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Background Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. Methods GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. Results In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09-0.55) and MIs (HR 0.24, 95% CI 0.08-0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27-3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43-3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19-2.57). In the PSM analysis, no significant association was found. Conclusion In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations.

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.

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10−54; CES1 G143E, P = 1.3 × 10−16; CYP2C19*17, P = 9.5 × 10−10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10−4; CYP2B6 516 G > T, P = 1.0 × 10−3; CYP2C9*2, P = 1.2 × 10−3; and CYP2C9*3, P = 1.5 × 10−3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14–2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35–14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. Conclusion Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype–guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y 12 inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19 *2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19 *17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel–treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. Results: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19 *17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45–2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48–1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56–0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68–1.90]). Conclusions: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19 *17 polymorphism. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/ ; Unique identifier: NL2872.

Introduction: The POPular Genetics trial demonstrated that a genotype-guided strategy to select antiplatelet therapy in patients with ST-elevation myocardial infarction (STEMI) compared to universal treatment with ticagrelor or prasugrel, resulted in a reduction in bleedings without an increase in the thrombotic risk. The objective of this analysis was to assess the cost-effectiveness of the genotype-guided strategy. Methods: In the POPular Genetics trial, STEMI patients who underwent primary percutaneous coronary intervention were randomized to an intervention or a control arm. In the intervention arm CYP2C19 genetic testing for the *2 and *3 loss-of-function alleles took place. Carriers of a loss-of-function allele were treated with ticagrelor or prasugrel, while noncarriers were treated with clopidogrel. In the control arm patients were treated with ticagrelor or prasugrel. An alongside clinical-trial cost-effectiveness analysis was conducted based on a decision-model with 1000 patients in both groups. A hybrid model, consisting of a 1-year decision tree combined with a 25-years Markov model was developed, to estimate the life-time cost-effectiveness from a societal perspective. Outcome measures were costs, quality-adjusted life-years (QALYs) and incremental cost per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted to account for the uncertainty around the key parameters. In an exploratory analysis the price for ticagrelor and prasugrel was the same as clopidogrel, to simulate the effect of generic ticagrelor and prasugrel in the future. Results: The genotype-guided strategy resulted in 26.87 QALY gained with cost-savings of є601,807 indicating that the genotype-guided strategy is a cost-saving intervention. The exploratory analysis - keeping the price of antithrombotic therapies at the same price level - resulted in cost-savings of є137,980. Deterministic and probabilistic sensitivity analyses confirmed the robustness of the base-case analysis. Conclusion: Based on the POPular Genetics trial, a genotype-guided strategy compared to universal ticagrelor or prasugrel treatment resulted in favorable cost-effectiveness with QALYs gained and cost-savings.

Objectives The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes. Background Clopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles. Methods Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel. Results A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate Conclusions The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.

Aim: A tailored antiplatelet strategy based on CYP2C19 genotype may reduce atherothrombotic and bleeding events. We describe our experience with CYP2C19 genotyping, using on-site TaqMan or Spartan genotyping or shipment to a central laboratory. Methodology: Data from two ongoing projects were used: Popular Risk Score project (non-urgent percutaneous coronary intervention patients) and the Popular Genetics study (ST-segment elevation myocardial infarction patients). For both projects, the time to genotyping result was calculated. Results: In the Popular Risk Score project (n = 2556), median time from blood collection to genotyping result was 4:04 h. In the Popular Genetics study (n = 1038), median time from randomization to genotyping result was 2:24 h. Conclusion: CYP2C19 genotyping is feasible in everyday clinical practice, both in the acute and non-acute settings.

Objectives: The aim of this study was to determine predictors of very late stent thrombosis (VLST; >1 year after stenting), and to evaluate whether addition of these predictors to the dual antiplatelet therapy (DAPT) score would improve the ability to identify patients at high risk of VLST who might benefit from DAPT. Background: VLST is a severe complication of percutaneous coronary intervention (PCI). Extended knowledge about the predictors of VLST is needed to prevent this life-threatening complication. Recent data showed a reduction in VLST after treatment with prolonged DAPT. The DAPT study developed a prediction score to identify patients after PCI who might benefit from prolonged DAPT duration. Methods: The Dutch stent thrombosis study is a multi-center case-control study. Consecutive patients with definite VLST were included between 2007 and 2014. Baseline characteristics from the index PCI were collected. Independent predictors of VLST were identified and added to the DAPT score to develop the VLST score. Results: In total, 155 VLST cases and 155 matched controls were included. Suboptimal result of stenting, right coronary artery as target vessel, and diffuse coronary artery ectasia were independent predictors of VLST, and added to the DAPT score. The power of the VLST score to identify patients who experienced VLST was increased (AUC, 95%CI; DAPT score: 0.64, 0.57-0.70; VLST score: 0.70, 0.63-0.76, P = 0.010). Conclusions: Addition of newly identified independent predictors of VLST resulted in a prediction model with a higher ability to identify patients at high risk of VLST who might benefit from prolonged DAPT.

Essentials Platelet reactivity is correlated with thrombotic risk after percutaneous coronary intervention (PCI). Hematocrit (HCT) is associated with platelet reactivity as measured with the VerifyNow P2Y12 assay. We tested a formula proposed to correct VerifyNow measurements for HCT in 978 PCI patients. Correcting platelet reactivity for HCT did not improve the prediction of thrombotic events after PCI. SummaryBackground High on-treatment platelet reactivity is predictive for the occurrence of atherothrombotic events following percutaneous coronary interventions (PCIs). A low hematocrit (HCT) value is associated with higher platelet reactivity values, expressed in P2Y12 reaction units (PRU), as measured with the VerifyNow P2Y12 assay. However, it is suggested that this is only an in vitro phenomenon. Objective To determine whether adjusting PRU for HCT improves the predictive value for thrombotic events following PCI. Material and methods The VerifyNow P2Y12 assay was performed in clopidogrel-treated patients undergoing non-urgent PCI included in a prospective cohort study. PRU values were corrected for HCT with a formula proposed in recent literature. Receiver operating characteristic (ROC) curves were made to determine the optimal cut-off values to predict the occurrence of the primary endpoint, a composite of all-cause death and non-fatal myocardial infarction, stent thrombosis and ischemic stroke, during 1 year of follow-up. The chi-squared test was performed to determine whether correcting PRU for HCT improved the prediction of the primary endpoint. Results A total of 978 patients were analyzed. A negative correlation between PRU and HCT was observed (R2 = 0.104). The optimal cut-off value for the corrected PRU was 215. ROC analyses showed that prediction of the primary endpoint did not differ for the corrected PRU (area under the curve, 0.61; sensitivity, 0.57; specificity, 0.64) and the uncorrected PRU (area under the curve, 0.61; sensitivity, 0.69; specificity, 0.53). Conclusion Correcting PRU for HCT does not improve the prediction of thrombotic events following PCI.

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.

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]; I 2 =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.

When switching from ticagrelor or prasugrel to clopidogrel early after myocardial infarction (MI), a loading dose is recommended ([1][1],[2][2]). However, this recommendation is based solely on pharmacodynamics studies, whereas studies investigating the effects on clinical outcomes (i.e., stent

Early recognition of myocardial infarction (MI) remains a challenge, especially in patients presenting with non-ST-segment elevation MI. Heart-type fatty acid binding protein (hFABP) has shown to be a more sensitive marker for myocardial necrosis as compared to non-high sensitive troponins (4th generation and older). However, since high sensitive troponin (hs TnT) assays are available, it is questionable whether hFABP still has value as a diagnostic tool for MI. A systematic search was conducted in Medline, Embase and Cochrane. After selecting the articles, they were assessed for risk of bias according to the QUADAS-2 criteria. Negative predictive value, positive predictive value, sensitivity and specificity were extracted or calculated if possible. Nine studies met the inclusion criteria. Overall, hs TnT showed higher sensitivity than hFABP, while hFABP had higher specificity. In patients presenting within 3 hours after onset of symptoms, sensitivity is low for both hFABP and hs TnT (19-63% vs 25-55%, respectively), while specificity seems higher for hFABP than for hs TnT (70-99% vs 57-86%, respectively). In these patients, the area under the curve for hs TnT is equal or better than that for hFABP (0.67-0.92 for hs TnT vs 0.69-0.85 for hFABP). The addition of hFABP to hs TnT did not improve sensitivity and specificity. This systematic review finds no advantage for using hFABP over hs TnT in either early presenting patients or overall. Furthermore, no advantage was found if a combination of hFABP and hs TnT was used for the diagnosis of MI.

Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically.Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular & nbsp;death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding).Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77 & ndash;1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66 & ndash;1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62 & ndash;1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively.Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and pa-tients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in pa-tients using clopidogrel.(c) 2021 Published by Elsevier B.V.

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016, A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.

The POPular Genetics trial demonstrated that a genotype-guided strategy benefits patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) compared to standard treatment with ticagrelor or prasugrel by reducing bleedings, without increasing

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.

SummaryPatients exhibiting high on-clopidogrel platelet reactivity (HPR) are at an increased risk of atherothrombotic events following percutaneous coronary interventions (PCI). The use of concomitant medication which is metabolised by the hepatic cytochrome P450 system, such as phenprocoumon, is associated with HPR. We assessed the level of platelet reactivity on clopidogrel in patients who received concomitant treatment with acenocoumarol (another coumarin derivative). Patients scheduled for PCI were included in a prospective, single centre, observational registry. Patients who were adequately pre-treated with clopidogrel were eligible for this analysis, which included 1,582 patients, of whom 104 patients (6.6 %) received concomitant acenocoumarol treatment. Platelet reactivity, as measured with the VerifyNow P2Y12 assay and expressed in P2Y12 Reaction Units (PRU), was significantly higher in patients on concomitant acenocoumarol treatment (mean PRU 229 ± 88 vs 187 ± 95; p< 0.001). In patients with concomitant acenocoumarol use, the proportion of patients with HPR was higher, defined as PRU > 208 (57.7 % vs 41.1 %; p=0.001) and PRU236 (49.0 % vs 31.4 %; p< 0.001). In multivariable analysis, concomitant acenocoumarol use was independently associated with a higher PRU and the occurrence of HPR defined as PRU236 (OR 2.00, [1.07–3.79]), but not with HPR defined as PRU > 208 (OR 1.37, [0.74–2.54]). PRU also was significantly increased after 1:1 propensity matching (+28.2; p< 0.001). As this was an observational study, confounding by indication cannot be excluded, although multivariable analyses and propensity matching were performed. The impact of the findings from this hypothesis-generating study on clinical outcome requires further investigation.

Background— Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. Methods and Results— We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was Conclusions— In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal.

Background International guidelines do not provide uniform recommendations regarding the use of antiplatelet treatment in the perioperative period in patients undergoing coronary artery bypass grafting (CABG). Methods A questionnaire was sent to all 16 cardiothoracic centres in the Netherlands to determine which antiplatelet treatment is used in the perioperative setting. Furthermore, a single-centre prospective observational cohort study was performed which included all patients undergoing isolated CABG in July 2014. Results Eleven centres responded to the survey. Acetylsalicylic acid monotherapy was discontinued before surgery in 6 centres. In patients with an acute coronary syndrome receiving dual antiplatelet therapy (DAPT), most centres discontinued the P2Y12 inhibitor preoperatively. DAPT was restarted after surgery in 4 centres. However, 6 centres continued DAPT in patients who had undergone coronary stenting within one month of surgery. In patients with coronary stents, variation in the management of antiplatelet therapy increased in proportion to the interval between stenting and surgery. A total of 70 patients were included in the registry. Acetylsalicylic acid monotherapy was discontinued in 51% of patients and restarted in all patients. P2Y12 inhibitor treatment was discontinued before surgery in 70% of patients and re-initiated after CABG in 29%. Conclusions Major differences were observed in the preoperative and postoperative management of antiplatelet treatment between different Dutch cardiothoracic centres and within a single centre. Part of this variation is probably due to lack of evidence and differences between the current guidelines; however, many of the strategies were not in accordance with any of these guidelines. Electronic supplementary material The online version of this article (doi: 10.1007/s12471-017-1006-z) contains supplementary material, which is available to authorized users.

RATIONALE: The P2Y(12) receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention or ischemic stroke. Platelet inhibition by clopidogrel shows wide inter-patient variability and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics and cardiovascular outcomes, to perform candidate gene and genome-wide association studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate (ADP) stimulated platelet function tests included Vasodilator-Stimulated Phosphoprotein (VASP) assay, Light Transmittance Aggregometry (LTA) and the VerifyNow P2Y(12) assay. A proof of principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (p-value = 5.1×10(−40)). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic techniques in a large cohort of clopidogrel-treated patients in order to better understand the genetic basis of on-treatment response variability.

Antiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of

Objectives: The PLATO trial revealed superiority of ticagrelor over clopidogrel for the prevention of atherothrombotic events in patients with acute coronary syndrome. However, adverse events such as bleeding, dyspnea, and bradycardia were frequently reported, potentially leading to excess early ticagrelor discontinuation (ETD), later confirmed in the PEGASUS trial. We here evaluated the incidence and causes for ETD in a real-world patient cohort in a high-volume nonacademic percutaneous coronary intervention center in the Netherlands. Methods: In a retrospective single-center registry, all patients discharged from the hospital with a new ticagrelor prescription were screened for ETD. Follow-up data were obtained using the hospital electronic patient file records and confirmed by telephone contact with the patient and/or general practitioner, if necessary, to complement the data. Results: Ticagrelor was prescribed in 354 patients between December 2011 and December 2012. The follow-up data were available in 301 patients with a mean follow-up duration of 330 days. ETD or switching to another antiplatelet agent occurred in 73 patients (24.3%), mostly due to dyspnea (11.6%), bleeding (3.7%), or planned major surgery (2.7%). Conclusions: Almost one quarter of ticagrelor patients were discontinued prematurely or switched to another antiplatelet agent within 1 year, mostly due to dyspnea or bleeding.

SummaryPatients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFRClinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

The recurrence rate of coronary stent thrombosis (ST) is high. Patients with ST often demonstrate high on-treatment platelet reactivity (HPR). It is suggested that patients at high risk of atherothrombotic events, that is patients with ST, could benefit from tailored antiplatelet therapy (APT). This study evaluated whether tailored APT, based on platelet function testing, reduced the rate of cardiac death and/or recurrent ST at 1 year after ST, compared with a historical cohort of patients with ST without tailored APT. Patients with definite ST visited our ST outpatient clinic for platelet function testing and tailored APT. These patients were evenly matched to a historical cohort of patients with ST treated with aspirin and clopidogrel, which was the standard of care at that time. The primary end point was a composite of cardiac death and/or recurrent definite ST after 1 year. In total, 113 patients who visited the outpatient clinic were included. HPR was observed in 46%, 6.7%, and 0% of the patients on clopidogrel, prasugrel, and ticagrelor, respectively. After tailored APT, 93% of the patients with HPR demonstrated normal platelet reactivity. The primary end point was observed in 4 patients who had visited the outpatient clinic and in 23 patients of the historical cohort. The odds ratio of tailored APT on the primary end point was 0.26 (95% confidence interval 0.11 to 0.64, p = 0.003), independent from the possible confounders prior myocardial infarction and stent type. In conclusion, the outpatient ST clinic was associated with lower HPR rates in patients with ST after tailored APT. Patients who visited the ST outpatient clinic had a lower risk for cardiac death and/or recurrent ST compared with a historical cohort of patients with ST without tailored APT. Regarding the high HPR rate in patients with ST on clopidogrel, these patients might benefit in particular from the strategy of tailored APT.

Objectives The aim of this study was to confirm prior modeling data suggesting that prasugrel 5 mg in low-body-weight (LBW) patients would be noninferior to prasugrel 10 mg in higher-body-weight (HBW) patients as assessed by maximal platelet aggregation (MPA). Background Prasugrel 10 mg reduced ischemic events compared with clopidogrel 75 mg but increased bleeding, particularly in LBW patients. Methods In this blinded, 3-period, crossover study in stable patients with coronary artery disease (CAD) taking aspirin, prasugrel 5 and 10 mg and clopidogrel 75 mg were administered to LBW (56.4 ± 3.7 kg; n = 34) and HBW patients (84.7 ± 14.9 kg; n = 38). Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN), and vasodilator-associated stimulated phosphoprotein (VASP) level measured predose and after each 12-day treatment. Results Median MPA by LTA for prasugrel 5 mg in LBW patients was noninferior to the 75th percentile for prasugrel 10 mg in HBW patients (primary endpoint) and mean MPA was similar, but active metabolite exposure was lowered by 38%. Within LBW patients, prasugrel 5 mg lowered MPA more than clopidogrel (least squares mean difference [95% confidence interval]: −3.7% [−6.72%, −0.69%]) and resulted in lower rates of high on-treatment platelet reactivity (HPR). Within HBW patients, prasugrel 10 mg lowered MPA more than clopidogrel (−16.9% [−22.3%, −11.5%]). Similar results were observed by VN and VASP. Prasugrel 10 mg in LBW patients was associated with more mild to moderate bleeding (mainly bruising) compared with prasugrel 5 mg and clopidogrel. Conclusions In aspirin-treated patients with CAD, prasugrel 5 mg in LBW patients reduced platelet reactivity to a similar extent as prasugrel 10 mg in HBW patients and resulted in greater platelet inhibition, lower HPR, and similar bleeding rates compared with clopidogrel. (Comparison of Prasugrel and Clopidogrel in Low Body Weight Versus Higher Body Weight With Coronary Artery Disease [FEATHER]; NCT01107925 )

The treatment of acute ST elevation myocardial infarction (STEMI) has greatly improved in the last three decades, especially after the introduction of primary percutaneous coronary intervention (PCI). However, primary PCI is available in selected centres only, thus necessitating transportation of the STEMI patient. Improvement in the logistics of care for these patients is associated with significant improvement of patient outcome. Both the American Heart Association (AHA) and the European Society of Cardiology (ESC) STEMI guidelines recommend pre-hospital infarct diagnosis as a class I recommendation.w1 w2 Despite this, the large majority of STEMI patients are only diagnosed after arrival in the hospital.1 Therefore, great care should be taken in the initial diagnosis, risk assessment and triage, subsequent transfer and the distance of transportation as well as pre- and in-hospital time delays in these patients. STEMI patients can be diagnosed in the pre-hospital phase in two ways. The first option is diagnosis in the ambulance via an emergency medical services (EMS) call (118 or 911) by the patient or by a general practitioner. The second option is diagnosis at a referral non-PCI centre after self-referral of the patient or when no pre-hospital ECG is performed by EMS in the ambulance. Pre-hospital diagnosis in the ambulance gives the best outcomes for STEMI patients, since pre-hospital treatment can be started directly in the ambulance after diagnosis and triage.2 ,3 Subsequently, these patients are directly transferred in an ambulance from the pick-up place to the nearest PCI centre with 24/7 service, bypassing the emergency departments of the nearby referral non-PCI centres. The second option, diagnosis at a non-PCI centre, also occurs often, especially in rural areas. These patients are transported to a PCI centre, following diagnosis and triage of STEMI, preferably …

Item does not contain fulltext RATIONALE: Dual antiplatelet therapy with acetylsalicylic acid in combination with a more potent P2Y12- inhibitor (ticagrelor or prasugrel) is recommended in patients with acute coronary syndrome without ST-segment elevation (NSTE-ACS) to prevent atherothrombotic complications. The evidence on which this recommendation is based shows that ticagrelor and prasugrel reduce atherothrombotic events at the expense of an increase in bleeding events when compared with clopidogrel. However, it remains unclear whether ticagrelor or prasugrel has a better net clinical benefit in elderly patients with NSTE-ACS when compared with clopidogrel. The POPular AGE trial is designed to address the optimal antiplatelet strategy in elderly NSTE-ACS patients. STUDY DESIGN: POPular AGE is a multicenter, open-label, randomized controlled trial that aims to include 1000 patients >/=70years of age with NSTE-ACS. Patients are randomly assigned to receive either clopidogrel or a more potent P2Y12 inhibitor (ticagrelor or prasugrel). The first primary end point is any bleeding event requiring medical intervention. The second primary end point is the net clinical benefit, a composite of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, "PLATelet inhibition and patient Outcomes" major bleeding, or "PLATelet inhibition and patient Outcomes" minor bleeding. Patients will be followed for 1 year after randomization, and analyses will be performed on the basis of intention to treat. CONCLUSION: The POPular AGE is the first randomized controlled trial that will assess whether the treatment strategy with clopidogrel will result in fewer bleeding events without compromising the net clinical benefit in patients >/=70years of age with NSTE-ACS when compared with a treatment strategy with ticagrelor or prasugrel.

Numerous studies have shown the preventive effect of the use of dual antiplatelet therapy using acetylsalicylic acid and clopidogrel in reducing the risk of cardiovascular events in patients after acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI). Consequently every clinical guideline has incorporated the use of dual antiplatelet therapy for ACS and PCI patients: clopidogrel for 1 year and acetylsalicylic acid for life. Clopidogrel is a prodrug which needs several biotransformation steps using cytochrome (CYP) P450 liver enzymes before it acquires its antiplatelet effect. 1 After the activation steps clopidogrel irreversibly blocks the P2Y12 adenosine diphosphate receptor, which is a key mediator of platelet activation. However, despite the success of clopidogrel, making it the second most prescribed drug in the world, a substantial number of patients still suffer from recurrent atherothrombotic events after ACS with or without PCI. Stent thrombosis is an especially feared complication associated with substantial mortality (15% to 45% of cases).

CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC([0-tlast])), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC((0-tlast)) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [Cl]: 0.86,1.17, pgreater than0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, pless than0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures pless than0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons pless than0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all pless than0.001), and comparable effects in EMs (all p greater than= 0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg. Funding Agencies|Daiichi Sankyo Co., Ltd.; Eli Lilly and Company

Providing optimal care to patients with ST-segment elevated myocardial infarction is challenging. If a patient experiences chest pain and calls the emergency number, a cascade of actions is initiated that should lead to a diagnosis, start of treatment and reperfusion of the infarcted myocardium. This should all happen within 90 min after first medical contact, irrespective of the location of the patient or the time of day. The complex organization that is needed to achieve this goal in every ST-segment elevated myocardial infarction patient accounts for a fascinating interplay between prehospital and in-hospital care, in a situation when every minute counts. State-of-the-art care should be provided according to the latest insights and guidelines.

In the TRITON trial prasugrel 10 mg reduced ischemic events vs. clopidogrel 75 mg but increased bleeding, notably in patients with low body weight (LBW