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not availableTimely and effective antithrombotic therapy is critical to improving outcome, including survival, in patients with acute coronary syndrome (ACS). Achieving effective platelet inhibition and anticoagulation, with minimal risk, is particularly important in high-risk ACS patients, especially those with cardiogenic shock (CS) or those successfully resuscitated following out-of-hospital cardiac arrest (OHCA), who have a 30-50% risk of death or a recurrent ischaemic event over the subsequent 30 days. There are unique challenges to achieving effective and safe antithrombotic treatment in this cohort of patients that are not encountered in most other ACS patients. This position paper focuses on patients presenting with CS or immediately post-OHCA, of presumed ischaemic aetiology, and examines issues related to thrombosis and bleeding risk. Both the physical and pharmacological impacts of CS, namely impaired drug absorption, metabolism, altered distribution and/or excretion, associated multiorgan failure, co-morbidities and co-administered treatments such as opiates, targeted temperature management, renal replacement therapy and circulatory or left ventricular assist devices, can have major impact on the effectiveness and safety of antithrombotic drugs. Careful attention to the choice of antithrombotic agent(s), route of administration, drug-drug interactions, therapeutic drug monitoring and factors that affect drug efficacy and safety, may reduce the risk of sub- or supra-therapeutic dosing and associated adverse events. This paper provides expert opinion, based on best available evidence, and consensus statements on optimising antithrombotic therapy in these very high-risk patients, in whom minimising the risk of thrombosis and bleeding is critical to improving outcome.

Coronary artery disease (CAD) is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive. This process can be modified by lifestyle adjustments, pharmacological therapies, and invasive interventions designed to achieve disease stabilization or regression. The disease can have long, stable periods but can also become unstable at any time, typically due to an acute atherothrombotic event caused by plaque rupture or erosion. However, the disease is chronic, most often progressive, and hence serious, even in clinically apparently silent periods. The dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either acute coronary syndromes (ACS) or chronic coronary syndromes (CCS). The Guidelines presented here refer to the management of patients with CCS. The natural history of CCS is illustrated in Figure 1.

Coronary bifurcations exhibit localized turbulent flow and enhanced propensity for platelet deposition, plaque rupture, and atherothrombosis. Percutaneous coronary intervention (PCI) of bifurcation lesions is associated with an increased risk of thrombotic events. Such risk is modulated by anatomical complexity, intraprocedural factors and pharmacological therapy. There is no consensus on the appropriate PCI strategy or the optimal regimen and duration of antithrombotic treatment in order to decrease the risk of ischemic and bleeding complications in the setting of coronary bifurcation. A uniform therapeutic approach meets a clinical need. The present initiative, promoted by the European Bifurcation Club (EBC), involves opinion leaders from Europe, America, and Asia with the aim to analyze the currently available evidence. Although mainly derived from sub-studies of large trials or small studies, or from authors' opinions, an algorithm for the optimal management of patients undergoing bifurcation PCI, developed on the basis of clinical presentation, bleeding risk, and intraprocedural strategy is here proposed.

Nach einer Koronarintervention erhalten Patienten eine duale antithrombozytäre Therapie mit ASS und Clopidogrel um das peri- und postinterventionelle Risiko thrombotischer Komplikationen zu reduzieren. Für Clopidogrel ist das individuelle Ansprechen auf die Behandlung jedoch nicht einheitlich. Vor allem das polymorph exprimierte Leberenzym CYP2C19 hat einen Einfluss auf die in vivo Wirkung von Clopidogrel. Ziel dieser Arbeit war es den isolierten und wechselseitigen Einfluss von zwei häufigen CYP-Allelen (CYP2C19*2 und CYP2C19*17) auf die Metabolisierung und damit auf die Aktivierung von Clopidogrel zu untersuchen und einen Zusammenhang mit ischämischen Ereignissen (*2) oder Blutungskomplikationen (*17) aufzuzeigen. Zusätzlich wurde die Wechselwirkung von Clopidogrel mit Omeprazol auf die Werte der ADP-induzierten Thrombozytenaggregation untersucht. Neben der Genotypisierung auf die zwei untersuchten Allele erfolgten Messungen der ADP-induzierten Thrombozytenaggregation mittels Multiplate Analyzer. Abhängig vom jeweiligen Genotypen und der hierdurch veränderten Metabolisierung von Clopidogrel zeigte sich ein gesteigertes Blutungsrisiko bei Patienten mit *17-Trägerstatus bzw. ein erhöhtes Risiko für ischämische Komplikationen wie Stentthrombosen für Patienten mit der *2-Allelvariante. Hinsichtlich des Einflusses von Omeprazol zeigte sich eine allelunabhängige, hemmende Wirkung auf den Clopidogrelmetabolismus., After coronary interventions patients get treated with a dual antiplatelet therapy with ASS and Clopidogrel to reduce the peri- and postinterventional risk for thrombotic complications. It is known that there is an individual, non uniform response to treatment with Clopidogrel. Especially the polymorphically expressed liver enzyme CYP2C19 has influence on the Clopidogrel metabolism and therefore its effects in patients. Aim of these two studies has been to inquire the isolated and mutual influence of the two most common CYP-alleles (CYP2C19*2 and CYP2C19*17) on the Clopidogrel metabolism by examinating the activation of Clopidogrel depending on the genotype and thereby to show a connection to ischemic events (*2) or bleedings (*17). Furthermore the interaction of Clopidogrel and Omeprazol regarding its effect on the ADP-induced platelet aggregation has been object of these studies. The alleles were identified by genotyping, platelet function was tested with the Multiplate Analyzer. Depending on the genotype and the hereby changed metabolism there is a higher risk for bleeding in patients carrying the *17-allel respectively an increased risk for ischemic events like stent thrombosis for *2-carriers. Concerning the influence of an interactive effect of Clopidogrel and Omeprazol, it was possible to show an independently inhibitory effect on the Clopidogrel metabolism.

Unter 2485 Stent-Patienten unter dualer Thrombozyten-Aggregationshemmung mit Aspirin und Clopidogrel erlitten CYP2C19*2-Träger signifikant häufiger Stent-Thrombosen, ST-Hebungsinfarkte und ischämische zerebrale Insulte als Wildtyp-Homozygote. An 69 Stent-Patienten zeigte sich über 8 Wochen durch wiederholte Thrombozyten-Aggregationsmessungen mittels Lichttransmissions-Aggregometrie und Multiple Electrode Aggregometrie kein Vorteil eines ausschleichenden versus abrupten Absetzens von Clopidogrel., In 2485 patients receiving coronary stents under dual antiplatelet therapy with aspirin and clopidogrel carriers of the CYP2C19*2 allele suffered significantly more frequently under stent thrombosis, STEMI and ischaemic stroke than wildtype-homozygotes. In 69 Stent-Patients weekly platelet function tests over 8 weeks with light-transmission aggregometry and multiple electrode aggregometry showed no benefit of a tapering versus an abrupt cessation of clopidogrel treatment.

Aim A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention. Methods and results The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU.min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203AU.min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered. Conclusion We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.

The presence of a patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions; however, the subject remains controversial and no official statements have been published. This interdisciplinary paper, prepared with involvement of eight European scientific societies, aims to review the available trial evidence and to define the principles needed to guide decision making in patients with PFO. In order to guarantee a strict process, position statements were developed with the use of a modified grading of recommendations assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements of particular management options were weighed and graded according to predefined scales. Despite being based often on limited and non-randomised data, while waiting for more conclusive evidence, it was possible to conclude on a number of position statements regarding a rational general approach to PFO management and to specific considerations regarding left circulation thromboembolism. For some therapeutic aspects, it was possible to express stricter position statements based on randomised trials. This position paper provides the first largely shared, interdisciplinary approach for a rational PFO management based on the best available evidence.