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Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

ABSTRACT: 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.

SUBMITTER: Empey PE

PROVIDER: S-EPMC6019555 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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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.

Project description:Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

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.

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Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

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