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Aims: Clinical guidelines recommend de-escalation antiplatelet strategies to reduce bleeding risk in acute coronary syndrome (ACS) patients, albeit with a weak recommendation. This substudy of the TROPICAL-ACS trial aimed to determine the impact of body mass on the efficacy of a platelet function testing-guided de-escalation regimen in ACS patients after percutaneous coronary intervention., Methods and Results: Patients were randomized to prasugrel (control group) or a platelet function testing-guided regimen with clopidogrel or prasugrel defined after 1-week clopidogrel. The primary endpoint was the net clinical benefit [cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium (BARC) 2-5 bleeding] for 12 months. Overweight was defined as a body mass index >25 kg/m2.Patients without overweight showed a significant net clinical benefit from the de-escalation strategy, while in overweight cases de-escalation was comparable to prasugrel treatment [hazard ratio (HR): 0.52; 95% confidence interval (CI): 0.31-0.88; P = 0.013 and HR: 0.95; 95% CI: 0.69-1.31, P = 0.717, P-non-inferiority = 0.03, respectively, P-interaction = 0.053]. The benefit of de-escalation in terms of the risk of bleeding or of the ischaemic events did not reach statistical significance. Bleeding events with de-escalation were less frequent in non-overweight patients but comparable in overweight patients (HR: 0.55; 95% CI: 0.30-1.03; P = 0.057 and HR: 0.95; 95% CI: 0.64-1.41, respectively, P-interaction = 0.147). Non-overweight patients had lower ischaemic event rates with de-escalation, while overweight cases had slightly less (HR: 0.47; 95% CI: 0.18-1.25; P = 0.128 and HR: 0.89; 95% CI: 0.53-1.50, respectively, P-interaction = 0.261)., Conclusion: The strategy of guided dual antiplatelet therapy de-escalation was associated with a significant net clinical benefit in non-overweight patients, while the two strategies were equivalent in overweight patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). De-escalation of the potent P2Y12 inhibtor is an appealing concept to balance the ischaemic and bleeding risks after PCI. An individual patient data meta-analysis was performed to compare de-escalation versus standard DAPT in patients with ACS., Methods and Results: Electronic databases, including PubMed, Embase, and the Cochrane database, were searched to identify randomised clinical trials (RCTs) comparing the de-escalation strategy with the standard DAPT after PCI in patients with ACS. Individual patient-level data were collected from the relevant trials. The co-primary endpoints of interest were the ischaemic composite endpoint (a composite of cardiac death, myocardial infarction, and cerebrovascular events) and bleeding endpoint (any bleeding) at 1-year post-PCI. Four RCTs (the TROPICAL-ACS, POPular Genetics, HOST-REDUCE-POLYTECH-ACS, and TALOS-AMI trials) including 10 133 patients were analysed. The ischaemic endpoint was significantly lower in the patients assigned to the de-escalation strategy than in those assigned to the standard strategy (2.3% vs. 3.0%, hazard ratio [HR] 0.761, 95% confidence interval [CI] 0.597-0.972, log rank P = 0.029). Bleeding was also significantly lower in the de-escalation strategy group (6.5% vs. 9.1%, HR 0.701, 95% CI 0.606-0.811, log rank P < 0.001). No significant intergroup differences were observed in terms of all-cause death and major bleeding events. Subgroup analyses revealed that compared to guided de-escalation, unguided de-escalation had a significantly larger impact on bleeding endpoint reduction (P for interaction = 0.007); no intergroup differences were observed for the ischaemic endpoints., Conclusion: In this individual patient data meta-analysis, DAPT-based de-escalation was associated with both decreased ischaemic and bleeding endpoints. Reduction in bleeding endpoints was more prominent for the unguided than the guided de-escalation strategy., Study Registration Number: This study was registered in the PROSPERO (ID: CRD42021245477)., Competing Interests: Conflict of interest K.W.P. reports speaker fees from Daichi Sankyo, InnoN Pharmaceutical, and DaeWoong Pharmaceutical, outside of the submitted work. All other authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults., Competing Interests: Conflict of interest: The authors declare that none received specific funding in relation to the work: ‘Acute, periprocedural and longterm antithrombotic therapy in older adults: 2022 Update by the ESC Working Group on Thrombosis’ by Felicita Andreotti, Tobias Geisler, Jean-Philippe Collet, Bruna Gigante, Diana A Gorog, Sigrun Halvorsen, Gregory YH Lip, Joao Morais, Eliano Pio Navarese, Carlo Patrono, Bianca Rocca, Andrea Rubboli, Dirk Sibbing, Robert F. Storey, Freek W.A. Verheugt, and Gemma Vilahur., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Whilst there is a clear clinical benefit of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in reducing the risks of thromboembolism, major bleeding events (especially intracranial bleeds) may still occur and be devastating. The decision to initiate and continue anticoagulation is often based on a careful assessment of both the thromboembolism and bleeding risk. The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but thromboembolism and bleeding risk factors often overlap. Also, many factors that increase bleeding risk are transient and modifiable, such as variable international normalized ratio values, surgical procedures, vascular procedures, or drug-drug and food-drug interactions. Bleeding risk is also not a static 'one off' assessment based on baseline factors but is dynamic, being influenced by ageing, incident comorbidities, and drug therapies. In this Consensus Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in patients with AF and VTE, with the view to summarizing 'best practice' when approaching antithrombotic therapy in these patients. We address the epidemiology and size of the problem of bleeding risk in AF and VTE, review established bleeding risk factors, and summarize definitions of bleeding. Patient values and preferences, balancing the risk of bleeding against thromboembolism are reviewed, and the prognostic implications of bleeding are discussed. We propose consensus statements that may help to define evidence gaps and assist in everyday clinical practice., Competing Interests: Conflict of interest: A.R.: speaker for Bayer, Daiichi-Sankyo, and Boehringer-Ingelheim. D.A.G.: grants from Bayer, Medtronic. Speaker for Bayer, Boehringer-Ingelheim, and AstraZeneca. D.L.: grants from BMS and Boehringer-Ingelheim; consultant and speaker for BMS, Boehringer-Ingelheim, and Bayer. F.M.: consultant and speaker for AstraZeneca and Boehringer-Ingelheim; grants from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo. G.V.: speaker for AstraZeneca. G.Y.H.L.: consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally. H.F.T.: grants from Abbott, Amgen, AstraZeneca, Bayer, Cooks Medical, Boehringer Ingelheim, Boston Scientific, Daichi Sankyo, Medtronic, Novartis, Pfizer, and Sanofi. J.L.F.: Speaker for AstraZeneca, Ferrer, Pfizer, Abbott Medical, Boehringer Ingelheim, Daiichi Sankyo, BMS, and Royi. K.H.: speaker for AstraZeneca, Bayer, and Boehringer-Ingelheim. L.F.: consultant and speaker activities for AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic, Novartis, Novo, and XO. The other authors have no conflict of interest to declare., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Aims: Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS., Methods and Results: We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments., Conclusion: In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS., Study Registration Number: This study is registered in PROSPERO (CRD42021258603)., Key Question: A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored., Key Finding: In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality., Take Home Message: A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

The aim of this collaborative document is to provide an update for clinicians on best antithrombotic strategies in patients with aortic and/or peripheral arterial diseases. Antithrombotic therapy is a pillar of optimal medical treatment for these patients at very high cardiovascular risk. While the number of trials on antithrombotic therapies in patients with aortic or peripheral arterial diseases is substantially smaller than for those with coronary artery disease, recent evidence deserves to be incorporated into clinical practice. In the absence of specific indications for chronic oral anticoagulation due to concomitant cardiovascular disease, a single antiplatelet agent is the basis for long-term antithrombotic treatment in patients with aortic or peripheral arterial diseases. Its association with another antiplatelet agent or low-dose anticoagulants will be discussed, based on patient's ischaemic and bleeding risk as well therapeutic paths (e.g. endovascular therapy). This consensus document aims to provide a guidance for antithrombotic therapy according to arterial disease localizations and clinical presentation. However, it cannot substitute multidisciplinary team discussions, which are particularly important in patients with uncertain ischaemic/bleeding balance. Importantly, since this balance evolves over time in an individual patient, a regular reassessment of the antithrombotic therapy is of paramount importance., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used 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 were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Timely 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Stroke is a common and devastating condition caused by atherothrombosis, thromboembolism, or haemorrhage. Patients with chronic coronary syndromes (CCS) or peripheral artery disease (PAD) are at increased risk of stroke because of shared pathophysiological mechanisms and risk-factor profiles. A range of pharmacological and non-pharmacological strategies can help to reduce stroke risk in these groups. Antithrombotic therapy reduces the risk of major adverse cardiovascular events, including ischaemic stroke, but increases the incidence of haemorrhagic stroke. Nevertheless, the net clinical benefits mean antithrombotic therapy is recommended in those with CCS or symptomatic PAD. Whilst single antiplatelet therapy is recommended as chronic treatment, dual antiplatelet therapy should be considered for those with CCS with prior myocardial infarction at high ischaemic but low bleeding risk. Similarly, dual antithrombotic therapy with aspirin and very-low-dose rivaroxaban is an alternative in CCS, as well as in symptomatic PAD. Full-dose anticoagulation should always be considered in those with CCS/PAD and atrial fibrillation. Unless ischaemic risk is particularly high, antiplatelet therapy should not generally be added to full-dose anticoagulation. Optimization of blood pressure, low-density lipoprotein levels, glycaemic control, and lifestyle characteristics may also reduce stroke risk. Overall, a multifaceted approach is essential to best prevent stroke in patients with CCS/PAD., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Aims: Prior analyses disclosed variations in antiplatelet drug response and clinical outcomes between smokers and non-smokers, thus the safety and efficacy of any dual antiplatelet therapy (DAPT) de-escalation strategy may differ in relation to smoking status. Hence, we assessed the impact of smoking on clinical outcomes and adenosine diphosphate-induced platelet aggregation following guided de-escalation of DAPT in invasively managed acute coronary syndrome (ACS) patients., Methods and Results: The multicentre TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to standard treatment with prasugrel for 12 months (control group) or a platelet function testing guided de-escalation of DAPT. Current smokers (n = 1182) showed comparable event rates between study groups [6.6% vs. 6.6%; hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.64-1.56, P > 0.99]. In non-smokers (n = 1428), a guided DAPT de-escalation was associated with a lower 1-year incidence of the primary endpoint [cardiovascular death, myocardial infarction, stroke, or bleeding ≥ Grade 2 according to Bleeding Academic Research Consortium (BARC) criteria] compared with control group patients (7.9% vs. 11.0%; HR 0.71, 95% CI 0.50-0.99, P = 0.048). This reduction was mainly driven by a lower rate of BARC ≥ Grade 2 bleedings (5.2% vs. 7.7%; HR 0.68, 95% CI 0.45-1.03, P = 0.066). There was no significant interaction of smoking status with treatment effects of guided DAPT de-escalation (Pint = 0.23). Adenosine diphosphate-induced platelet aggregation values were higher in current smokers [median 28 U, interquartile range (IQR: 20-40)] vs. non-smoker [median 24 U (16-25), P < 0.0001] in the control group and in current smokers [median 42 U, IQR (27-68)] vs. non-smoker [median 37 U, IQR (25-55), P < 0.001] in the monitoring group., Conclusion: Guided DAPT de-escalation appears to be equally safe and effective in smokers and non-smokers. Regardless of smoking status and especially for those patients deemed unsuitable for 1 year of potent platelet inhibition this DAPT strategy might be used as an alternative antiplatelet treatment regimen., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

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., (The article has been co-published with permission in the European Heart Journal and EuroIntervention. All rights reserved. © The Author(s) 2018. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article.)

Aims: The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel., Methods and Results: Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2-5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57-1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47-1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01-4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18-2.56), P = 0.005], without interaction (Pint = 0.76) between study groups., Conclusion: Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Guided de-escalation of P2Y12-inhibitor treatment was recently identified as an effective alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention. Safety and efficacy of this strategy may differ in relation to patient's age. This pre-specified analysis of the TROPICAL-ACS trial aimed to assess the impact of age on clinical outcomes following guided de-escalation of antiplatelet treatment in ACS patients., Methods and Results: Patients were randomly assigned in a 1:1 fashion to either standard treatment with prasugrel for 12 months (control group) or to a guided de-escalation regimen (1 week prasugrel followed by 1 week clopidogrel and platelet function testing guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). We used Cox regression models to assess the associations of age on clinical endpoints and interactions. In younger patients (age ≤70, n = 2240), the 1 year incidence of the primary endpoint (cardiovascular death, myocardial infarction, stroke, or bleeding ≥ grade 2 according to Bleeding Academic Research Consortium criteria) was significantly lower in guided de-escalation vs. control group [5.9% vs. 8.3%; hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.51-0.96; P = 0.03, number needed to treat = 42]. In elderly patients (age >70, n = 370), the absolute risk of events was higher without significant differences between guided de-escalation vs. control group (15.5% vs. 13.6%; HR 1.17, 95% CI 0.69-2.01; P = 0.56). When the impact of age, as a continuous variable, was analysed on outcomes after guided de-escalation vs. control treatment, an increasing relative risk reduction was observed in the primary endpoint by decreasing age (Pint = 0.02), due to significant reductions in bleeding., Conclusion: Treatment effects of guided de-escalation for P2Y12 inhibitors depend on patient's age with younger patients deriving a significant net clinical benefit. Although the safety and efficacy of guided de-escalation in the elderly was similar to uniform prasugrel therapy, this should be further investigated due to the limited sample size of this group.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12receptor inhibitor is the mainstay of treatment for acute coronary syndrome (ACS) patients, whether they undergo a percutaneous coronary intervention (PCI) or are managed medically. In recent years, the most appropriate timing for initiation and duration of P2Y12receptor inhibition has been a focus of great interest. Many observational studies and a single prospective trial (CREDO) utilizing clopidogrel had focused on whether pre-treatment with clopidogrel, i.e. its administration upstream of coronary angiography and PCI, is beneficial. Although the rationale for pre-treatment is obvious, large-scale randomized trials supporting a pre-treatment strategy with clopidogrel or with the newer P2Y12inhibitors prasugrel and ticagrelor did not exist. Proponents of a pre-treatment strategy had to rely on their best guess, on non-randomized studies, or on negative studies in which a trend for a benefit had been demonstrated. Recently, however, two randomized trials directly evaluated the value of pre-treatment-one in patients with a non-STE elevation myocardial infarction (NSTEMI)-the Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) trial, and a second trial evaluating the use of ticagrelor in ST-elevation myocardial infarction (STEMI) patients, the Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST-elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial. Neither of the two trials, however, answered all the questions clinicians have about pre-treatment. And given the recent approval of the intravenous and rapidly acting P2Y12inhibitor cangrelor, the choice of who should receive treatment with a P2Y12inhibitor, which one should be used, and when it should be administered, should be carefully re-evaluated for all patients. This clinical review aims at evaluating the available evidence regarding the value of pre-treatment with the now four available oral and intravenous P2Y12inhibitors that can be administered to patients in whom coronary angiography followed by a possible PCI is planned., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices., Methods and Results: Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as <95, 95-208, and >208 PRU for VerifyNow, <19, 19-46, and >46 U for the Multiplate analyser and <16, 16-50, and >50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71-0.99), P = 0.04] compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47-2.06), P < 0.00001], without any further benefit in ST [RR: 1.06 (0.68-1.65), P = 0.78] in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3)., Conclusions: Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: In clopidogrel-treated patients undergoing coronary stenting, high on-treatment platelet reactivity was linked to a higher risk of stent thrombosis (ST). Platelet response to clopidogrel is significantly influenced by genetic factors. Recently published findings showed a highly significant impact of a common polymorphism (Q192R) within the paraoxonase-1 (PON1) gene on clopidogrel treatment efficacy but no influence of the CYP2C19*2 genetic variant as previously demonstrated. The aim of this study was to assess the impact of the PON1 Q192R genotype in parallel to that of CYP2C19*2 on the antiplatelet effect of clopidogrel and the risk of ST in clopidogrel-treated patients., Methods and Results: In 1524 patients undergoing percutaneous coronary intervention, ADP-induced platelet aggregation was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. The clinical impact of genetic variants was investigated by comparing genotype frequencies of both genetic variants in a registry of 127 cases with early ST vs. an early ST-free control cohort (n = 1439). For PON1 Q192R genotypes, platelet aggregation values were similar across all genotype groups (P = 0.65). For CYP2C19*2 genotypes, significantly higher aggregation values were found in CYP2C19 wt/*2 and *2/*2 patients when compared with wt/wt allele carriers (P < 0.0001). Comparing genotype frequencies between ST cases and controls, no differences were observed for PON1 Q192R genotype distributions (P = 0.23), whereas the genotype distribution differed for CYP2C19*2 genotypes (P = 0.019)., Conclusion: The PON1 Q192R genotype did not influence platelet response to clopidogrel or the risk of ST in clopidogrel-treated patients, whereas the CYP2C19*2 genotype impacted on both antiplatelet effect of clopidogrel and risk of coronary ST.

Aims: Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases., Methods and Results: Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism., Conclusion: For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden.

Aims: A relevant proportion of patients receiving aspirin and clopidogrel after percutaneous coronary intervention (PCI) also require oral anticoagulation with a coumarin derivative such as phenprocoumon. Both clopidogrel and phenprocoumon are metabolized by the hepatic cytochrome P450 system and a drug-drug interaction may exist at this level. The aim of this study was to investigate the impact of phenprocoumon on the antiplatelet effects of clopidogrel in patients with coronary artery disease., Methods and Results: Patients (n = 1223) eligible for this study were under dual maintenance antiplatelet treatment with aspirin and clopidogrel. Adenosine diphosphate-induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry on a Multiplate analyzer (Dynabyte, Munich, Germany). From the entire study population, 124 (10.1%) patients were under concomitant phenprocoumon treatment at the time point of platelet function testing. Platelet aggregation (median [interquartile range]) was significantly higher in patients with (n = 124) concomitant phenprocoumon treatment compared with patients without (n = 1099) phenprocoumon treatment (308 [190-493] AU*min vs. 224 [145-390] AU*min; P = 0.0001, adjusted P = 0.002)., Conclusion: Phenprocoumon significantly attenuates the antiplatelet effects of clopidogrel. The impact of this interaction on the risk of thrombotic and bleeding events after PCI requires further investigations.

Aims: Several studies have demonstrated that the mutant *2 allele of the CYP2C19 681G>A loss-of-function polymorphism is associated with diminished metabolization of clopidogrel into its active thiol metabolite and an attenuated platelet response to clopidogrel treatment. It is not known whether patients carrying the mutant CYP2C19*2 allele have a higher risk of stent thrombosis (ST) compared with homozygous CYP2C19*1 wild-type allele carriers following percutaneous coronary intervention (PCI). The aim of this study was to assess the impact of the CYP2C19 681G>A loss-of-function polymorphism on ST following PCI performed after pre-treatment with clopidogrel., Methods and Results: The study population included 2485 consecutive patients undergoing coronary stent placement after pre-treatment with 600 mg of clopidogrel. Genotypes were determined with a TaqMan assay. The primary endpoint of the study was the incidence of definite ST within 30 days following PCI. Of the patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes (*1/*1) and 680 (27%) carried at least one *2 allele (*1/*2 or *2/*2). The cumulative 30-day incidence of ST was significantly higher in CYP2C19*2 allele carriers (*1/*2 or *2/*2) vs. CYP2C19 wild-type homozygotes (*1/*1) [10 patients (1.5%) in CYP2C19*2 allele carriers vs. 7 (0.4%) in CYP2C19 wild-type homozygotes (*1/*1), HR 3.81, 95% CI 1.45-10.02, P = 0.007; P = 0.006 after adjustment for confounding variables]. The risk of ST was highest (2.1%) in patients with the CYP2C19 *2/*2 genotype (P = 0.002)., Conclusion: CYP2C19*2 carrier status is significantly associated with an increased risk of ST following coronary stent placement.

Aims: The aim of this study was to assess the impact of bivalirudin or unfractionated heparin (UFH) on platelet aggregation in patients, pretreated with a 600 mg loading dose clopidogrel, undergoing elective percutaneous coronary intervention (PCI)., Methods and Results: Patients (n = 100) were recruited consecutively in the setting of a double-blind, randomized trial. Bivalirudin or UFH was administered during PCI. Blood was drawn immediately before PCI, following administration of bivalirudin or UFH directly after PCI, and 24 h after PCI. Adenosine diphosphate (ADP)-induced platelet aggregation was assessed with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA). Before PCI, ADP-induced platelet aggregation was similar in UFH and bivalirudin patients (P = 0.99 for LTA; P = 0.28 for MEA). Administration of bivalirudin during PCI resulted in significant additional suppression of platelet aggregation (P = 0.012 for LTA; P = 0.008 for MEA). Administration of UFH did not have a significant influence on platelet aggregation (P = 0.42 for LTA; P = 0.78 for MEA). Platelet aggregation was again similar in the two groups 24 h after PCI (P > 0.05 for LTA and MEA)., Conclusion: Bivalirudin, given during PCI in patients pretreated with 600 mg of clopidogrel, is in contrast to UFH associated with further inhibition of platelet aggregation.

Aims: We sought to test whether an increase in the clopidogrel maintenance dose results in increased inhibition of platelet aggregation., Methods and Results: Sixty patients after pre-treatment with 600 mg of clopidogrel and within 12 h after successful PCI were included in this trial. They were allocated to receive one of two clopidogrel daily maintenance doses (75 or 150 mg) for 30 days in a double-blind randomized manner. Platelet function was evaluated 30 days after the intervention with optical aggregometry and with a new point-of-care test (VerifyNowtrade mark P2Y12 assay). Maximal 5 microM ADP-induced platelet aggregation 30 days after PCI in the group treated with 150 mg/day clopidogrel (45.1 +/- 20.9%) was significantly lower than in the group treated with 75 mg/day (65.3 +/- 12.1%; P < 0.001). The VerifyNowtrade mark P2Y12 assay also indicated a higher degree of platelet function inhibition in the group treated with 150 mg/day (60.0 +/- 72.0 P2Y12 Reaction Units) than in the group treated with 75 mg/day (117.0 +/- 64.3 P2Y12 Reaction Units; P = 0.004)., Conclusion: Administration of a 150 mg oral maintenance dose of clopidogrel results in more intense inhibition of platelet aggregation than administration of the currently recommended 75 mg maintenance dose.