LOF alleles may benefit from prasugrel/ticagrelor compared with clopidogrel. However, it is important to acknowledge the limitations of the current investigation. Importantly, the decision to genotype and prescribe alternative therapy was left to the sole discretion of the treating physician. Although this approach was useful in identifying factors that are predictive of genetic testing and prescribing decision, patient risk stratification and lack of a randomization procedure can lead to inherent biases in analyses pertaining to clinical end points. Indeed, differences in baseline clinical characteristics in those who were or were not genotyped as well as those who did or did not receive alternative therapy were observed in this study. Although covariates were included in statistical models in an attempt to minimize potential confounding, it is unlikely that such methods could fully account for differences between groups.
Another limitation to consider is that study data (eg, clinical events, PCI indication, genetic test result, medication usage, etc) were retrospectively abstracted from electronic health records. Although such methods ultimately facilitated the completion of this study, important questions remain unanswered. For example, it is impossible to determine whether some CYP2C19 LOF allele carriers were prescribed clopidogrel because the physician failed to consider genetic test results or because other clinical factors (eg, increased bleeding risk) led to the prescribing decision. Furthermore, cardio- and cerebrovascular events were not adjudicated by an independent committee but through physician-reported diagnoses, discharge summaries, and outpatient clinic notes, thus leading to potential variability in clinical end point definitions. In addition, little to no data were available about drug adherence, which is potentially important given that many of the highlighted analyses in this investigation were dependent on the prescribed medication and the assumption that patients were regularly taking them.
Despite these limitations, Lee et al9 have provided valuable insights about implementation of CYP2C19 genetic testing in real-world settings and the potential clinical impact of such approaches as the field awaits the results from large, prospective randomized trials. Indeed, trials that assess the efficacy of genotype-directed antiplatelet therapy over standard of care are currently underway (eg, URL: https://www.clinicaltrials.gov. Unique identifier: NCT01742117) but results will not likely be available for a few more years. In the interim, additional studies are needed, including those like the current investigation, to better implement genetic testing into clinical workflows, establish the cost-effectiveness of genotype-directed strategies, and to strengthen the evidence base about clinical utility and improved health outcomes. In parallel, there is a continuing need to identify additional genetic determinants of variable antiplatelet therapy as current heritability estimates suggest that most response-modifying variants remain unidentified.12 A more comprehensive understanding of interindividual variation in response to antiplatelet agents will be critical for improving cardiovascular pharmacotherapy, reducing therapeutic failure and adverse drug events, and improving patient outcomes.

References

1.
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al.; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. doi: 10.1056/NEJMoa0904327.
2.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al.; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015. doi: 10.1056/NEJMoa0706482.
3.
Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574–e651. doi: 10.1161/CIR.0b013e31823ba622.
4.
Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al.; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94:317–323. doi: 10.1038/clpt.2013.105.
5.
Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, et al.; IGNITE Network. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv. 2018;11:181–191. doi: 10.1016/j.jcin.2017.07.022.
6.
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;67:232–236. doi: 10.1097/FJC.0000000000000337.
7.
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;168:3736–3740. doi: 10.1016/j.ijcard.2013.06.014.
8.
Sánchez-Ramos J, Dávila-Fajardo CL, Toledo Frías P, Díaz Villamarín X, Martínez-González LJ, Martínez Huertas S, et al. Results of genotype-guided antiplatelet therapy in patients who undergone percutaneous coronary intervention with stent. Int J Cardiol. 2016;225:289–295. doi: 10.1016/j.ijcard.2016.09.088.
9.
Lee CR, Sriramoju VB, Cervantes A, Howell LA, Varunok N, Madan S, et al. Clinical outcomes and sustainability of using CYP2C19 genotype–guided antiplatelet therapy after percutaneous coronary intervention. Circ Genom Precis Med. 2018;11:e002069. doi: 10.1161/CIRCGEN.117.002069.
10.
Kim HS, Chang K, Koh YS, Park MW, Choi YS, Park CS, et al. CYP2C19 poor metabolizer is associated with clinical outcome of clopidogrel therapy in acute myocardial infarction but not stable angina. Circ Cardiovasc Genet. 2013;6:514–521. doi: 10.1161/CIRCGENETICS.113.000109.
11.
Sorich MJ, Rowland A, McKinnon RA, Wiese MD. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet. 2014;7:895–902. doi: 10.1161/CIRCGENETICS.114.000669.
12.
Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849–857. doi: 10.1001/jama.2009.1232.

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.

Information & Authors

Information

Published In

Go to Circulation: Genomic and Precision Medicine
Go to Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine
PubMed: 29615455

History

Received: 26 February 2018
Accepted: 1 March 2018
Published in print: April 2018
Published online: 3 April 2018

Permissions

Request permissions for this article.

Keywords

  1. Editorials
  2. aspirin
  3. clopidogrel
  4. genotype
  5. percutaneous coronary intervention
  6. pharmacogenetics

Subjects

Authors

Affiliations

Joshua P. Lewis, PhD
Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore.

Notes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Joshua P. Lewis, PhD, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, 660 W Redwood St, Room 498, Baltimore, MD 21201. E-mail [email protected]

Disclosures

Dr Lewis receives National Institutes of Health grant support to study the pharmacogenetics of antiplatelet therapy.

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

  1. Role of genetic polymorphisms in clopidogrel response variability: a systematic review, Open Heart, 10, 2, (e002436), (2023).https://doi.org/10.1136/openhrt-2023-002436
    Crossref
  2. Platelet response to aspirin in UK and Irish pregnancy cohorts: a genome-wide approach, Platelets, 33, 6, (911-917), (2021).https://doi.org/10.1080/09537104.2021.2007872
    Crossref
Loading...

View Options

View options

PDF and All Supplements

Download PDF and All Supplements

PDF/EPUB

View PDF/EPUB
Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

Purchase this article to access the full text.

Purchase access to this article for 24 hours

Implementation of Genotype-Guided Antiplatelet Therapy
Circulation: Genomic and Precision Medicine
  • Vol. 11
  • No. 4

Purchase access to this journal for 24 hours

Circulation: Genomic and Precision Medicine
  • Vol. 11
  • No. 4
Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Figures

Tables

Media

Share

Share

Share article link

Share

Comment Response