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Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

ABSTRACT: 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.

SUBMITTER: Lee CR

PROVIDER: S-EPMC5889089 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Clinical Outcomes and Sustainability of Using <i>CYP2C19</i> Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Lee Craig R CR Sriramoju Vindhya B VB Cervantes Alexandra A Howell Lucius A LA Varunok Nicholas N Madan Shivanshu S Hamrick Kasey K Polasek Melissa J MJ Lee John Andrew JA Clarke Megan M Cicci Jonathan D JD Weck Karen E KE Stouffer George A GA

Circulation. Genomic and precision medicine 20180401 4

<h4>Background</h4><i>CYP2C19</i> loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using <i>CYP2C19</i> genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear.<h4>Methods</h4>A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that reco ...[more]

PMID: 29615454

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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:BackgroundThe 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.MethodsPatients 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.ResultsIn 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).ConclusionThese 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.

Project description:Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ?2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300-3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864-2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582-2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.

Project description:Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients.The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider's perspective.A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding) for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs) were calculated for the treatment strategies, with quality-adjusted life years (QALYs) as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed.Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs) and genotype-guided therapy (USD19,231, 10.05 QALYs). The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost-effective with <21% certainty at willingness-to-pay of >USD170,000/QALY.Our modeling analyses suggest that genotype-guided therapy is a cost-effective strategy in patients with acute coronary syndrome undergoing planned percutaneous coronary intervention.

Project description:BackgroundSubjects undergoing coronary stenting with complex lesion anatomy may experience different risks and benefits with prolonged dual antiplatelet therapy.ObjectivesThe authors assessed the effect of 30 months versus 12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) based on the presence or absence of anatomically-complex target lesions.MethodsIn the DAPT Study, combined myocardial infarction (MI) or stent thrombosis and moderate/severe bleeding were assessed in enrolled (n = 25,416) and randomized (n = 11,554) subjects. Complex lesions had any of the following characteristics: unprotected left main, >2 lesions/vessel, length ≥30 mm, bifurcation with side branch ≥2.5 mm, vein bypass graft, or thrombus-containing lesion. Events were evaluated according to increasing number of complexity characteristics and compared according to DAPT score.ResultsEnrolled subjects with more complex target lesions had higher rates of MI or stent thrombosis in the first 12 months after PCI (3.9% vs. 2.4%; p < 0.001). Among those who were event-free at 12 months, rates of MI or stent thrombosis between 12 and 30 months were similar between those with versus without complex anatomy (3.5% vs. 2.9%; p = 0.07). Reduction of MI or stent thrombosis with continued thienopyridine beyond 12 months versus placebo was similar for subjects with (2.5% vs. 4.5%; hazard ratio: 0.55; 95% confidence interval: 0.38 to 0.79; p = 0.001) and without (2.0% vs. 3.8%; hazard ratio: 0.52; 95% confidence interval: 0.39 to 0.69; p < 0.001) anatomic complexity (pinteraction = 0.81), as was increase in moderate/severe bleeding (pinteraction = 0.44). Among subjects with anatomic complexity, those with DAPT scores ≥2 randomized to continued thienopyridine had greater reductions in MI or stent thrombosis (3.0% vs. 6.1%; p < 0.001) compared with subjects with scores <2 (1.7% vs. 2.3%; p = 0.42; p value comparing risk differences = 0.03).ConclusionsComplex target-lesion anatomy is associated with increased ischemic events, particularly within the first year after PCI. Among those without events in the first 12 months, the benefits of extending DAPT were similar in subjects with and without complex lesions. A high DAPT score identified those experiencing the most benefit from extended treatment among patients with and without complex anatomy. (The Dual Antiplatelet Therapy Study [DAPT Study]; NCT00977938).

Dataset Information

Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Publications

Clinical Outcomes and Sustainability of Using <i>CYP2C19</i> Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

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