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Aims Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. Methods and results A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor ( P = 1.1 × 10−6) and ARC ( P = 4.6 × 10−13). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10−15 and rs56324128, P = 9.7 × 10−12) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 ( P = 3.0 × 10−14) in UGT2B7 . At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. Conclusion In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci ( SLCO1B1 , UGT2B7 , and CYP3A4 ). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment. Clinical trial registration NCT00391872

AIMS: Optimal blood pressure for prevention of cardiovascular (CV) events in patients with Type 2 diabetes mellitus (T2DM) remains uncertain and there is concern for increased risk with low diastolic blood pressure (DBP). This study analysed the association between blood pressure and CV outcomes in high-risk patients with T2DM. METHODS AND RESULTS: Patients with T2DM and elevated CV risk were enrolled in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus—Thrombolysis in Myocardial Infarction 53 trial. Cardiovascular outcomes were compared in the biomarker subgroup (n = 12 175) after stratification by baseline systolic blood pressure (SBP) and DBP. Adjusted risk was calculated by blood pressure stratum using clinical covariates plus N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT). Trends were tested using linear and quadratic models. Adjusted risk of the composite endpoint of CV death, myocardial infarction (MI), or ischaemic stroke showed U-shaped relationships with baseline SBP and DBP (P(quadratic) ≤ 0.01) with nadirs at SBP 130–140 or DBP 80–90 mmHg. Diastolic blood pressure median, suggesting that the relationship was not due to confounding from diagnosed or undiagnosed heart failure. CONCLUSIONS: In patients with diabetes and elevated CV risk, even after extensive adjustment for underlying disease burden, there was a persistent association for low DBP with subclinical myocardial injury and risk of MI.

Aims To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed. Methods and results Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT usage between the two groups up to 4 years. At 4-year follow-up, the primary outcome occurred in 1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46–0.85), P = 0.003]. The composite of all-cause death or large MI occurred in 6.7% of E-ZES vs. 8.0% of C-SES-treated patients [HR 0.84 (95% CI 0.71–0.98), P = 0.024]. Conclusions Drug-eluting coronary stents with different healing characteristics demonstrated different late safety profiles: after 4 years, compared with C-SES, E-ZES reduced the risk of stent thrombosis and the risk of the composite endpoints of death or MI. Appropriately powered large-scale trials with long-term follow-up are critical to determine clinical safety and efficacy of permanently implanted coronary stents. This trial is registered with ClinicalTrials.gov, number [NCT00476957][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00476957&atom=%2Fehj%2Fearly%2F2014%2F08%2F07%2Feurheartj.ehu318.atom

Randomized clinical trials (RCTs) are the gold standard for building evidence. However, the strength of evidence in cardiovascular disease guidelines is not keeping pace with the number of emerging recommendations,1 perhaps reflecting the growing difficulties in developing adequately powered RCTs. In the context of secondary prevention after acute coronary syndromes (ACS), the increase in sample size needed to establish benefit, the rising costs, and the growing complexity of the regulatory environment and study logistics are challenging the development of new therapies. In response to these concerns, the European Society of Cardiology (ESC) convened an ad hoc meeting in May 2009. This paper summarizes the discussions and offers suggestions for improvement ( Table 1 ), which may complement previous proposals.2 [Note: the ideas presented are those of the individual participants (listed in the Appendix) and do not reflect the ideas of the participating bodies]. View this table: Table 1 Strategies to improve research on secondary prevention after acute coronary syndromes In spite of major advances, our understanding of the pathophysiology of coronary atherosclerosis progression and triggers of recurrent thrombotic events after ACS remains limited. To enhance therapeutic development, a clearer picture of coronary atherothrombosis is required. For that, large collaborative consortia between Pharma and acadaemia focused on pathophysiology, genetic epidemiology, new biomarkers, and other intermediate measurements, as well as clinical research on traditional outcomes are needed to better understand the natural history of coronary artery disease. The identification of new pathways and therapeutic targets, as well as the genetic, phenotypic, or behavioural causes underlying the wide individual variations in responses to therapies, particularly antithrombotic treatments should be prioritized. Traditional and new ways of research will be essential to achieve these objectives ( Table 1 ).3 Better ways are also needed to identify patients at high risk for coronary or other vascular recurrences as well as the …

Aims To determine 3-year event rates in outpatients with vascular disease enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry. Methods and results REACH enrolled 67 888 outpatients with atherothrombosis [established coronary artery disease (CAD), cerebrovascular disease, or peripheral arterial disease (PAD)], or with at least three atherothrombotic risk factors, from 44 countries. Among the 55 499 patients at baseline with symptomatic disease, 39 675 were eligible for 3-year follow-up, and 32 247 had data available (81% retention rate). Among the symptomatic patients at 3 years, 92% were taking an antithrombotic agent, 91% an antihypertensive, and 76% were on lipid-lowering therapy. For myocardial infarction (MI)/stroke/vascular death, 1- and 3-year event rates for all patients were 4.2 and 11.0%, respectively. Event rates (MI/stroke/vascular death) were significantly higher for patients with symptomatic disease vs. those with risk factors only at 1 year (4.7 vs. 2.3%, P < 0.001) and at 3 years (12.0 vs. 6.0%, P < 0.001). One and 3-year rates of MI/stroke/vascular death/rehospitalization were 14.4 and 28.4%, respectively, for patients with symptomatic disease. Rehospitalization for a vascular event other than MI/stroke/vascular death was common at 3 years (19.0% overall; 33.6% for PAD; 23.0% for CAD). For patients with symptomatic vascular disease in one vascular bed vs. multiple vascular beds, 3-year event rates for MI/stroke/vascular death/rehospitalization were 25.5 vs. 40.5% ( P < 0.001). Conclusion Despite contemporary therapy, outpatients with symptomatic atherothrombotic vascular disease experience high rates of recurrent vascular events and rehospitalizations.

Aims To evaluate the influence of achieving secondary prevention target treatment goals for cardiovascular (CV) risk factors on clinical outcomes in patients with prior coronary artery bypass surgery (CABG). Methods and results Accordingly, we analysed treatment to target goals in patients with prior CABG and atherothrombotic disease or known risk factors (diabetes, hypertension, hypercholesterolaemia, smoking, obesity) enrolled in the global REduction in Atherothrombosis for Continued Health (REACH) Registry, and their association with 1 year outcomes. A total of 13 907 of 68 236 patients (20.4%) in REACH had a history of prior CABG, and 1 year outcomes data were available for 13 207 of these. At baseline 75% risk factors at goal, respectively; P for trend 0.059). Conclusion Risk-factor control varied greatly in CABG patients. Although CABG patients are frequently treated with appropriate therapies, these treatments fail to achieve an adequate level of prevention in many. This failure was associated with a trend for worse age-, gender-, and region-adjusted clinical outcomes. Thus, perhaps secondary prevention after CABG needs to focus on more comprehensive modification of risk factors to target goals in the hope of preventing subsequent CV events, and represents an opportunity to improve CV health.

To determine the relationship between anticoagulation levels during percutaneous coronary intervention, and ischaemic events and bleeding.A sub-analysis from the STEEPLE trial was conducted. Pre-defined target anticoagulation levels were achieved in 86% of patients receiving enoxaparin, compared with 20% receiving unfractionated heparin (UFH) (P0.001). A significant relationship was observed between anti-Xa levels0.9 IU/mL and covariate-adjusted rate of non-coronary artery bypass graft-related major and minor bleeding [odds ratio (OR) 1.6, 95% CI 1.0-2.5 for each unit of anti-Xa; P = 0.03]; anti-Xa levels and covariate-adjusted incidence of death, myocardial infarction, or revascularization showed no significance (P = 0.47). Major bleeding increased significantly with an activated clotting time (ACT)325 s (OR 1.6, 95% CI 1.1-2.2 per 100 s; P = 0.04). A significant relationship with increasing ischaemic events was observed when ACT was325 s (OR 0.7, 95% CI 0.2-0.8 per 100 s; P = 0.006) indicating a narrow therapeutic window.Target anticoagulation levels were achieved more readily in patients receiving enoxaparin. An anti-Xa level of up to 0.9 IU/mL has a good safety and efficacy profile; poor achievement of target ACT with UFH makes assessing the optimal range difficult.

Aims Men and women differ in terms of presentation and management in coronary artery disease (CAD). Whether these differences translate into different clinical outcomes in stable CAD is unclear. We analysed data from the international prospective CLARIFY registry to compare cardiovascular clinical outcomes in men and women with stable CAD.\ud \ud Methods and results We analysed 1-year outcomes in 30 977 outpatients with stable CAD [23 975 (77.4%) men; 7002 (22.6%) women]. Women were older than men, more likely to have hypertension and diabetes, and less likely to exercise or smoke. They had more frequent angina, but were less likely to have undergone diagnostic non-invasive testing or coronary angiography. Women received less optimized treatment for stable CAD. One-year outcomes were similar for men and women for the composite of cardiovascular death, non-fatal myocardial infarction, or stroke [adjusted rates 1.7 vs. 1.8%, respectively, odds ratio (OR) 0.93, 95% confidence interval (CI) 0.75–1.15]; all-cause death (adjusted 1.5 vs. 1.6%, OR: 0.91, 95% CI: 0.72–1.13); fatal or non-fatal myocardial infarction (adjusted 1.0 vs. 0.9%, OR: 0.81, 95 CI: 0.60–1.08); and cardiovascular death or non-fatal myocardial infarction (adjusted 1.4 vs. 1.4%, OR: 0.89, 95% CI: 0.70–1.12). Fewer women underwent revascularization (2.6 vs. 2.2%, OR: 0.77, 95% CI: 0.64–0.93), although appropriateness was not analysed.1522-9645\ud \ud Conclusion The risk profiles of women and men with stable CAD differ substantially. However, 1-year outcomes were similar. Fewer women underwent revascularization. Further research is needed to better understand gender determinants of outcome and devise strategies to minimize bias in the management and treatment of women.

Aims To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS). Methods In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia. Results Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13–4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose–response relationship ( P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. ( P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity. Conclusions Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: [NCT00994292][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00994292&atom=%2Fehj%2Fearly%2F2011%2F08%2F27%2Feurheartj.ehr334.atom

Aims In acute coronary syndromes (ACS), the optimal revascularization strategy for unprotected left main coronary disease (ULMCD) has been little studied. The objectives of the present study were to describe the practice of ULMCD revascularization in ACS patients and its evolution over an 8-year period, analyse the prognosis of this population and determine the effect of revascularization on outcome. Methods and results Of 43 018 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, 1799 had significant ULMCD and underwent percutaneous coronary intervention (PCI) alone ( n = 514), coronary artery bypass graft (CABG) alone ( n = 612), or no revascularization ( n = 673). Mortality was 7.7% in hospital and 14% at 6 months. Over the 8-year study, the GRACE risk score remained constant, but there was a steady shift to more PCI than CABG over time. Patients undergoing PCI presented more frequently with ST-segment elevation myocardial infarction (STEMI), after cardiac arrest, or in cardiogenic shock; 48% of PCI patients underwent revascularization on the day of admission vs. 5.1% in the CABG group. After adjustment, revascularization was associated with an early hazard of hospital death vs. no revascularization, significant for PCI (hazard ratio (HR) 2.60, 95% confidence interval (CI) 1.62–4.18) but not for CABG (1.26, 0.72–2.22). From discharge to 6 months, both PCI (HR 0.45, 95% CI 0.23–0.85) and CABG (0.11, 0.04–0.28) were significantly associated with improved survival in comparison with an initial strategy of no revascularization. Coronary artery bypass graft revascularization was associated with a five-fold increase in stroke compared with the other two groups. Conclusion Unprotected left main coronary disease in ACS is associated with high mortality, especially in patients with STEMI and/or haemodynamic or arrhythmic instability. Percutaneous coronary intervention is now the most common revascularization strategy and preferred in higher risk patients. Coronary artery bypass graft is often delayed and performed in lower risk patients, leading to good 6-month survival. The two approaches therefore appear complementary.