Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis

Objective To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel

The Clinical Implementation of CYP2C19 Genotyping in Patients with an Acute Coronary Syndrome:Insights From the FORCE-ACS Registry

BACKGROUND: Guidelines recommend prasugrel or ticagrelor for acute coronary syndrome (ACS) patients. However, these P2Y12 inhibitors increase bleeding risk compared to clopidogrel. Although genotype-guided P2Y12-inhibitor selection has been shown to reduce bleeding risk, data on its clinical implementation is lacking. METHODS: The study included ACS patients receiving genotype-guided antiplatelet therapy, utilising either a point-of-care (POC) device or laboratory-based testing. We aimed to collect qualitative and quantitative data on genotyping, eligibility for de-escalation, physician adherence to genotype results, time to de-escalation and cost reduction. RESULTS: Of the 1,530 patients included in the ACS registry from 2021 to 2023, 738 ACS patients treated with ticagrelor received a CYP2C19 genotype test. The median turnover time of genotyping was 6.3 hours (interquartile range [IQR], 3.2-16.7), with 82.3% of the genotyping results known within 24 hours after admission. POC genotyping exhibited significantly shorter turnaround times compared to laboratory-based testing (with respective medians of 5.7 vs 47.8 hours; P &lt; .001). Of the genotyped patients, 81.7% were eligible for de-escalation which was carried out within 24 hours in 70.9% and within 48 h in 93.0%. The time to de-escalation was significantly shorter using POC (25.4 hours) compared to laboratory-based testing (58.9 hours; P &lt; .001). Implementing this strategy led to a reduction of €211,150.50 in medication costs. CONCLUSIONS: CYP2C19 genotype-guided-de-escalation in an all-comers ACS population is feasible. POC genotyping leads to shorter turnaround times and quicker de-escalation. Time to de-escalation from ticagrelor to clopidogrel in noncarriers was short, with high physician adherence to genotype results.</p

aspirin therapy in primary cardiovascular disease prevention a position paper of the european society of cardiology working group on thrombosis

Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as $2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding. (J Am Coll Cardiol 2014;64:319–27) © 2014 by the American College of Cardiology Foundation

Effects of CYP3A4*22 and CYP3A5 on clinical outcome in patients treated with ticagrelor for ST-segment elevation myocardial infarction: POPular Genetics sub-study

Aims: To determine the clinical efficacy, adverse events and side-effect dyspnea of CYP3A4*22 and CYP3A5 expressor status in ticagrelor treated patients.Methods and results: Ticagrelor treated patients from the POPular Genetics randomized controlled trial were genotyped for CYP3A4*22 and CYP3A5*3 alleles. Patients were divided based on their genotype. In total 1,281 patients with ST-segment elevation myocardial infarction (STEMI) were included. CYP3A4*22 carriers (n = 152) versus CYP3A4*22 non-carrier status (n = 1,129) were not found to have a significant correlation with the primary thrombotic endpoint: cardiovascular death, myocardial infarction, definite stent thrombosis and stroke [1.3% vs. 2.5%, adjusted hazard ratio 1.81 (0.43–7.62) p = 0.42], or the primary bleeding endpoint: PLATO major and minor bleeding [13.2% vs. 11.3%, adjusted hazard ratio 0.93 (0.58–1.50) p = 0.77]. Among the CYP3A4*1/*1 patients, CYP3A5 expressors (n = 196) versus non-expressors (n = 926) did not show a significant difference for the primary thrombotic [2.6% vs. 2.5%, adjusted hazard ratio 1.03 (0.39–2.71) p = 0.95], or the primary bleeding endpoint [12.8% vs. 10.9%, adjusted hazard ratio 1.13 (0.73–1.76) p = 0.58]. With respect to dyspnea, no significant difference was observed between CYP3A4*22 carriers versus CYP3A4*22 non-carriers [44.0% vs. 45.0%, odds ratio 1.04 (0.45–2.42) p = 0.93], or in the CYP3A4*1/*1 group, CYP3A5 expressors versus CYP3A5 non-expressors [35.3% vs. 47.8%, odds ratio 0.60 (0.27–1.30) p = 0.20].Conclusion: In STEMI patients treated with ticagrelor, neither the CYP3A4*22 carriers, nor the CYP3A5 expressor status had a statistical significant effect on thrombotic and bleeding event rates nor on dyspnea.Clinical Trial Registration:ClinicalTrials.gov, identifier NCT01761786

Dabigatran dual therapy versus warfarin triple therapy post-PCI in patients with atrial fibrillation and diabetes

OBJECTIVES: The aim of this study was to evaluate dabigatran dual therapy versus warfarin triple therapy in patients with or without diabetes mellitus in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.BACKGROUND: It is unclear whether dual therapy is as safe and efficacious as triple therapy in patients with atrial fibrillation with diabetes following percutaneous coronary intervention.METHODS: In RE-DUAL PCI, 2,725 patients with atrial fibrillation (993 with diabetes) who had undergone PCI were assigned to warfarin triple therapy (warfarin, clopidogrel or ticagrelor, and aspirin) or dabigatran dual therapy (dabigatran 110 mg or 150 mg twice daily and clopidogrel or ticagrelor). Median follow-up was 13 months. The primary outcome was the composite of major bleeding or clinically relevant nonmajor bleeding, and the main efficacy outcome was the composite of death, thromboembolic events, or unplanned revascularization.RESULTS: Among patients with diabetes, the incidence of major bleeding or clinically relevant nonmajor bleeding was 15.2% in the dabigatran 110 mg dual therapy group versus 27.5% in the warfarin triple therapy group (hazard ratio [HR]: 0.48; 95% confidence interval [CI] 0.35 to 0.67) and 23.8% in the dabigatran 150 mg dual therapy group versus 25.1% in the warfarin triple therapy group (HR: 0.87; 95% CI: 0.62 to 1.22). Risk for major bleeding or clinically relevant nonmajor bleeding was also reduced with both dabigatran doses among patients without diabetes (dabigatran 110 mg dual therapy: HR: 0.54; 95% CI: 0.42 to 0.70; dabigatran 150 mg dual therapy: HR: 0.63; 95% CI: 0.48 to 0.83). Risk for the efficacy endpoint was comparable between treatment groups for both patients with and those without diabetes. No interaction between treatment and diabetes subgroup could be observed, either for bleeding or for composite efficacy endpoints.CONCLUSIONS: In this subgroup analysis, dabigatran dual therapy had a lower risk for bleeding and a comparable rate of the efficacy endpoint compared with warfarin triple therapy in patients with atrial fibrillation with or without diabetes following percutaneous coronary intervention.</p

Cost-effectiveness of clopidogrel vs. ticagrelor in patients of 70 years or older with non-ST-elevation acute coronary syndrome

OBJECTIVE: The POPular AGE trial showed that clopidogrel significantly reduced bleeding risk compared with ticagrelor without any signs of an increase in thrombotic events. The aim of this analysis was to estimate the long-term cost-effectiveness of clopidogrel compared with ticagrelor in these patients aged 70 years or older with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS AND RESULTS: A 1-year decision tree based on the POPular AGE trial in combination with a lifelong Markov model was developed to compare clopidogrel with ticagrelor in terms of clinical outcomes, costs, and quality-adjusted life years (QALYs) in elderly patients (above 70 year) with NSTE-ACS. Cost-effectiveness was assessed from a Dutch healthcare system perspective. Events rates and utility data observed in the POPular AGE trial were combined with lifetime projections to evaluate costs and effects for a fictional cohort of 1000 patients. Treatment with clopidogrel instead of ticagrelor led to a cost saving of €1484 575 (€1485 per patient) and a decrease of 10.96 QALYs (0.011 QALY per patient) in the fictional cohort. In an alternative base case with equal distribution over health states in the first year, treatment with clopidogrel led to an increase in QALYs. In all scenario analyses, treatment with clopidogrel was cost-saving. CONCLUSION: Clopidogrel is a cost-saving alternative to ticagrelor in elderly patients after NSTE-ACS, though regarding overall cost-effectiveness clopidogrel was not superior to ticagrelor, as it resulted in a small negative effect on QALYs. However, based on the results of the alternative base case and clinical outcomes of the POPular AGE trial, clopidogrel could be a reasonable alternative to ticagrelor for elderly NSTE-ACS patients with a higher bleeding risk

NT-proBNP level before primary PCI and risk of poor myocardial reperfusion: Insight from the On-TIME II trial.

Background N-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP), a marker for neurohumoral activation, has been associated with adverse outcome in patients with myocardial infarction. NT-proBNP levels may reflect extensive ischemia and microvascular damage, therefore we investigated the potential association between baseline NTproBNP level and ST-resolution (STR), a marker of myocardial reperfusion, after primary percutaneous coronary intervention (pPCI).Methods we performed a post-hoc analysis of the On-TIME II trial (which randomized ST-elevation myocardial infarction (STEMI) patients to pre-hospital tirofiban administration vs placebo). Patients with measured NT-proBNP before angiography were included. Multivariate logistic-regression analyses was performed to investigate the association between baseline NTproBNP level and STR one hour after pPCI.Results Out of 984 STEMI patients, 918 (93.3%) had NT-proBNP values at baseline. Patients with STR 70% had higher NT-proBNP values compared to patients with complete STR (70%) [Mean +/- SD 375.2 +/- 1021.7 vs 1007.4 +/- 2842.3, Median (IQR) 111.7 (58.4-280.0) vs 168.0 (62.3-601.3), P < .001]. At multivariate logistic regression analysis, independent predictors associated with higher risk of poor myocardial reperfusion (STR < 70%) were: NT-proBNP (OR 1.17, 95%CI 1.041.31, P = .009), diabetes mellitus (OR 1.87, 95%CI 1.14-3.07, P = .013), anterior infarct location (OR 2.74, 95% CI 2.00-3.77, P < .001), time to intervention (OR 1.06, 95%CI 1.01-1.11, P = .021), randomisation to placebo (OR 1.45, 95%CI 1.05-1.99, P = .022).Conclusions In STEMI patients, higher baseline NT-proBNP level was independently associate with higher risk of poor myocardial reper fusion, suppor ting the potential use of NT-proBNP as an early marker for risk stratification of myocardial reperfusion after pPCI in STEMI patients

Cost Effectiveness of a CYP2C19 Genotype-Guided Strategy in Patients with Acute Myocardial Infarction:Results from the POPular Genetics Trial

INTRODUCTION: The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y12 inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI). OBJECTIVE: In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel. METHODS: A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y12 inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y12 inhibitors, and equal distribution of thrombotic events between the two strategies). RESULTS: Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant. CONCLUSION: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872

Association of Factor V Leiden with Subsequent Atherothrombotic Events:A GENIUS-CHD Study of Individual Participant Data

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population