Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and the Netherlands: insights from the ETNA-AF-Europe study.

BACKGROUND: Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. METHODS: With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50 ml/min, weight ≤60 kg, and/or use of strong p­glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). RESULTS: Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. CONCLUSION: There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. TRIAL REGISTRATION: NCT02944019; Date of registration 24 October 2016.

Increased left atrial size in obese children and its association with insulin resistance: a pilot study.

Subclinical cardiac abnormalities represent predisposing factors for cardiovascular disease (CVD) in obese subjects. The aim of this study was to evaluate early cardiac abnormalities in obese youth and the potential association with insulin resistance (IR). Thirty obese (12 males (M)/18 females (F); age = 11.5 ± 2.4 years; body mass index (BMI)-standard deviation score (SDS) = +2.1 ± 0.5) and 15 normal weight (10 M/5 F; age = 12.8 ± 3.1 years; BMI-SDS = +0.3 ± 0.9) children and adolescents underwent Doppler two-dimensional echocardiographic assessments of left atrial (LA) and ventricular (LV) geometry and LV diastolic function (peak early [E] and late waves, E wave deceleration time, myocardial flow velocities). Homeostasis model assessment of IR (HOMA-IR) was used as an IR index. LA size was increased in obese children, as indicated by higher LA diameter (4.9 ± 0.5 vs 4.1 ± 0.4 cm, p < 0.001), area (14.3 ± 2.5 vs 10.7 ± 2.0 cm(2), p < 0.001), and volume (33.8 ± 10.6 vs 23.7 ± 6.4 ml, p = 0.003). LV mass was also increased in obese children (87.0 ± 16.6 vs 68.8 ± 13.2 g, p = 0.003), who also showed subtle diastolic dysfunctions, as indicated by higher values of E (97.1 ± 14.3 vs 86.2 ± 11.9 cm/s, p = 0.02). All the above parameters were significantly associated with BMI-SDS (p < 0.05). In addition, HOMA-IR was independently associated with LA diameter, area, and volume (ß = 0.314, p = 0.040; ß = 0.415, p = 0.008; ß = 0.535, p = 0.001). CONCLUSION: Obese children feature increased LA size, which emerged to be mainly correlated to, and possibly driven by IR, suggesting an increased CVD risk. WHAT IS KNOWN: Left atrial and ventricular alterations have been reported in obese adults, and they represent predisposing factors for cardiovascular disease. There is some evidence suggesting that obese children show increased left ventricular mass and also increased atrial size, although with conflicting results. WHAT IS NEW: Obese normotensive children showed a moderately increased atrial size, subtle alterations in left cardiac diastolic function, and ventricular mass. An association between insulin resistance and left cardiac changes was found, although its mechanism remains to be determined.

Management of atrial fibrillation in the Emergency Department: current approach and future expectations.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia and occurs in 3.3%-10% of emergency admissions. It is frequently quoted for people over the age of 75, but the cases of AF in young subjects without structural heart disease are also increasing, therefore, leading to the evaluation of "lonely atrial fibrillation" as a new challenge for the clinician. The first diagnosis and treatment often occur in the emergency room and the emergency physician has therefore to evaluate the initial step towards the therapeutic decisions. Although international standard guidelines are available, AF treatment in the Emergency Department (ED) is still heterogeneous in terms of the management strategy chosen. There are two main strategies for the management of AF: rate and rhythm control. Moreover, antithrombotic treatment is pivotal in AF to prevent cardioembolic stroke and it is considered a primary objective after an accurate assessment of antithrombotic treatment risks and benefits. The introduction of innovative echocardiographic approach, directly in ED, seems to improve the management and risk stratification of patients with AF. This review aims to provide an overview about the current approach and the future expectations in the management of AF in ED. This manuscript represents a synopsis of the lectures on AF management in the ED of the Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012. We decided to use only the most relevant references for each contribution as suggested by each participant at this review.

Circulating soluble receptor for advanced glycation end product (sRAGE) and left ventricular hypertrophy in patients with chronic kidney disease (CKD).

BACKGROUND AND AIM: A decoy receptor for advanced glycation end product (soluble RAGE or sRAGE) is involved in left ventricular hypertrophy (LVH), and cardiomyopathy myocardial damage in experimental models and observational studies in patients with heart failure support the hypothesis that sRAGE attenuates the progression of heart disease and prevents death. Since sRAGE accumulates in patients with chronic kidney disease (CKD) we studied the relationship between plasma sRAGE with LVH in CKD patients. METHODS AND RESULTS: We enrolled 142 patients with an average estimated glomerular filtration rate (eGFR) of 32 ml/min/1.73 m(2) and 49 healthy control individuals matched for age and gender. Plasma sRAGE was significantly higher in CKD patients than in healthy controls. Significant inverse relationships were found between sRAGE with left ventricular mass index (LVMI) and mean wall thickness (MWT) but no such associations were found in controls. A bootstrap re-sampling validation study confirmed the estimates of the link between sRAGE and these variables. On covariance analysis, the slopes of LVMI and MWT to sRAGE were significantly steeper in CKD patients than in the controls. On logistic regression analysis 1 log unit increase in sRAGE was associated with a 82% decrease in the odds for LVH in CKD patients. CONCLUSIONS: sRAGE is an inverse marker of LVH in CKD patients. This association generates the hypothesis that the RAGE pathway could be a causal risk factor for LVH in this population and that blockade of this pathway by the endogenous decoy receptor sRAGE could attenuate LVH in the same population.

Sulfido-peptide leukotrienes in coronary heart disease - relationship with disease instability and myocardial ischaemia.

BACKGROUND: Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate. METHODS AND RESULTS: Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9). CONCLUSIONS: In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

NA+/H+ exchanger 1- and aquaporin-1-dependent hyperosmolarity changes decrease nitric oxide production and induce VCAM-1 expression in endothelial cells exposed to high glucose.

Since diabetic hyperglycaemia causes hyperosmolarity, we investigated the contribution of hyperosmolarity in the proinflammatory endothelial effects of hyperglycemia, and investigated the mechanisms involved. Human aortic endothelial cells (HAEC) were incubated for short-term (1-3 days) or long-term (1-2 weeks) exposures to 5.5 mmol/L glucose (normoglycemia, basal), high glucose (25 and 45 mmol/L, HG), or a hyperosmolar control (mannitol 25 and 45 mmol/L, HM), in the presence or absence of the aquaporin-1 (AQP1) inhibitor dimethylsulfoxide (DMSO), the Na+/H+ exchanger 1 (NHE-1) inhibitor cariporide (CA), the protein kinase C (PKC) inhibitor calphostin C or the PKCbeta isoform inhibitor LY379196 (LY). Both short- and long-term exposures to HG and HM decreased the expression of the active, phosphorylated form of endothelial nitric oxide synthase (Ser1146-eNOS) and, in parallel, increased vascular cell adhesion molecule(VCAM)-1 protein at immunoblotting. After 24 h incubation with HG/HM, we observed a significant similar and concentration-dependent enhancement of AQP1 expression. DMSO and CA inhibited hyperosmolarity-induced VCAM-1 expressions, while increasing nitrite levels and Ser1146-eNOS expression. Gene silencing by small interfering RNA reduced the expression of AQP1, and suppressed HG and HM-stimulated VCAM-1 expression. Calphostin C and LY blunted hyperosmolarity-induced VCAM-1 expression, while increasing the expression of Ser1146-eNOS and nitrite production. HG decreases eNOS activation and induces total VCAM-1 expression in HAEC through a hyperosmolar mechanism. These effects are mediated by activation of the water channels AQP1 and NHE-1, and a PKCbeta-mediated intracellular signaling pathway. Targeting osmosignaling pathways may represent a novel strategy to reduce vascular effects of hyperglycemia.

Omega-3 fatty acids, inflammation and angiogenesis: basic mechanisms behind the cardioprotective effects of fish and fish oils.

Atherosclerosis is now widely accepted to be an inflammatory disease, characterized by degenerative as well as proliferative changes and extracellular accumulation of lipid and cholesterol, in which an ongoing inflammatory reaction plays an important role both in initiation and progression/destabilization, converting a chronic process into an acute disorder. Neovascularization has also been recognized as an important process for the progression/destabilization of atherosclerotic plaques. In fact, vulnerable atherosclerotic plaques prone to rupture are characterized by an enlarged necrotic core, containing an increased number of vasa vasorum, apoptotic macrophages, and more frequent intraplaque haemorrhage. Various functional roles have been assigned to intimal microvessels, however the relationship between the process of angiogenesis and its causal association with the progression and complications of atherosclerosis are still challenging and controversial. In the past 30 years, the dietary intake of omega-3 (n-3) polyunsaturated fatty acids--mainly derived from fish--has emerged as an important way to modify cardiovascular risk through beneficial effects on all stages of atherosclerosis, including plaque angiogenesis. This review specifically focuses on the modulating effects of n-3 fatty acids on molecular events involved in early and late atherogenesis, including effects on endothelial expression of adhesion molecules, as well as pro-inflammatory and pro-angiogenic enzymes. By accumulating in endothelial membrane phospholipids, omega-3 fatty acids have been shown to decrease the transcriptional activation of several genes through an attenuation of activation of the nuclear factor-kappaB system of transcription factors. This occurs secondary to decreased generation of intracellular reactive oxygen species. This series of investigations configures a clear example of nutrigenomics--i.e., how nutrients may affect gene expression, ultimately affecting a wide spectrum of human diseases.

Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008.

Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimer's disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).

High plasma levels of the soluble receptor for advanced glycation endproducts in patients with symptomatic carotid atherosclerosis.

BACKGROUND: Advanced glycation endproducts (AGEs), particularly carboxymethyl(lysine)-adducts (CML), exert part of their cellular effects by binding to a receptor, named receptor for AGEs (RAGE). The soluble form of this receptor (sRAGE) has been shown to have an athero-protective role. We hypothesized the existence of a relationship between the AGE-RAGE axis and the occurrence of symptoms related to carotid atherosclerosis in nondiabetic conditions. MATERIALS AND METHODS: We evaluated plasma levels of CML and sRAGE (by ELISA), and tissue levels (tAGEs and tRAGE, semiquantitatively, by immunohistochemistry) in endarterectomy carotid plaque tissue in 29 nondiabetic patients. At the time of surgery, 10 patients were asymptomatic and 19 were symptomatic. RESULTS: Plasma levels of sRAGE were higher in symptomatic patients than in asymptomatic patients [median (interquartile range): 676 (394-858) pg mL(-1) vs. 347 (284-479) pg mL(-1), P = 0.009]. In symptomatic patients, plasma levels of sRAGE correlated positively with CML (r = 0.60, P < 0.01), C-reactive protein (CRP) (r = 0.618, P < 0.01) and fibrinogen (r = 0.522, P<0.005), while in asymptomatic patients, no correlation was observed. Although tissue and plasma levels of AGEs and RAGE did not correlate between each other, tAGEs and tRAGE were also positively correlated only in symptomatic patients (chi(2) = 8.93, P = 0.003). CONCLUSIONS: Plasma levels of sRAGE are higher in symptomatic than asymptomatic carotid atherosclerosis. Higher levels of sRAGE in symptomatic patients may be markers of a higher degree of vascular inflammation in such patients.

Impaired adenylate cyclase signaling in acute myocardial ischemia: Impact on effectiveness of P2Y12 receptor antagonists.

INTRODUCTION: P2Y12 receptor antagonists reduce risk of thrombotic complications after stent implantation but increase bleeding risk. Activation of P2Y12 receptors by ADP causes Gi-protein-mediated inhibition of adenylate cyclase (AC), thus limiting platelet response to anti-aggregatory effect of prostacyclin (PGI2). However, P2Y12 blockade reverses this ADP-induced suppression of the platelet PGI2/AC signaling pathway. We previously demonstrated that impairment of this pathway predicts poor response to clopidogrel. OBJECTIVES: To identify clinical correlates of variability in PGI2/AC signaling, and to assess the impact of such variability on individual responses to the direct P2Y12 receptor antagonists ticagrelor (in vivo) and 2-methyl-thioadenosine-monophosphate (2MeSAMP) (in vitro). PATIENTS/METHODS: We compared the inhibitory effects of prostaglandin E1 (PGE1) and the PGI2 analog Iloprost (Ilt) on platelet aggregation in whole blood samples from healthy control subjects (n = 17), and patients with stable angina pectoris (SAP; n = 35) or acute coronary syndromes (ACS; n = 23), with or without associated diabetes/hyperglycemia. RESULTS: Compared to control subjects, patients with ACS and - to a lesser extent - those with SAP, exhibited impaired responses to PGE1, accentuated in the presence of hyperglycemia. Efficacy of ticagrelor treatment, measured as change in platelet reactivity index, was directly related to pre-treatment PGE1 response, both at univariate and multivariate analysis. There was a strong correlation between extent of inhibition of platelet aggregation, whether by PGE1 or Ilt, and the anti-aggregatory effect of 2MeSAMP in vitro. CONCLUSIONS: The integrity of PGI2/AC signaling, which is impaired in the presence of ACS and hyperglycemia, predetermines the anti-aggregatory efficiency of P2Y12 receptor antagonists.

Prognostic value of pulmonary blood volume by first-pass contrast-enhanced CMR in heart failure outpatients: the PROVE-HF study.

Aims: Pulmonary blood volume (PBV) is a novel clinical application of cardiovascular magnetic resonance (CMR) imaging for the quantitative grading of haemodynamic congestion. In this study, we aimed to assess the prognostic value of PBV in a cohort of outpatients with chronic heart failure (HF). Methods and results: One hundred and twelve consecutive patients (91 men, 67 ± 12 years) and 53 age- and sex-matched healthy controls underwent echocardiography and contrast-enhanced CMR. PBV was calculated as the product of stroke volume and the number of cardiac cycles for an intravenous bolus of gadolinium contrast to pass through the pulmonary circulation determined by first-pass perfusion imaging. Compared with healthy controls, HF outpatients showed significantly higher PBV index (PBVI, 308 ± 92 vs. 373 ± 175, mL/m2, P = 0.012) and pulmonary transit time (6.8 ± 1.8 vs. 9.5 ± 4 s, P ≤0.001). During a median follow-up of 26 ± 17 months, 27 patients (24%) reached the composite end point of cardiovascular death, HF hospitalization, or sustained ventricular arrhythmias/appropriate implantable cardioverter-defibrillator intervention. Using a cut-off point of PBVI >492 mL/m2, corresponding to two standard deviations above the mean of healthy controls, event-free survival was significantly lower in patients with higher PBVI (P < 0.001). At multivariable-adjusted Cox regression analysis, PBVI was an independent predictor of the composite cardiovascular end point (per 10% increase hazard ratio 1.31, 95% confidence interval: 1.02-1.69, P = 0.03). Conclusions: PBVI is a novel application of perfusion CMR potentially useful to quantitatively determine haemodynamic congestion as a surrogate marker of left ventricular diastolic dysfunction. PBVI might prove to be helpful in stratifying the prognosis of asymptomatic or mildly symptomatic patients with left ventricular dysfunction.

State of play and future direction with NOACs: An expert consensus.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.

Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NO's ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall.

The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells.

Insulin levels are a marker for cardiovascular events, but the link between hyperinsulinemia and atherosclerosis is poorly understood. We previously showed that insulin increases monocyte-endothelial interactions and the endothelial expression of the pro-atherogenic vascular cell adhesion molecule-1 (VCAM-1). The aim of this study is to examine molecular mechanisms involved in the effect of insulin on VCAM-1 expression. Human umbilical vein endothelial cells (HUVEC) were incubated with insulin (0-24 h)+/- inhibitors of signaling pathways potentially involved. At pathophysiological concentrations (10(-9)-10(-7) M), insulin selectively induced VCAM-1 expression. The p38 mitogen activated protein(MAP) kinase inhibitors SB203580 and SB202190, and partially the c-Jun NH2-terminal kinase (JNK) inhibitor SP600127, decreased insulin effect on VCAM-1. Gene silencing by small interfering RNA significantly reduced the expression of p38MAP kinase, and this was accompanied by suppression of insulin-stimulated VCAM-1 expression. Treatment with insulin also led to the activation of NF-KB and induction of IKB-alpha phosphorylation, thus accounting for NF-KB translocation into the nucleus. Co-treatment of HUVEC with insulin and SB202190 strongly reverted the stimulatory effect of insulin on NF-KB activation, thus establishing a link between NF-KB activation and p38MAPkinase-mediated induction of VCAM-1 by insulin. In conclusion, pathophysiological insulin concentrations increase VCAM-1 expression and activate NF-KB. This mostly occurs through stimulation of p38MAP kinase.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.