Thank you for taking the time to learn more about the use of pharmacogenetics in the prescribing of antiplatelet therapy. Starting in October 2018, UCHealth and University of Colorado are using genotypes of patients to inform the choice of antiplatelet medications.
Pharmacogenetics (PGx), also referred to as pharmacogenomics, is the use of genetic information to help guide drug selection and dosing. The Colorado Center for Personalized medicine, in collaboration with UCHealth, is enrolling patients in a research Biobank, primarily focused on genetics. Biobank participants may give permission to return available genetic test results, including select, clinically-actionable, PGx test results, to their electronic health record (EHR). The first PGx result that is being returned to the EHR is CYP2C19 genotype.
Clopidogrel (Plavix) is a pro-drug, meaning that after being taken orally it must be metabolized to its active, platelet-inhibiting form 2-oxo-clopidogrel, in the liver. The protein in the liver responsible for this activation is the cytochrome p450 enzyme CYP2C19 (pronounced "sip two see nineteen"). Across populations, CYP2C19 protein alleles can have different genetic variants that impact its ability to activate clopidogrel. The different alleles can produce five different metabolism phenotypes: ultrarapid, rapid, normal, intermediate and poor metabolism. Of these, the intermediate and poor metabolism phenotypes have been shown to increase the risk of inadequate platelet response and may result in adverse cardiovascular and cerebrovascular events in individuals prescribed clopidogrel. For this reason, if a patient is known to be an intermediate or poor metabolizer of clopidogrel and is prescribed clopidogrel, they should be prescribed a different antiplatelet agent, such as ticagrelor (Brilinta), which does not require activation by CYP2C19.
There are several organizations that support the use of CYP2C19 in the prescribing of clopidogrel. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a group of volunteer pharmacists, nurses, physicians, and researchers who evaluate the evidence for the use of pharmacogenetics and then develop clinical practice guidelines. For clopidogrel, extensive guideline information can be found at https://cpicpgx.org/guidelines/guideline-for-clopidogrel-and-cyp2c19/
VIDEO
Multiple studies have supported the use of CYP2C19 genotype in prescribing antiplatelet therapy. In several well conducted trials, a reduction in vascular thrombotic events is observed with using pharmacogenetics to inform therapy. In practice changing work published by Mega JL et al. in the New England Journal of Medicine (NEJM 2009 360:354-362.), it was shown that in a cohort of 1477 patients who participated in the TRITON-TIMI 38 study, carriers of CYP2C19 alleles that produced reduced function of the CYP2C19 enzyme (either intermediate or poor metabolizers) demonstrated a 53% relative increase in a composite outcome of CV death, MI or stroke as compared to non-carriers when treated with clopidogrel. Risk for in-stent thrombosis was 3.09 for the same comparator populations (see graphs below).
Because of this evidence of reduced efficacy of clopidogrel in certain populations, the US FDA issued a "black box" warning for clopidogrel in 2010 (https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm)
Additional Information on Clopidogrel and CYP2C19 response
VIDEO
In 2018, a "real world" multi-institution study was published demonstrating the clinical benefit of implementing a pharmacogenetic testing strategy for CYP2C19. This "Multisite Investigation of CYP2C19 Implementation of Outcomes Study" demonstrated that implementing CYP2C19 genotyping was feasible and those who were impaired metabolizers of clopidogrel benefitted from being prescribed alternate antiplatelet agents. The full manuscript is provided by the link below.
A recent study describing a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was published in New England Journal of Medicine in October 2019. Patients in the genotype-guided group had a significantly lower number of adverse clinical events, including death, myocardial infarction, definite stent thrombosis, stroke or major bleeding, compared to patients in the standard-treatment group (p < 0.001).
At UCHealth the use of pharmacogenetics when prescribing clopidogrel will occur in patients who meet the following conditions:
1) Provided a sample to the Colorado biobank.
2) Have consented for the return of their results.
3) Are prescribed clopidogrel.
The technical workflow for this is complicated, but is outlined below. First, in an initial contact with UCHealth, patients are prompted to consent to participation in the Colorado biobank for scientific discovery. At the patient's next blood draw, an additional amount of blood is collected and used to extract DNA for the biobank. This DNA undergoes genotyping which includes CYP2C19 alleles. If a patient has not already consented for release of genetic results, he or she will then be contacted via the MyHealthConnection patient portal to sign a second consent to release select clinical genotyping results to his or her EHR. The first such result is a patient's CYP2C19 genotype. This process takes a minimum of 4-6 weeks, but may take several years. Therefore, results would not be available at initial presentation.
If a patient has CYP2C19 genotyping results and has signed a consent for their return, the Best Practice Alert (BPA) below will be triggered if he or she is prescribed clopidogrel. This BPA will fire in both the inpatient and ambulatory settings in the UCHealth EHR only. The BPA prompts the selection of an alternate antiplatelet agent.
Best Practice Alert for Clopidogrel in Inpatient & Ambulatory Settings
Best Practice Alert in Action: Video showing how the BPA works in the EHR
Additional Powerpoint of Clopidogrel Pharmacogenetics Implementation (With Audio)
The following FAQs are provided for your reference:
- Will patients be notified of their CYP2C19 genotype?
Yes. After a participant signs the second consent to return results to their EHR, CYP2C19 genotype results will be placed into the EHR and sent to the participant via the MyHealthConnection patient portal. There will be also be patient education text in the discharge paperwork for patients where the BPA fires. There will also be patient education text available for providers to use in discharge paperwork or the after visit summary (AVS).
- Will CYP2C19 genotyping will be available for patients with acute MI?
No. There is at minimum a 4-6 week turnaround time from blood draw to genotype result. However, this time could be much longer, several months to years. Thus, genotyping results will not be returned in a clinically meaningful timeframe.
If a patient presents with an acute MI and has previously consented to both the biobank research study AND for his or her results to be returned to the EHR, then CYP2C19 genotyping may be available for this patient.
- Is this program available for patients outside of UCHealth?
The Biobank Research study is open to all UCHealth patients ages 18 and over, who are able to consent for themselves. This program is available to patients throughout the UCHealth system, including North, Metro and South. The program is not available outside the UCHealth system.
- What if my patient cannot afford another antiplatelet agent?
Several alternative agents are on formulary for many insurance plans; however, if your patient is not provided with coverage, please contact the pharmacogenetics consult pager at 303-266-4510 for assistance with prior authorization.
- What if a patient is already on clopidogrel and they are found to be a poor/intermediate metabolizer via the Biobank?
If a patient was prescribed clopidogrel previously, it would be reasonable to consider changing their antiplatelet medication. However, this is an individualized decision based on each patient's risk and history.
- How will providers be informed if their patients on clopidogrel are found to be a poor or intermediate metabolizer via the Biobank?
The BPA will fire when clopidogrel is renewed in the inpatient or ambulatory settings.
- What is the medico-legal risk to providers for using or not using the recommendations provided in clinical decision support tools created for the consideration of pharmacogenetics in prescribing?
There is no way to completely eliminate all risk, but the goal is to reduce risk as much as possible. If a CDS alert is not considered or if it is ignored by a provider, then the provider must have a valid reason for why the alert information was not considered. If, in the provider's medical judgment, the information in the alert is not applicable or if the provider believes another course of action is warranted, it is appropriate to not use the alert information. Liability is case-specific and depends on a number of factors (e.g. patient's diagnosis, condition, prior history, follow-up, etc). In order for a provider to be liable, the patient must have experienced an injury as a result of the provider's actions. Poor response/tolerance, ineffectiveness, and side effects of medications do not constitute an injury (unless the provider knew a patient had experienced poor outcomes as a result of a specific medication).
- Who should I contact if I have more questions?
For questions regarding direct patient care, please page the pharmacogenetics pager at 303-266-4510. For general feedback, please use the form below.
Webpage updated as of: 11/13/2021
Did you find this information useful?
Yes
No
Please provide any feedback or additional questions to improve these materials.
Thank you for providing feedback. Please provide an email address so we can follow up on your feedback.