Implementation of Genotype-Guided Antiplatelet Therapy: Feasible but Not Without Obstacles.
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ABSTRACT:
SUBMITTER: Lewis JP
PROVIDER: S-EPMC5886747 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
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Implementation of Genotype-Guided Antiplatelet Therapy: Feasible but Not Without Obstacles.
Circulation. Genomic and precision medicine 20180401 4
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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:Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.
| S-EPMC4899238 | biostudies-literature
Project description:Precision medicine entails tailoring treatment based on patients' unique characteristics. As drug therapy constitutes the cornerstone of treatment for most chronic diseases, pharmacogenomics (PGx), the study of genetic variation influencing individual response to drugs, is an important component of precision medicine. Over the past decade investigations have identified genes and single-nucleotide polymorphisms (SNPs) and quantified their effect on drug response. Parallel development of point-of-care (POC) genotyping platforms has enabled the interrogation of the genes/SNPs within a timeline conducive to the provision of care. Despite these advances, the pace of integration of genotype-guided drug therapy (GGTx) into practice has faced significant challenges. These include difficulty in identifying SNPs with sufficiently robust evidence to guide clinical decision making, lack of clinician training on how to order and use genotype data, lack of clinical decision support (CDS) to guide treatment, and limited reimbursement. The University of Alabama at Birmingham's (UAB) efforts in precision medicine were initiated to address these challenges and improve the health of the racially diverse patients we treat.
| S-EPMC5526751 | biostudies-literature
Project description: Not available
| S-EPMC7270838 | 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:Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.
| S-EPMC9245803 | biostudies-literature
Project description:Cardiovascular diseases are the leading cause of death in the Western world. Several factors have led to the increase in vascular disorders, including the aging population, unhealthy lifestyles, increasing rates of diabetes and raised lipids, and further risk factors resulting in inflammation and calcification of the vascular endothelium. Activated platelets in damaged blood vessels can trigger arterial thrombus formation, leading to vascular occlusion with subsequent organ hypoperfusion and clinical manifestation of myocardial infarction, stroke, or peripheral artery disease. Platelet inhibitors such as aspirin and clopidogrel (Plavix(®) and generics) are prescribed as primary or secondary prevention to attenuate chronic platelet activation. However, a significant proportion of patients do not respond adequately to uniform antiplatelet treatment. These 'non-responders' have an increased risk for stent thrombosis, stroke, and other ischemic complications. Platelet function (PF) tests can identify these patients thus enabling physicians to offer personalized and alternative treatment strategies. Recent alternatives to clopidogrel include prasugrel (Efient(®)) and ticagrelor (Brilique(®)) - that are both more potent than clopidogrel but also more expensive and associated with a higher risk of bleeding complications. Given these drawbacks, PF testing might help clinicians to prescribe optimal antiplatelet agent to maximize patient safety and efficacy while minimizing costs. While randomized studies using different test systems have left clinicians puzzled about the medical value of tailored antiplatelet therapy, accumulated evidence from recent studies on tailored antiplatelet therapies and the association with improved outcomes have now resulted in a consensus expert opinion for the specific adoption of PF diagnostics into clinical practice.
| S-EPMC4975182 | biostudies-other
Project description:Dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin remains the standard of care for all patients undergoing percutaneous coronary intervention (PCI). It is well-established that patients carrying CYP2C19 no function alleles have impaired capacity to convert clopidogrel into its active metabolite and thus, are at higher risk of major adverse cardiovascular events (MACE). The metabolism and clinical effectiveness of prasugrel and ticagrelor are not affected by CYP2C19 genotype, and accumulating evidence from multiple randomized and observational studies demonstrates that CYP2C19 genotype-guided antiplatelet therapy following PCI improves clinical outcomes. However, most antiplatelet pharmacogenomic outcome studies to date have lacked racial and ethnic diversity. In this review, we will (1) summarize current guideline recommendations and clinical outcome evidence related to CYP2C19 genotype-guided antiplatelet therapy, (2) evaluate the presence of potential racial and ethnic disparities in the major outcome studies supporting current genotype-guided antiplatelet therapy recommendations, and (3) identify remaining knowledge gaps and future research directions necessary to advance implementation of this precision medicine strategy for dual antiplatelet therapy in diverse, real-world clinical settings.
| S-EPMC9445150 | biostudies-literature
Project description:BackgroundDespite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity.SummaryThere is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.
| S-EPMC7606720 | biostudies-literature