Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy.
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ABSTRACT:
SUBMITTER: Bergmeijer TO
PROVIDER: S-EPMC6021912 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
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Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy.
Bergmeijer Thomas O TO Vos Gerrit Ja GJ Claassens Daniël Mf DM Janssen Paul Wa PW Harms Remko R der Heide Richard van RV Asselbergs Folkert W FW Ten Berg Jurriën M JM Deneer Vera Hm VH
Pharmacogenomics 20180427 7
<h4>Aim</h4>A tailored antiplatelet strategy based on CYP2C19 genotype may reduce atherothrombotic and bleeding events. We describe our experience with CYP2C19 genotyping, using on-site TaqMan or Spartan genotyping or shipment to a central laboratory.<h4>Methodology</h4>Data from two ongoing projects were used: Popular Risk Score project (non-urgent percutaneous coronary intervention patients) and the Popular Genetics study (ST-segment elevation myocardial infarction patients). For both projects ...[more]
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Project description:BACKGROUND:The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation. METHODS:Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping. RESULTS:In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p?=?0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p?<?0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p?=?0.008 across groups; p?=?0.020 for PMs versus those without a nonfunctional allele). CONCLUSION:These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months. Trial registration ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7.
| S-EPMC5896099 | biostudies-literature
Project description:CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.
| S-EPMC6019555 | biostudies-literature
Project description:OBJECTIVES:This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND:CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS:After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS:Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS:These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
| S-EPMC5775044 | biostudies-literature
Project description:Dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin within 48 h of acute minor strokes and transient ischemic attacks (TIAs) has been indicated to effectively reduce the rate of recurrent strokes. However, the efficacy of clopidogrel has been shown to be affected by cytochrome P450 2C19 (CYP2C19) polymorphisms. Patients carrying loss-of-function alleles (LoFAs) at a low risk of recurrence (ESRS < 3) cannot benefit from clopidogrel plus aspirin at all and may have an increased bleeding risk. In order to optimize antiplatelet therapy for these patients and avoid the waste of medical resources, it is important to identify the subgroups that genuinely benefit from DAPT with clopidogrel plus aspirin through CYP2C19 genotyping. This study sought to assess the cost-effectiveness of CYP2C19 genotyping to guide drug therapy for acute minor strokes or high-risk TIAs in China. A decision tree and Markov model were constructed to evaluate the cost-effectiveness of CYP2C19 genotyping. We used a healthcare payer perspective, and the primary outcomes included quality-adjusted life years (QALYs), costs and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to evaluate the robustness of the results. CYP2C19 genotyping resulted in a lifetime gain of 0.031 QALYs at an additional cost of CNY 420.13 (US$ 59.85), yielding an ICER of CNY 13,552.74 (US$ 1930.59) per QALY gained. Probabilistic sensitivity analysis showed that genetic testing was more cost-effective in 95.7% of the simulations at the willingness-to-pay threshold of CNY 72,100 (GDP per capita, US$ 10,300) per QALY. Therefore, CYP2C19 genotyping to guide antiplatelet therapy for acute minor strokes and high-risk TIAs is highly cost-effective in China.
| S-EPMC8016871 | biostudies-literature
Project description:BackgroundTo mitigate the risk of stent thrombosis, patients treated by percutaneous coronary intervention (PCI) are administered dual anti-platelet therapy comprising aspirin and a platelet P2Y12 receptor inhibitor. Clopidogrel is a prodrug requiring activation by the cytochrome P450 enzyme, CYP2C19. In Saudi Arabia, it has been reported that approximately 26% of the population carries CYP2C19*2 and/or *3 loss-of-function polymorphisms in addition to a high prevalence of CVD.MethodsThis prospective (April 2013-December 2020) parallel assignment clinical trial focuses on ST-Elevation Myocardial Infarction (STEMI) patient outcomes. The clinical trial includes 1500 STEMI patients from two hospitals in the Eastern Province of Saudi Arabia. Patients are assigned to one of two groups; the control arm receives conventional therapy with clopidogrel, while in the active arm the Spartan RX CYP2C19 assay is used to determine the *2 genotype. Carriers of a CYP2C19*2 loss-of-function allele receive prasugrel or ticagrelor, while non-carriers are treated with clopidogrel. Follow-up is one year after primary PCI. The primary end point is the number of patients who develop an adverse major cardiovascular event, including recurrent MI, non-fatal stroke, cardiovascular death, or major bleeding one year after PCI.DiscussionThe risk of stent thrombosis in PCI patients is usually reduced by dual anti-platelet therapy, comprising aspirin and a P2Y12 inhibitor, such as clopidogrel. However, clopidogrel requires activation by the cytochrome P450 enzyme, CYP2C19. Approximately 20% of the population are unable to activate clopidogrel as they possess the CYP2C19*2 loss-of function (LoF) allele. The primary goal of this trial is to study the benefits of treating only those patients that cannot activate clopidogrel with an alternative that has shown to be a more effective platelet inhibitor and does not require bioactivation by the cytochrome P450 enzyme. We expect an improvement in net clinical benefit outcome in the active arm patients, thus supporting pharmacogenetic testing in PCI patients post STEMI.Trial registrationTrial registration name is "Bedside Testing of CYP2C19 Gene for Treatment of Patients with PCI with Antiplatelet Therapy" (number NCT01823185) retrospectively registered with clinicaltrials.gov on April 4, 2013. This trial is currently at the patient recruitment stage.
| S-EPMC7271437 | biostudies-literature
Project description:BACKGROUND:CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear. METHODS:A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression. RESULTS:CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing (P<0.001) and alternative DAPT use in LOF allele carriers (P=0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22-10.0; P<0.001), whereas no significant difference was observed in those without a LOF allele (adjusted hazard ratio, 1.37; 95% confidence interval, 0.72-2.85; P=0.347). Bleeding event rates were similar across groups (log-rank P=0.816). CONCLUSIONS:Implementing CYP2C19 genotype-guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.
| S-EPMC5889089 | biostudies-literature
Project description:Between 20% and 50% of cardiovascular patients treated with clopidogrel, an anti-P2Y12 drug, display high on-treatment platelet reactivity (HTPR) and are not adequately protected from major adverse cardiovascular events (MACE). Despite a minor influence of the CYP2C19*2 genetic variant on the pharmacodynamic response to clopidogrel (5% to 12%) and a limited or absent value for predicting stent thrombosis and MACE, this latter polymorphism is currently considered an important candidate to tailor anti-P2Y12 therapy during percutaneous coronary intervention. Seven studies have examined the value of CYP2C19*2 for predicting HTPR in comparison to a specific pharmacodynamic assay (VASP assay). Overall, the summarized sensitivity of the CYP2C19*2 genotype for predicting HTPR was 37.6% (95% CI: 32.2 to 43.3%), yielding a negative likelihood ratio of only 0.77 (95% CI: 0.68 to 0.86) which confirms its limited value as a routine clinical aid. A tailored anti-P2Y12 treatment strategy restricted to CYP2C19*2 carriers may be of some help, but this restrictive approach leaves out noncarriers with HTPR. As for platelet function testing, there is currently no convincing data to support that using CYP2C19*2 genotyping as a tailored anti-P2Y12 treatment would be an effective strategy and there is no urgency for CYP2C19 genotyping in clinical practice. Strategies incorporating genotyping, phenotyping, and clinical data in a stratified and sequential approach may be more promising.
| S-EPMC3647256 | biostudies-literature
Project description:Both high platelet reactivity (HPR) and CYP2C19 genotyping have been proposed to stratify cardiovascular event risk and to personalize maintenance dual antiplatelet therapy (DAPT) in stented patients. However, how well CYP2C19 genotype correlates with HPR in patients on maintenance DAPT is less clear. We determined the association of CYP2C19 loss-of-function (*2) and gain-of-function (*17) allele status with platelet reactivity in 118 stented patients on DAPT ≥2 weeks and in 143 patients with stable coronary artery disease on aspirin therapy alone. Thirty-three percent and 39% carried at least 1 copy of *2 and *17 alleles, respectively. Neither allele was associated with platelet reactivity in patients on aspirin therapy alone. On DAPT, platelet aggregation was higher in those with *2 allele than noncarriers (P ≤ .01) but did not differ between those with the *17 allele and noncarriers. The prevalence of HPR using the 20 μM adenosine diphosphate-induced aggregation cutpoint was 34% in the total population: 26% in *1/*1 homozygotes, 49% in those with the *2 allele, and 20% in those with the *17 allele (P = .006). Determination of diplotype status enhanced identification of HPR. However, platelet function on DAPT is highly variable within diplotype groups. Therefore, CYP2C19 genotype and HPR are imperfect correlates of each other. Because both predict cardiovascular events with similar risk ratios, CYP2C19 genotyping and HPR may provide complementary information to stratify risk and personalized DAPT in stented patients than either alone.
| S-EPMC3061841 | biostudies-literature
Project description:Background: The clinical benefits of cytochrome P450 (CYP) 2C19 genotype-guided antiplatelet therapy in Asians remain unclear. In this study, we aimed to investigate the clinical outcomes of pharmacogenomic antiplatelet therapy in Chinese patients. Methods: Patients with acute coronary syndrome planning to undergo percutaneous coronary intervention were eligible for this study and were randomly divided into a genotype-guided treatment (GT) group and routine treatment (RT) group, with a ratio of 2:1. Patients in the GT group underwent CYP2C19 genotyping (*2 and *3 alleles), and the results were considered in selecting P2Y12 receptor inhibitors. Patients in the RT group were treated with P2Y12 receptor inhibitors according to their clinical characteristics. The primary endpoint was a composite of major adverse cardiovascular or cerebrovascular events (MACCE). The secondary endpoint was significant bleeding events. Results: Finally, 301 patients were enrolled; 75.1% were men and the mean age was 59.7 ± 9.8 years. In total, 281 patients completed the follow-up procedure. The primary endpoint occurred in 16 patients, 6 patients in the GT group and 10 in the RT group. The GT group showed lower MACCE rates than the RT group (6/189 vs. 10/92, 3.2 vs. 10.9%, hazard ratio: 0.281, 95% confidence interval: 0.102-0.773, P = 0.009). There was no statistically difference in significant bleeding events between the GT and RT groups (4.2 vs. 3.3%, hazard ratio: 1.315, 95% confidence interval: 0.349-4.956, P = 0.685). Conclusion: Personalized antiplatelet therapy that is based on CYP2C19 genotypes could decrease MACCE within a 12-month period in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000034352.
| S-EPMC8242578 | biostudies-literature
Project description:OBJECTIVE:To assess the feasibility of clinical pharmacist-led CYP2C19 genotype-guided P2Y12 inhibitor antiplatelet drug therapy recommendations to cardiologists in an outpatient cardiology practice. METHODS:This was a prospective, open-labeled, single-arm study conducted in an integrated healthcare delivery system between March 1, 2013 and January 23, 2014. Patients requiring non-emergent cardiac catheterization were included. A clinical pharmacist provided interpretation and recommendations from genotyping results. The feasibility of implementing CYP2C19 genotype-guided antiplatelet therapy was assessed by the: 1) percentage of patients approached who consented to CYP2C19 genotyping, 2) percentage of patients with CYP2C19 genotyping results available prior to cardiac catheterization, and 3) percentage of clinical pharmacist CYP2C19 genotype-based antiplatelet recommendations accepted by cardiologists. RESULTS:Of the 43 patients identified for potential recruitment, 22 of these were eligible for study enrollment and 6 (27%) patients consented and received CYP2C19 genotyping. All patients had genotyping results available prior to catheterization and all clinical pharmacists' antiplatelet therapy recommendations were accepted by the patients' cardiologists. Three patients had the CYP2C19 wild-type (*1/*1) genotype and the clinical pharmacist recommended clopidogrel therapy. CYP2C19 variant genotypes (i.e., *1/*2, *1/*17, and *2/*17) were found in the other three patients; alternative antiplatelet therapy was recommended for the patient with the *1/*2 genotype, while clopidogrel was recommended for those with *1/*17 and *2/*17 genotypes. CONCLUSION:A relatively small proportion of patients undergoing non-emergent cardiac catheterization consented to pharmacogenetic testing; however, their cardiologists were receptive to clinical pharmacists conducting such testing and providing corresponding pharmacotherapy recommendations. Future studies should identify patient barriers to pharmacogenetic testing.
| S-EPMC5499354 | biostudies-literature