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Aims: Frailty is common in patients with atrial fibrillation (AF), with possible impact on therapies and outcomes. However, definitions of frailty are variable, and may not overlap with frailty perception among physicians. We evaluated the prevalence of frailty as perceived by enrolling physicians in the Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular AF (ETNA-AF)-Europe registry (NCT02944019), and compared it with an objective frailty assessment., Methods and Results: ETNA-AF-Europe is a prospective, multi-centre, post-authorization, observational study. There we assessed the presence of frailty according to (i) a binary subjective investigators' judgement and (ii) an objective measure, the Modified Frailty Index. Baseline data on frailty were available in 13 621/13 980 patients. Prevalence of perceived frailty was 10.6%, with high variability among participating countries and healthcare settings (range 5.9-19.6%). Conversely, only 5.0% of patients had objective frailty, with minimal variability (range 4.5-6.7%); and only <1% of patients were identified as frail by both approaches. Compared with non-frailty-perceived, perceived frail patients were older, more frequently female, and with lower body weight; conversely, objectively frail patients had more comorbidities. Non-recommended edoxaban dose regimens were more frequently prescribed in both frail patient categories., Conclusions: Physicians' perception of frailty in AF patients is variable, mainly driven by age, sex, and weight, and quite different compared with the results of an objective frailty assessment. Whatever the approach, frailty appears to be associated with non-recommended anticoagulant dosages. Whether this apparent inappropriateness influences hard outcomes remains to be assessed., Competing Interests: Conflict of interest: I.D. reports having received speaker fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Medtronic, Boston Scientific, and Biotronik. A.B. reports being involved in research sponsored by and is a member of advisory panels and speakers’ bureau for Daiichi Sankyo, Pfizer, BMS, Bayer, and Boehringer Ingelheim. P.-E.R., M.C.M., and J.A.G.d.S. are employees of Daiichi Sankyo Europe GmbH. L.P. has received fees and honoraria from Daiichi-Sankyo, SOTIO Biotech, and Beckman-Coulter. P.K. receives research support from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies. He is listed as inventor on two patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). He is co-principal investigator of ETNA-AF-Europe. R.D.C. co-authored ESC Guidelines on Atrial Fibrillation 2010–2012; acted as a Steering Committee member and National Coordinator for Italy, and co-authored manuscripts published on APPRAISE-2, ARISTOTLE, AVERROES, ENGAGE AF-TIMI 48, and Re-DUAL PCI. R.D.C. has received fees, honoraria, and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Novartis, Portola, Roche, and Merck. He is co-principal investigator of ETNA-AF-Europe. All remaining authors have declared no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: This subgroup analysis of the ENTRUST-AF PCI trial (ClinicalTrials.gov Identifier: NCT02866175; Date of registration: August 2016) evaluated type of AF, and CHA 2 DS 2 -VASc score parameters as predictors for clinical outcome., Methods: Patients were randomly assigned after percutaneous coronary intervention (PCI) to either edoxaban (60 mg/30 mg once daily [OD]; n = 751) plus a P2Y 12 inhibitor for 12 months or a vitamin K antagonist [VKA] (n = 755) plus a P2Y 12 inhibitor and aspirin (100 mg OD, for 1-12 months). The primary outcome was a composite of major/clinically relevant non-major bleeding (CRNM) within 12 months. The composite efficacy endpoint consisted of cardiovascular death, stroke, systemic embolic events, myocardial infarction (MI), and definite stent thrombosis., Results: Major/CRNM bleeding event rates were 20.7%/year and 25.6%/year with edoxaban and warfarin, respectively (HR [95% CI]: 0.83 [0.654-1.047]). The event rates of composite outcome were 7.26%/year and 6.86%/year, respectively (HR [95% CI]): 1.06 [0.711-1.587]), and of overall net clinical benefit were 12.48%/year and 12.80%/year, respectively (HR [(95% CI]: 0.99 [(0.730; 1.343]). Increasing CHA 2 DS 2 -VASc score was associated with increased rates of all outcomes. CHA 2 DS 2 -VASc score ≥ 5 was a marker for stent thrombosis. Paroxysmal AF was associated with a higher occurrence of MI (4.87% versus 2.01%, p = 0.0024)., Conclusion: After PCI in AF patients, increasing CHA 2 DS 2 -VASc score was associated with increased bleeding rates and CHA 2 DS 2 -VASc score (≥ 5) predicted the occurrence of stent thrombosis. Paroxysmal AF was associated with MI. These findings may have important clinical implications in AF patients.

Background: Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the standard of care for stroke prevention in patients with atrial fibrillation (AF). However, DOAC prescriptions at dosages that do not adhere to labeling are common in daily practice. This analysis from the observational Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program focuses on edoxaban-treated patients from South Korea and Taiwan to identify patient baseline characteristics that may be associated with non-recommended dosing., Methods: We report baseline data from ETNA-AF, including patient demographics, clinical characteristics, and bleeding/stroke history of patients receiving recommended or non-recommended edoxaban dosing., Results: A total of 2677 patients were enrolled. Among 1543 patients who did not meet dose-reduction criteria, 1033 (66.9%) were prescribed the recommended 60-mg dose, and 510 (33.1%) were prescribed the non-recommended 30-mg dose. Among 1134 patients meeting ≥1 of the dose-reduction criteria, 863 (76.1%) were prescribed the recommended 30-mg dose; 271 (23.9%) were prescribed the nonrecommended 60-mg dose. Compared with the recommended 60-mg group, the nonrecommended 30-mg group had a higher proportion of patients aged ≥75 years, higher stroke and bleeding risks, and a history of major bleeding. The non-recommended 60-mg group had a lower proportion of patients aged ≥75 years, a higher history of stroke, and lower history of bleeding compared with the recommended 30-mg group., Conclusion: The baseline data from ETNA-AF indicate that physicians take patient clinical characteristics (e.g., bleeding risks) into consideration when deviating from the dosing recommendation per label., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Aims: Non-vitamin K oral anticoagulants are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are limited in Europe. We report 1-year outcomes in patients with AF treated with edoxaban in routine care., Methods and Results: ETNA-AF-Europe is a prospective, multicentre, post-authorization, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban's post-approval safety plan. Altogether 13 092 patients in 852 sites completed the 1-year follow-up [mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days (median: 366 days)]. Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualized event rate: 0.82%/year), and major bleeding events were reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low [30 patients (0.24%/year)]. Death occurred in 442 patients (3.50%/year); cardiovascular (CV) death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and CV mortality were higher in patients receiving edoxaban 30 mg vs. 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg vs. 60 mg., Conclusion: The rates of stroke, systemic embolism, and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Non-vitamin K antagonist oral anticoagulants such as edoxaban are the standard of care for stroke prevention in patients with atrial fibrillation (AF). The Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program integrates prospective, observational, noninterventional regional studies from Europe, Japan, and other Asian countries, collecting data on patient characteristics and clinical outcomes in unselected patients treated with edoxaban for stroke prevention in AF. Overall, 26,823 patients completed a 1-year follow-up and were treated with edoxaban; either 60 or 30 mg once daily. The majority (82.6%) of patients received the recommended doses according to the local label. At baseline, the median (interquartile range) age was 75 (68, 80) years, the CHA 2 DS 2 -VASc score was 3.0 (2.0, 4.0), and the hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs, or alcohol (HAS-BLED) score was 2.0 (2.0, 3.0). At one year, there were 273 (1.12%/year) major bleeding events, including 75 (0.31%/year) intracranial hemorrhages and 140 (0.57%/year) major gastrointestinal (GI) bleeds. There were 214 ischemic strokes (0.87%/year). Mortality was 3.03%/year (745 deaths), and cardiovascular mortality accounted for 40% of all deaths (1.22%/year, 299 cardiovascular deaths). In conclusion, stroke, intracranial hemorrhage, and other major bleeding events were low in patients with AF treated with edoxaban in routine care. Even on anticoagulation, cardiovascular death remained common.

Aims: This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy., Methods and Results: Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0-3.0). Uninterrupted anticoagulation was mandated for 21-28 days' pre-ablation and 90 days' post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300-400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1-Q3) time from last dose to ablation procedure was 14.8 (13.3-16.5) vs. 16.5 (14.8-19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU)., Conclusion: The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To compare the safety and efficacy of edoxaban combined with P2Y12 inhibition following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or chronic coronary syndrome (CCS)., Methods and Results: In this pre-specified sub-analysis of the ENTRUST-AF PCI trial, participants were randomly assigned 1:1 to edoxaban- or vitamin K antagonist (VKA)-based strategy and randomization was stratified by ACS (edoxaban n = 388, VKA n = 389) vs. CCS (edoxaban n = 363, VKA = 366). Participants received edoxaban 60 mg once-daily plus a P2Y12 inhibitor for 12 months, or VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1-12 months). The primary bleeding endpoint at 12 months occurred in 59 (15.2%) vs. 79 (20.3%) ACS patients [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.59-1.02, P = 0.063], and in 69 (19.0%) vs. 73 (19.9%) CCS patients (HR: 0.94, 95%CI: 0.68-1.31, P = 0.708) with edoxaban- and VKA-based therapy, respectively [P for interaction (P-int) = 0.2741]. The main secondary endpoint (composite of CV death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) in ACS patients was 33 (8.5%) vs. 28 (7.2%) (HR: 1.16, 95%CI: 0.70-1.92), compared with 16 (4.4%) vs. 18 (4.9%) (HR: 0.91, 95%CI: 0.47-1.78) CCS patients with edoxaban and VKA-based therapy, respectively (P-int = 0.5573)., Conclusions: In patients with AF who underwent PCI, the edoxaban-based regimen, as compared with VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Edoxaban had a positive risk-benefit ratio for the treatment of venous thromboembolism (VTE) compared to conventional therapy with warfarin. The objective of this analysis of the ongoing ETNA-VTE Europe study was to assess the real-world benefits and risks of edoxaban during the first 3 months of treatment, the highest risk period for further VTE events., Methods: ETNA-VTE Europe is a prospective, non-interventional, post-authorization study, conducted in eight European countries. Participants had initial or recurrent acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) that occurred ≤2 weeks prior to enrolment and received edoxaban therapy., Results: The analysis set included 2672 patients (PE ± DVT, n = 1117; DVT only, n = 1555); mean age 62.9 ± 16.0 years, bodyweight 81.9 ± 17.4 kg, estimated glomerular filtration rate 95.4 ± 42.8 mL/min; 46.4% were female. Overall, 66.4% of patients (PE ± DVT, 68.5%; DVT-only, 64.8%) received heparin lead-in treatment for at least 5 days. Most patients (87.7%) received edoxaban at a dose of 60 mg once daily. Event rates at 3 months were: recurrent VTE 0.34% (n = 9), major bleeding 0.97% (n = 26), all-cause mortality 0.79% (n = 21). Rates were numerically higher in the PE ± DVT group compared with the DVT-only group (recurrent VTE, 0.45% (n = 5) versus 0.26% (n = 4); major bleeding, 1.34% (n = 15) versus 0.71% (n = 11); and all-cause mortality 1.16% (n = 13) versus 0.51% (n = 8))., Conclusions: The results support the safety and effectiveness of edoxaban in a general VTE population during the most critical time period, the first 3 months. The outcomes of this study extend the principal efficacy and safety data on edoxaban into the routine clinical practice setting., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Edoxaban has proven its efficacy and safety in the ENGAGE AF-TIMI 48 and HOKUSAI-VTE clinical trials. Clinical practice patients, however, may differ from those enolled in clinical trials. We aimed to compare patients from the HOKUSAI-VTE clinical trial with those treated in clinical practice., Materials and Methods: ETNA-VTE-Europe is a prospective, non-interventional post-authorisation safety study conducted in eight European countries., Results: A total of 2,879 patients presenting with acute symptomatic venous thromboembolism (VTE) were enrolled at 339 sites. Of the 2,680 patients with complete data, 23.6% reported prior VTE and 2.8% had a history of bleeding. Patients in ETNA-VTE were older (65vs.57 years), more likely to be female (46.5vs.39.8%) and had a higher prevalence of chronic venous insufficiency (11.1vs.1.6%) than those in the European cohort of the HOKUSAI-VTE trial (n=1,512). Bodyweight and creatinine clearance were substantially lower in clinical practice. Edoxaban dosing was adherent to label in 90% of patients, with higher (60 mg) and lower than recommended doses (30 mg) used in 6.6% and 3.3% of the patients, respectively. Heparin lead-in was used in 84.7% of the patients overall, and was more frequently used in patients with PE than patients with DVT only (91.3% vs. 80.1%; p<0.0001)., Conclusions: These data reinforce the largely appropriate use of edoxaban in routine clinical practice, where the study population differs from those in prior randomised controlled trials. CLINICALTRIALS., Gov Identifier: NCT02943993., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Randomized controlled trials showed the nonvitamin K oral anticoagulant (NOAC) edoxaban was effective and safe for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolism (VTE; including pulmonary embolism and deep vein thrombosis). Additional research is needed to evaluate the effects of edoxaban in routine clinical practice. Therefore, the Edoxaban Treatment in routine cliNical prActice (ETNA) program is being conducted to provide routine clinical care data on characteristics and outcomes in patients with AF or VTE receiving edoxaban., Methods: The Global ETNA program integrates prospectively collected data from edoxaban patients in regional ETNA noninterventional studies across Europe, Japan, and East and Southeast Asia into indication-specific databases for AF and VTE. Targeted enrollment is >31 000 patients (AF >26 000; VTE >4500), with a follow-up of 2 years for AF and 1 year for VTE. Data integration will be possible using consistent terminology, parameter definitions, and data collection across the regional noninterventional studies. Safety and effectiveness data will be assessed. Crude rates of outcomes including bleeding and thromboembolic events will be reported., Results: Globally, enrollment began in early 2015 and is ongoing., Conclusions: Global ETNA will generate the largest integrated prospective repository of routine clinical care data for a single NOAC in patients with AF or VTE. It will provide important information on the safety of edoxaban in routine clinical care and gather further information on its effectiveness., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI)., Methods: ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed., Findings: From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority)., Interpretation: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events., Funding: Daiichi Sankyo., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aims: Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested., Methods and Results: The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62)., Conclusion: Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018., Methods: ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years., Results: Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA 2 DS 2 -VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA 2 DS 2 -VASc = 0), intermediate (CHA 2 DS 2 -VASc = 1) and high (CHA 2 DS 2 -VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA 2 DS 2 -VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label., Conclusion: Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label., Trial Registration: NCT02944019; Date of registration: October 24, 2016.

Aim: Edoxaban, a nonvitamin K antagonist oral anticoagulant, is an oral factor Xa inhibitor approved for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation and for the treatment and secondary prevention in adult patients with venous thromboembolism (VTE). This study details the design of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study - a postauthorization observational study, which is part of the postapproval plan for edoxaban agreed with the European Medicines Agency., Methods: The ETNA-AF-Europe study (Clinicaltrials.gov: NCT02944019) is a multicenter, prospective, observational study that enrolled 13 980 patients with atrial fibrillation treated with edoxaban from 852 sites across 10 European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Portugal, Spain, Switzerland, and the United Kingdom). Patients treated with edoxaban were prospectively enrolled and will be followed up for 4 years with yearly follow-up visits., Assessments: The primary objective of the ETNA-AF-Europe study is to assess the real-world safety of edoxaban by evaluating bleeding events, including intracranial hemorrhage; drug-related adverse events, such as hepatic events; and cardiovascular and all-cause mortality. In addition, efficacy will be assessed by recording major adverse cardiovascular events including stroke, systemic embolic events, transient ischemic attacks, and also VTE episodes, acute coronary syndromes, and hospitalizations related to cardiovascular condition. Event rates will be compared with event rates reported in the PREvention oF thromboembolic events-European Registry in Atrial Fibrillation in atrial fibrillation (PREFER in AF) and PREFER in AF Prolongation registries, and in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis in Myocardial Infarction 48 study datasets.

The efficacy and safety of olmesartan medoxomil (OM) vs active control (AC) monotherapy among elderly patients aged 60-79 years (N = 4487) was evaluated by meta-analysis (25 studies). In all patients, change from baseline to end point in blood pressure (BP) was significantly greater with OM vs AC (-19.5/-11.9 vs -16.8/-10.7 mm Hg). Greater proportions of OM- vs AC-treated patients achieved BP goals. In patients with impaired renal function (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ), OM treatment resulted in a greater mean change from baseline in systolic BP vs AC (-21.2 vs -18.7 mm Hg, respectively) and a greater proportion of patients achieving BP goals. These parameters were similar in both groups for elderly patients with diabetes. OM was well tolerated with few adverse events. OM monotherapy can be used as an initial treatment for hypertension in elderly patients, including those with renal impairment or diabetes., (©2018 Wiley Periodicals, Inc.)

Background: The optimal antithrombotic treatment after percutaneous coronary intervention (PCI) with stenting in patients with atrial fibrillation (AF) is unknown. In the ENGAGE AF-TIMI 48 trial, edoxaban was noninferior to a vitamin K antagonist (VKA) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF. The effects of edoxaban in combination with single- or dual-antiplatelet therapy in the setting of PCI are unexplored., Design: The ENTRUST-AF PCI trial is a multinational, multicenter, randomized, open-label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF. Patients are randomized between 4 hours and 5 days after successful PCI to either an edoxaban-based strategy (experimental arm; 60 mg [or 30 mg according to dose reduction criteria] once daily plus a P2Y 12 antagonist [default clopidogrel, 75 mg once daily] for 12 months) or a VKA-based strategy (control arm; VKA plus a P2Y 12 antagonist [as above] plus acetylsalicylic acid [100 mg once daily] for 30 days to 12 months). The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis-defined major or clinically relevant nonmajor bleeding. The main efficacy end point is the composite of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis., Summary: The ENTRUST-AF PCI trial tests the hypothesis that an edoxaban-based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual-antiplatelet therapy in patients with AF in need of oral anticoagulation. The relative risk of ischemic events between groups will be compared., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Antihypertensive monotherapy is often insufficient to control blood pressure (BP). Several recent guidelines advocate for initial combination drug therapy in many patients. This meta-analysis of seven randomized, double-blind studies (N = 5888) evaluated 8 weeks of olmesartan medoxomil (OM)-based single-pill dual-combination therapy (OM+amlodipine/azelnidipine or hydrochlorothiazide) vs OM monotherapy in adults with hypertension. BP-lowering efficacy, goal achievement, and adverse events were assessed in the full cohort and subgroups (elderly/nonelderly and patients with and without chronic kidney disease). In the full cohort at week 8, for dual therapy vs monotherapy, seated BP was lower (137.5/86.1 mm Hg vs 144.4/89.9 mm Hg), and the mean change from baseline in BP and BP goal achievement (<140/90 mm Hg) were greater (-22.7/-15.0 mm Hg vs -16.0/-11.3 mm Hg and 51.2% vs 34.7%, respectively). Adverse events were similar between groups. BP-lowering efficacy among subgroups mirrored the findings in the full cohort whereby changes were significantly greater following OM dual-combination therapy vs OM monotherapy., (© 2017 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals, Inc.)

Introduction: Results from two long-term studies (ROADMAP and ORIENT) indicated a numerical imbalance in the number of cardiovascular deaths between the olmesartan medoxomil (OM) and placebo groups., Objective: Our objective was to conduct an individual patient data meta-analysis to provide more complete information regarding OM-associated cardiovascular risks and/or benefits., Methods: We created an integrated database based on 191 clinical trials from the OM development program. Events were identified and adjudicated by an independent, blinded clinical events committee. The incidence of major cardiovascular events and total mortality for OM versus placebo/active control were evaluated, and the effect of OM on cardiovascular mortality (main endpoint of interest) and morbidity was calculated using a two-stage approach (Tian method)., Results: A total of 46 studies (~27,000 patients) met the US FDA-specified inclusion criteria (phase II-IV randomized, double-blind, placebo- or active-controlled studies [OM-based monotherapy or combination, double-blind period ≥28 days] and adult patients). The incidence of known adjudicated endpoints in the analysis of all studies combined was low among OM (0.11-0.53 %) and placebo/active control (0.08-0.76 %) groups. For cardiovascular mortality, the estimated risk difference (OM vs. control) was 0.00070 (95 % confidence interval [CI] -0.0011 to 0.0024; p = 0.60); the risk difference for each endpoint was <1/1000, with no statistically significant difference between groups. Results were similar with and without ROADMAP and ORIENT., Discussion: The results from this meta-analysis did not show a clinically meaningful or statistically significant difference in cardiovascular risk between OM and the placebo/active control groups, and thus did not corroborate the numerical imbalance observed in ROADMAP and ORIENT.

Purpose: Combined oral anticoagulant (OAC) and antiplatelet (AP) therapy is generally discouraged in atrial fibrillation (AF) outside of acute coronary syndromes or stenting because of increased bleeding. We evaluated its frequency and possible reasons in a contemporary European AF population., Methods: The PREvention oF thromboembolic events-European Registry in Atrial Fibrillation (PREFER in AF) prospectively enrolled AF patients in France, Germany, Austria, Switzerland, Italy, Spain and the UK from January 2012 to January 2013. We evaluated patterns of combined VKA-AP therapy in this population., Results: Out of 7243 patients enrolled, 5170 (71.4%) were treated with OAC alone, 808 (11.2%) with AP alone and 791 (10.9%) with a combination of OAC and one (dual) or two AP (triple combination therapy). Compared with patients only prescribed OAC, patients on combination treatment had similar Body Mass Index, but more frequently diabetes (p<0.05), dyslipidaemia (p<0.01), coronary heart disease (54.2 vs 18.6%; p<0.01) or peripheral arterial disease (10.2 vs 3.7%; p<0.01). Accordingly, they had a higher mean CHA2DS2VASc (3.7 vs 3.4), and HAS-BLED (2.7 vs 1.9) scores (for both, p<0.01). Of the 660 patients on dual AP+OAC combination therapy, 629 (95.3%) did not have an accepted indication. Out of the 105 patients receiving triple combination therapy, 67 (63.8%) did not have an accepted indication., Conclusions: The combined use of OAC and AP therapy is not uncommon in AF, largely inappropriate, explained by the coexistence of coronary or peripheral arterial disease, and not influenced by considerations on the risk of bleeding., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives. Previous studies of antipsychotics have mainly focused on efficacy and tolerability. However, patient subjective well-being is increasingly being accepted as a valid and important measure of antipsychotic treatment outcomes and tolerability. Methods. In this open-label, observational trial data from 1322 outpatients with schizophrenia treated with flexibly dosed quetiapine were collected at baseline, Week 4 and Week 12. Patient well-being was assessed using Subjective Well-being under Neuroleptics (SWN-K) scale and disease severity with the Clinical Global Impressions-Severity of Illness (CGI-S) scale following quetiapine treatment. In addition, safety and tolerability were monitored throughout the study. Results. Quetiapine treatment, mean endpoint dose 337 mg/day, led to a significant reduction in disease severity, with improvements in CGI-S score of -0.7 at Week 4 and -1.3 at Week 12 (both P<0.001). In addition, patients' subjective well-being was significantly improved at Week 12, with a mean (SD) increase from baseline in SWN-K total score of 22.9 (18.7) (P<0.001). Further, an improved tolerability profile compared with previous medication was reported. Conclusions. This study emphasises the importance of patients' subjective well-being and the favourable acceptability of quetiapine among patients with schizophrenia.

Background: The delay in the therapeutic effect of antidepressants is a considerable impediment to their successful clinical use, and attention has recently been focused on antidepressant drugs that may have a faster onset of action., Data Synthesis: Several methodologies exist for evaluating differences in time to response between antidepressants including the identification of the timepoint at which statistically or clinically significant differences between treatment groups emerge, pattern analysis, and survival analytical approaches. All have conceptual as well as practical advantages and disadvantages., Conclusion: The survival analytical approach is generally considered to be the most rigorous and sensitive in detecting differences in the speed of response of antidepressants, but the other methodologies provide useful information.

There is a widely spread belief that different patients are being recruited into antidepressant clinical trials conducted in Europe and the USA which is probably generated by the fact that recruitment strategies vary between the two continents. In order to get an insight into the patients' characteristics in clinical studies on both continents, we compared the baseline characteristics of depressed patients in a database of a cancelled development program of an antidepressant (2220 patients, Intention-to-Treat group). For the evaluation of continental differences, we compared the elements of demographics, previous psychiatric history, DSM-III-R criteria, HAM-D and MADRS total scores and separate items and/or factors and CGI severity scores at baseline. USA patients had statistically significantly higher baseline values on height, weight and BMI. European patients showed statistically significantly higher baseline severity scores on HAM-D, MADRS and CGI. Furthermore, European patients had statistically significantly higher baseline scores on HAM-D factors I ('anxiety/somatization'), VI ('sleep disturbance'), and HAM-D Angst anxiety/agitation factor, whereas USA patients had a statistically significantly higher baseline value on the Bech depression factor and the HAM-D Angst retarded depression factor. European patients appear to have a more severe depressive episode with more anxiety and melancholic features. Some of the statistically significant differences found may be the result of a large sample size and are probably without any clinical relevance when the absolute size of the difference is taken into account. Our opinion is that the differences found in our sample between European and USA populations are much smaller than is generally expected and not of a magnitude that would question the reliability of the results obtained in our global world-wide, antidepressant drug development program. If our findings were reproducible in other antidepressant databases it would indicate that data gathered in Europe and the USA within a global antidepressant drug development can be pooled.

The issue of early onset of action (EOA) of an antidepressant was addressed by several authors. Unfortunately so far there is neither consensus nor convention on the definitions of EOA, or on measures and methods of assessments. There are several quite different approaches to the statistical analysis of the data. Our objective was to compare the results concerning EOA obtained by different statistical techniques applied on a data set which was generated by several independent conclusive double-blind, placebo controlled randomised trials with two antidepressants. The following statistical techniques were used: 1) statistically significant difference for the first time; 2) statistically significant and clinically relevant difference for the first time; 3) pattern analysis; 4) classical survival analysis without 'sustained response'; 5) survival analysis with sustained response. The advantages and drawbacks of different methods are discussed.

Of 580 patients randomly assigned to short-term, double-blind treatment with either mirtazapine, amitriptyline or placebo, a total of 217 patients clinically judged to be responders subsequently continued on the same medication for up to 2 years in the long-term treatment study (mirtazapine, n = 74; amitriptyline, n = 86 and placebo, n = 57). The efficacy of mirtazapine in relapse prevention was seen in an analysis of the first 20 weeks data. Significantly fewer patients relapsed during treatment with mirtazapine compared with placebo (p < 0.05), and a significantly longer time to relapse was shown on the survival analysis. There was a significant advantage for amitriptyline compared with placebo in the first 20 weeks, with fewer patients relapsing. There was a significant advantage for mirtazapine compared with amitriptyline at 20 weeks seen on the survival analysis (p < 0.05). The significant advantage for mirtazapine compared with placebo was also seen in the prophylactic phase of treatment after 20 weeks. At the endpoint there were significantly more patients in the placebo group with a return of symptoms and significantly fewer showing sustained response. Amitriptyline was better than placebo with fewer patients suffering a recurrence of symptoms, but there was no difference from placebo in the proportion of patients with sustained response. Mirtazapine was well tolerated with a side-effect profile similar to that of placebo. The only adverse event reported significantly more frequently on mirtazapine than on placebo was weight gain. Objectively measured weight gain was more frequent with amitriptyline (22% of patients) compared with mirtazapine (13% of patients). Amitriptyline was associated with significantly more adverse events than either mirtazapine or placebo, in particular sedative and anticholinergic side effects. The efficacy of mirtazapine in reducing the risk of relapse and the recurrence of depression, which on some measures showed an advantage compared with amitriptyline, coupled with its improved side-effect profile, commends this antidepressant for the long-term treatment of depression.

Objective: To compare local tolerance and clinical efficacy after i.m. or s.c. injection of recombinant FSH (Puregon; NV Organon, Oss, The Netherlands)., Design: An open-label, prospective, randomized, group-comparative, multicenter study., Setting: Twelve IVF clinics in 10 countries., Patient(s): Two hundred eighteen infertile pituitary-suppressed women undergoing IVF-ET were randomized, of whom 195 (i.m., n = 77; s.c., n = 118) received recombinant FSH., Intervention(s): One cycle of controlled ovarian hyperstimulation induced by either i.m. or s.c. injection of recombinant FSH, followed by IVF-ET., Main Outcome Measure(s): Local tolerance symptoms, number of oocytes retrieved, ongoing pregnancy rate., Result(s): The incidences after i.m. injection of bruising, pain, redness, swelling, and itching were 37.7%, 31.2%, 13.0%, 7.8%, and 6.5%; after s.c. injection, the corresponding figures were 54.2%, 28.0%, 16.1%, 5.9%, and 3.4%. Only bruising was significantly lower in the i.m. group, which could be attributed to the more visible superficial injection site with s.c. administration. The overall occurrence of local symptoms were 63.6% after i.m. injection and 68.6% after s.c. injection. The mean numbers of oocytes recovered were 9.8 (i.m) and 10.4 (s.c.) and the ongoing pregnancy rates per attempt were 27.1% (i.m.) and 26.1% (s.c.), respectively., Conclusion(s): There were no marked differences in local tolerance symptoms and clinical efficacy between i.m. and s.c. administration of recombinant FSH.

An important issue in judging the therapeutic potential of a new antidepressant drug is the effect size it generates in placebo-controlled trials which has to be compared with the effect of an active control. As this effect size tends to vary substantially it is not easy to predict the sample size in a clinical trial. We carried out two dose finding placebo- and imipramine-controlled, double-blind, multicenter and multinational trials (northern part of Europe) with a new psychotropic compound (NPC) currently being investigated in Phase II/III as a potential antidepressant in the indication major depressive disorder (MDD). Statistical analysis showed that the effect size of 150 mg per day imipramine was meager (1.04 points difference from placebo after 6 weeks according to total scores on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] based on the Intent-to-Treat group using last observation carried forward [LOCF] approach). To increase the discriminative power of the analysis we selected centers that were able to detect a difference of at least two points between imipramine and placebo on the HAM-D-17 total score at 6 weeks in the LOCF analysis (discriminative centers, DC). The other group of centers will be called non-discriminative centers (NDC). We found that 36 percent of centers were DC and recruited about 45 percent of patients. Further analysis revealed no statistically significant differences between the groups of centers concerning the important baseline characteristics of the patients. Also the pattern of reported adverse events did not differ between DC and NDC. We found a tendency for the DC to select more patients with recurrent illness, in particular with a previous good response to antidepressant therapy. The groups of centers differed in dropout rates for both active treatments (DC 19.3-20.4% vs. NDC 35.1-37.7%) but not for the placebo (DC 38.2% vs. NDC 30.5%) that could suggest that different treatment strategies were employed by different centers regarding the occurrence of adverse events with and without therapeutic effects.

A meta-analysis was performed on efficacy and safety data from 4 randomized, double-blind, 6-week, single-center studies comparing mirtazapine (n = 194; 5-35 mg/day) with amitriptyline (n = 193, 40-280 mg/day) and placebo (n = 193) in outpatients with a DSM-III diagnosis of major depressive episode. On all the main efficacy variables both active drugs consistently produced significantly greater improvements and significantly greater percentages of responders or remitters than placebo. The meta-analysis of adverse events shows that mirtazapine was better tolerated than amitriptyline, particularly with respect to anticholinergic and cardiac adverse events. There were no differences between mirtazapine and placebo regarding the incidence of serotonergic adverse events. In conclusion, the results of this meta-analysis demonstrate that mirtazapine is as effective as amitriptyline but has a better tolerability profile.

The "Lifeway" is a device for rescue breathing consisting of a mouthpiece for the rescuer, a non-rebreathing valve, a mouth-sealing cap and a glosso-palatinal tube (GPT) reaching into the patient's mouth. 54 patients--22 toothless and 32 with firm teeth--were ventilated mechanically via the original "Lifeway", via a variant with additional side-holes in the GPT, and, for comparison, via anaesthesia mask plus oropharyngeal airway and via endotracheal tube. Ventilation was sufficient: The arterial oxygen saturations, measured by pulse oximetry, and the end-tidal CO2 partial pressures were equal to those during ventilation via mask. Placing the modified "Lifeway" in toothless patients was significantly easier than placing the original and as easy as placing the mask; with the patients having firm teeth there were no significant differences. The incidence of obstructions, as registered by impediments to exhalation and by increases in peak inspiratory pressure, was significantly less frequent with the modified device, since the tongue could be "scooped" to a ventro-caudal direction if necessary. The modified "Lifeway" was as effective as the combination of anaesthesia mask and pharyngeal airway. The problems of the latter are, however, avoided; the use of the device by laymen thus seems feasible.

In 72 patients with dilated cardiomyopathy the degree of morphological alterations were studied by transvenous endomyocardial biopsy. These findings were correlated to the clinical status, left ventricular ejection fraction, and to the catecholamine concentrations in plasma and myocardium. Muscle fiber diameter was negatively correlated to ejection fraction (r = -0.3, p = 0.02) and to the volume fraction of mitochondria (r = -0.32, p = 0.001). Between plasma norepinephrine concentration and ejection fraction a significant negative correlation was found (r = -0.37, p = 0.001). In contrast, myocardial norepinephrine concentration was positively correlated to ejection fraction (r = 0.25, p = 0.04). Between myocardial norepinephrine concentration and muscle fiber diameter a negative correlation was found (r = -0.46, p = 0.004). Patients with an EF of less than 30% and an EF of greater than 45% could be differentiated with an accuracy of 79%, when muscle fiber diameter, plasma norepinephrine concentration, and the density of capillary vessels were entered into a multi-variant analysis. In conclusion, dilated cardiomyopathy is associated with morphological alterations and alterations in plasma and myocardial catecholamine concentrations. Patients with highly reduced ventricular function could be best identified by the combined assessment of plasma catecholamine concentration, muscle fiber diameter, and density of capillary vessels.

To analyze the relationships between left ventricular function, catecholamine concentrations in plasma and myocardium, and morphological alterations, 20 patients were studied. Fifteen patients had idiopathic dilated cardiomyopathy, and 5 had normal left ventricular function. All patients underwent right ventricular endomyocardial biopsy to determine muscle fibre thickness, percent volume fraction of interstitium, and myocardial catecholamine content. Blood was sampled to measure plasma catecholamine concentrations, and left ventricular cineangiography was performed to determine global ejection fraction. In a simple correlation analysis a significant correlation was found between left ventricular ejection fraction and myocardial norepinephrine content (r = 0.80, P less than 0.001). Left ventricular ejection fraction was negatively correlated with plasma epinephrine concentration (r- = 0.53, P less than 0.02), and with muscle fibre thickness (r = -0.50, P less than 0.03). Myocardial norepinephrine concentration was negatively correlated with plasma epinephrine (r = -0.62, P less than 0.01). Multiple linear regression analysis revealed a strong correlation between myocardial norepinephrine depletion and left ventricular dysfunction, which was independent of all other variables. These data suggest that myocardial norepinephrine depletion determined from right ventricular endomyocardial biopsies strongly correlates with left ventricular dysfunction in idiopathic dilated cardiomyopathy, and seems to be independent of the degree of muscle fibre hypertrophy, volume fraction of interstitium, and of the increased sympathetic tone.

The accuracy with which intracoronary thallium and technetium pyrophosphate scintigraphy during intracoronary thrombolysis predicts myocardial salvage was studied in 58 patients with acute myocardial infarction by comparing the acute scintigraphic findings with subsequent left ventricular function. Scintigrams obtained before and immediately after thrombolysis were interpreted by three independent observers using a scoring system. Regional wall motion in the infarct area was determined from left ventricular (LV) cine angiograms using the center-line method. Patients with mild hypokinesis (hypokinesis less than or equal to -2 SD from normal) could be distinguished from those with severe hypokinesis (hypokinesis greater than -2 SD) using the prethrombolysis thallium score with an accuracy of 83%. Accuracy using the post-thrombolysis score was 76%. When the post-thrombolysis thallium and technetium pyrophosphate scores were combined, differentiation was possible in 91% of all patients studied, and in 100% of patients with anterior myocardial infarction. Thus, analysis of combined thallium and technetium pyrophosphate scintigraphy accurately predicts recovery of LV function after thrombolysis and may be helpful in deciding whether acute percutaneous transluminal coronary angioplasty or bypass surgery should be performed after thrombolysis.

The clinical diagnosis of malignant melanoma (MM) is based on the subjective evaluation of objective measurable parameters (criteria). The accuracy of melanoma diagnosis by dermatologists is only 75%. Particularly difficult is the diagnosis of precursors or early stages of MM. Therefore, we have studied on the one hand the intra- and interindividual reproducibility of the clinical diagnosis of pigmented lesions, and on the other hand the clinico-histopathological correlation. In addition, we have conducted a preliminary investigation designed to evaluate whether image analysis (objective and reproducible) could be used as an auxiliary instrument to differentiate between benign and malignant melanocytic lesions. In the clinical study, the intraindividual reproducibility of the combination of criteria was 69%. The interindividual reproducibility of single criteria even exhibited a range of up to 36%. Histologically "atypical/dysplastic" melanocytic lesions were considered to require excision as frequently as histologically regular melanocytic lesions. Using image analysis (single threshold segmentation, standard deviation of intensity distribution, ratio of area to circumference, Fourier analysis), we could show that it may be possible to differentiate between benign and malignant melanocytic lesions. Therefore, image analysis may be very helpful in determining the dignity of melanocytic lesions.

To evaluate the prognosis of patients with idiopathic dilated cardiomyopathy (EF less than 50%) in 55 patients the myocardial catecholamine concentration, plasma catecholamine concentration, and left ventricular ejection fraction were determined. The follow-up time ranged from 7 to 47 months. At the time of follow-up 10 of the 55 patients (group A) had died and three had undergone hearttransplantation. Group A patients had a significant lower EF (27 +/- 10 vs 36 +/- 9%, p less than 0.03), a lower myocardial norepinephrine (254 +/- 168 vs 579 +/- 416 pg/mg, p less than 0.007), higher plasma norepinephrine (640 +/- 333 vs 372 +/- 254 pg/ml, p less than 0.008) and plasma epinephrine (391 +/- 340 vs 116 +/- 81 pg/ml, p less than 0.006) in comparison to patients, who were still alive and not transplanted (group B). Survival was significantly lower in patients with an EF less than 30%, a plasma norepinephrine concentration greater than 350 pg/ml, a plasma epinephrine concentration greater than 125 pg/ml, and a myocardial norepinephrine content less than 400 pg/mg. Cox regression analysis revealed that the ratio of plasma vs myocardial norepinephrine was the best prognostic indicator for patients with an EF less than 30% and this ratio plus the plasma norepinephrine concentration were the best prognostic indicators for the whole group of patients. These data suggest that myocardial norepinephrine content is an important prognostic factor in patients with idiopathic dilated cardiomyopathy.