PPAR-α genetic variants influence on-treatment platelet reactivity in patients treated with clopidogrel and lipid-lowering drugs and undergoing non-urgent percutaneous coronary intervention with stent implantation

Background: Response to clopidogrel varies between patients, due to many factors, like polymorphisms in genes encoding for metabolizing enzymes. The CYP3A4∗22 polymorphism has been proven to decrease the expression of CYP3A4, while the PPAR-α genetic variants G209A and A208G have been identified as determinants that affect CYP3A4. Statins and fibrates, which are the ligands of PPAR-α as well as being metabolized by CYP3A4, might also affect the response of clopidogrel through these two proteins. Objectives: To investigate the association between on-treatment platelet reactivity and the CYP3A4∗22 allele and genetic variations of the PPAR-α genes in clopidogrel-treated patients undergoing non-urgent percutaneous coronary intervention (PCI) with stenting and to evaluate the influence of statin/fibrate co-medication on these associations. Methods: A total of 1126 patients with non-urgent PCI and stenting pre-treated with clopidogrel and aspirin were genotyped for CYP3A4∗22 and PPAR-α (G209A and A208G). Platelet reactivity was measured using the VerifyNow® P2Y12-assay, expressed in PRU. Multivariate linear regression analysis was used to assess the association between the genetic variants and platelet reactivity, adjusted for confounders, including the CYP2C19 metabolizer status. A stratified analysis was conducted for patients with statin/fibrate co-medication. A recessive model was used for all associations. Results: The CYP3A4∗22/∗22 genotype was present in 0.4% of patients, 6.8% had the PPAR-α G209A AA genotype, and 7.0% had the PPAR-α A208G GG genotype. CYP3A4∗22 was not associated with platelet reactivity. PPAR-α genetic variants were significantly associated with platelet reactivity (PPAR-α G209A AA: -23.87 PRU [-43.54, -4.19]; PPAR-α A208G GG: -23.70 PRU [-43.13, -4.27]). In patients who were on statin/fibrate co-medication, these PPAR-α genetic variants were associated with an even lower platelet reactivity (-29.74 PRU [-50.94, -8.54], and -29.38 PRU [-50.26, -8.49], respectively), while those without statin/fibrate co-medication did not show a significant change in platelet reactivity (13.00 PRU [-39.79, 65.80]). Conclusions: Two genetic variants in PPAR-α (G209A and A208G) were associated with lower platelet reactivity in patients with non-urgent PCI and stenting co-treated with clopidogrel and lipid-lowering drugs

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

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

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

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes

Safety of Ticagrelor Compared to Clopidogrel after Prehospital Initiation of Treatment

Objectives  The objective of this registry was to study the safety of prehospital initiation of ticagrelor compared with clopidogrel. Background  Ticagrelor has replaced clopidogrel in many hospitals as the routinely used antiplatelet drug in patients with ST-segment elevation myocardial infarction (STEMI). Nevertheless, in the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with an increase in non-CABG (non-coronary artery bypass grafting)-related major bleeding. Data comparing the safety of ticagrelor and clopidogrel after prehospital initiation of treatment are not available. Methods  A retrospective, multicenter registry was performed. Selection criteria were the administration of a prehospital loading dose of ticagrelor or clopidogrel according to the ambulance STEMI treatment protocol and the presentation to a percutaneous coronary intervention-capable hospital in our region between January 2011 and December 2012. Follow-up was performed using the electronic patient files for the time period between the antiplatelet loading dose and hospital discharge. The data were analyzed using a primary bleeding end point (any bleeding) and a secondary thrombotic end point (all-cause mortality, spontaneous myocardial infarction, definite stent thrombosis, stroke, or transient ischemic attack). Results  Data of 304 clopidogrel-treated and 309 ticagrelor-treated patients were available for analysis. No significant difference in bleeding rate was observed between both groups, using univariate (17.8 vs. 20.1%; p  = 0.47; odds ratio, 1.16 [95% confidence interval, 0.78-1.74]) and multivariate ( p  = 0.42) analysis. Also for the secondary thrombotic end point (6.3 vs. 4.9%, p  = 0.45), no significant differences were observed. Conclusion  In this real-world registry, no significant differences in bleeding or thrombotic event rate were found between ticagrelor and clopidogrel after prehospital initiation of treatment