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Masahiro Shinoda,1 Osamu Hataji,2 Motohiko Miura,3 Masaharu Kinoshita,4 Akira Mizoo,5 Kazunori Tobino,6 Toru Soutome,7 Takanobu Nishi,7 Takeo Ishii,7 Bruce E Miller,8 Ruth Tal-Singer,8 Ryan Tomlinson,8 Taizo Matsuki,7 Paul W Jones,9 Yoko Shibata10 1Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Shinagawa, Tokyo, Japan; 2Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Mie, Japan; 3Department of Respiratory Medicine, Tohoku Rosai Hospital, Sendai, Miyagi, Japan; 4Department of Respiratory Medicine, Nagata Hospital, Yanagawa, Fukuoka, Japan; 5Department of Pulmonary Medicine Japan, Japan Community Healthcare Organization Tokyo Shinjuku Medical Center, Shinjuku, Tokyo, Japan; 6Department of Respiratory Medicine, Iizuka Hospital, Iizuka, Fukuoka, Japan; 7Japan Medical & Development, GSK K.K, Minato-Ku, Tokyo, Japan; 8GSK Pharma R&D, Collegeville, PA, USA; 9General Medicine, GSK, Brentford, Middlesex, UK; 10Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, JapanCorrespondence: Taizo Matsuki, Value Evidence Outcomes, Japan Medical & Development, GSK K.K, Akasaka Intercity AIR 1-8-1 Akasaka, Minato-Ku, Tokyo, 107-0052, Japan, Tel +81-8036928935, Email taizo.2.matsuki@gsk.comBackground: Telemedicine may help the detection of symptom worsening in patients with chronic obstructive pulmonary disease (COPD), potentially resulting in improved outcomes. This study aimed to determine the feasibility and acceptability of telemedicine among patients with COPD and physicians and facility staff in Japan.Methods: This was a 52-week multicenter, prospective, single-arm, feasibility and acceptability cohort study of Japanese patients ≥ 40 years of age with COPD or asthma-COPD overlap. Participants underwent training to use YaDoc, a telemedicine smartphone App, which included seven daily symptom questions and weekly COPD Assessment Test (CAT) questions. The primary endpoint was participant compliance for required question completion. The secondary endpoint was participant and physician/facility staff acceptability of YaDoc based on questionnaires completed at Week 52. The impact of the Japanese COVID-19 pandemic state of emergency on results was also assessed.Results: Of the 84 participants enrolled (mean age: 68.7 years, 88% male), 72 participants completed the study. Completion was high in the first six months but fell after that. Median (interquartile range [IQR]) compliance for daily questionnaire entry was 66.6% (31.0– 91.8) and 81.0% (45.3– 94.3) for weekly CAT entry. Positive participant responses to the exit questionnaire were highest regarding YaDoc ease of use (83.8%), positive impact on managing health (58.8%), and overall satisfaction (53.8%). Of the 26 physicians and facility staff enrolled, 24 completed the study. Of these, the majority (66.7%) responded positively regarding app facilitation of communication between physicians and participants to manage disease. Compliance was similar before and after the first COVID-19 state of emergency in Japan.Conclusion: Daily telemedicine monitoring is potentially feasible and acceptable to both patients and physicians in the management of COPD. These results may inform potential use of telemedicine in clinical practice and design of future studies.Clinical Trial Registration: JapicCTI-194916.Keywords: Japan, patient-reported outcome measure, feasibility, acceptability, telemonitoring, smartphone

BackgroundHeart Rate Score (HRSc), the percent of all atrial paced and sensed event in the largest 10 bpm rate histogram bin of a pacemaker, predicts survival in patients with cardiac devices. No correlation between HRSc and development of atrial fibrillation (AF) has been reported.ObjectiveTo evaluate the relationship between pacemaker post-implantation HRSc and newly-developed AF incidence.MethodsPatients with dual-chamber pacemakers, implanted 2013-2017, with ALTITIUDE remote monitoring data with ≥600,000 beats of histogram data collected at baseline were included (N=34,543). HRSc was determined from the post-implantation histogram data during the initial 3 months. Patients were excluded if they had AF, defined as atrial high-rate episodes >5 minutes or >1% of right atrial beats >170 bpm during the initial 3-months post-implantation. New AF, after the baseline period, was defined by each of the following: >1%, >10% or >25% of atrial beats >170 bpm or Atrial Tachycardia Response (ATR) events >24 hr.ResultsPatients were followed a median of 2.8 (1.0-4.0) years. Patients with initial HRSc≥70% were older, had higher %RA pacing, had lower %RV pacing and were more likely programmed with rate-response vs subjects with HRScConclusionHRSc predicts subsequent AF independent of well-known risk factors in pacemaker patients.

Introduction Many patients with chronic obstructive pulmonary disease (COPD) do not report exacerbations and may benefit from simple guidance about when to seek medical attention, so we developed a COPD Exacerbation Recognition Tool (CERT). Methods The study was run across three sites in China in patients who had an exacerbation within the previous year. Step 1: focus group qualitative study (total 48 patients) captured symptoms associated with an exacerbation. Step 2: cognitive debriefing to ensure items were appropriately worded. Step 3: 150 patients (69 years, 21% female, FEV1 63% predicted, CAT 15, 2 exacerbations in previous year) completed a questionnaire composed of the items from Steps 1 and 2 using two response options – severity during an exacerbation and magnitude of change from usual state. Responses were analysed in terms of frequency and tested for influence of demographic factors. Exploratory factor analysis (EFA) identified key domains. Using these results, an expert panel guided choice of items that formed the CERT. Results Following Steps 1 and 2, 29 candidate items were selected for Step 3. Response rates with the two response options were very similar. There was minimal influence of demographic factors on response to the items. EFA using the 11 items with the highest response rates identified two principal factors, Factor 1: breathlessness and activity limitation (79.1% of variance), Factor 2: cough and sputum (20.9% of variance). Five items were selected for the CERT based on response rate and EFA factor loading: worsening cough, increased sputum volume, shortness of breath, laborious breathing, and limitation of motion. Sensitivity analysis suggested that worsening of two or more symptoms had good sensitivity and specificity for the presence of an exacerbation. Discussion The CERT is an evidence-based tool to provide patients with simple-to-follow guidance about when to seek medical attention when their COPD symptoms worsen., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/1mVxioLvjfE

Background Systemic corticosteroids for the treatment of COPD exacerbations decrease treatment failure and shorten the length of hospitalization. However, the optimal dose is unclear. Research Question Is personalized-dose corticosteroid administered according to a dosing scale more effective than fixed-dose corticosteroid administration in hospitalized patients with COPD with exacerbations? Study Design and Methods This was a prospective, randomized, open-label trial. In-hospital patients with COPD with exacerbations were randomly assigned at a 1:1 ratio to either the fixed-dose group (receiving the equivalent of 40 mg of prednisolone) or the personalized-dose group for 5 days. The primary end point was a composite measure of treatment failure that included in-hospital treatment failure and medium-term (postdischarge) failure. Secondary end points were length of stay and cost. Results A total of 248 patients were randomly assigned to the fixed-dose group (n = 124) or personalized-dose group (n = 124). One patient in each group was not included in the intention-to-treat population because of incorrect initial COPD diagnosis. Failure of therapy occurred in 27.6% in the personalized-dose group, compared with 48.8% in the fixed-dose group (relative risk, 0.40; 95% CI, 0.24-0.68; P = .001). The in-hospital failure of therapy was significantly lower in the personalized-dose group (10.6% vs 24.4%; P = .005), whereas the medium-term failure rate, adverse event rate, hospital length of stay, and costs were similar between the two groups. After treatment failure, a lower additional dose of corticosteroids and a shorter duration of treatment were needed in the personalized-dose group to achieve control of the exacerbation. In the personalized-dose cohort, those receiving 40 mg or less had an average failure rate of 44.4%, compared with 22.9% among those receiving more than 40 mg (P = .027). Interpretation Personalized dosing of corticosteroids reduces the risk of failure because more patients were provided with a higher initial dose, especially > 60 mg, whereas 40 mg or less was too low in either group. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT02147015; URL: www.clinicaltrials.gov

David MG Halpin,1 Robyn Kendall,2 Soham Shukla,3 Alan Martin,4 Dhvani Shah,5 Dawn Midwinter,6 Kai M Beeh,7 Janwillem WH Kocks,8– 11 Paul W Jones,12 Chris Compton,12 Nancy A Risebrough,13 Afisi S Ismaila3,14 1University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 2ICON Health Economics, ICON plc, Vancouver, BC, Canada; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Value Evidence and Outcomes, GSK, Uxbridge, UK; 5ICON Health Economics, ICON plc, New York, NY, USA; 6Biostatistics, GSK, Brentford, UK; 7Insaf Respiratory Research Institute, Wiesbaden, Germany; 8General Practitioners Research Institute, Groningen, the Netherlands; 9Observational and Pragmatic Research Institute, Singapore; 10Groningen Research Institute Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 11Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 12Global Respiratory Franchise, GSK, Brentford, UK; 13ICON Health Economics, ICON plc, Toronto, ON, Canada; 14Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: David MG Halpin, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK, Tel +44 01392 201178, Email d.halpin@nhs.netPurpose: The 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective.Patients and Methods: The analysis was conducted using the validated GALAXY COPD disease progression model. Baseline characteristics, treatment effect parameters (forced expiratory volume in 1 second and St. George’s Respiratory Questionnaire score [derived from exploratory COPD Assessment Test score mapping]), and discontinuation data from INTREPID were used to populate the model. UK healthcare resource and drug costs (2020 British pounds) were applied, and costs and outcomes were discounted at 3.5%. Analyses were conducted over a lifetime horizon from a UK NHS perspective. Model outputs included exacerbation rates, total costs, life years (LYs), quality-adjusted LYs (QALYs) and incremental cost-effectiveness ratio per QALY. Sensitivity analyses were conducted to assess the robustness of the results by varying parameter values and assumptions.Results: Over a lifetime horizon, FF/UMEC/VI provided an additional 0.174 (95% confidence interval [CI]: 0.024, 0.344) LYs (approximately 2 months), and 0.253 (95% CI: 0.167, 0.346) QALYs (approximately 3 months), at a cost saving of £ 1764 (95% CI: −£ 2600, −£ 678) per patient, compared with non-ELLIPTA MITT. FF/UMEC/VI remained the dominant treatment option, meaning greater benefits at lower costs, across all scenario and sensitivity analyses.Conclusion: Based on this analysis, in a UK setting, FF/UMEC/VI would improve health outcomes and reduce costs compared with non-ELLIPTA MITT for the treatment of patients with symptomatic COPD. SITT may help to reduce the clinical and economic burden of COPD and should be considered by physicians as a preferred treatment option.Keywords: chronic obstructive pulmonary disease, cost-effectiveness, health technology assessment, pragmatic, real-world, triple therapy

Janelle Yorke,1,2 Naimat Khan,1,3 Adam Garrow,1 Sarah Tyson,1 Dave Singh,1,3 Jorgen Vestbo,1,4 Paul W Jones5 1Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; 2Christie Patient Centred Research, The Christie NHS Foundation Trust, Whittington, Manchester, UK; 3Medicines Evaluation Unit, Wythenshawe, Manchester, UK; 4Department of Respiratory Medicine, Wythenshawe Hospital, Manchester, UK; 5St George’s Hospital, University of London, London, UKCorrespondence: Janelle Yorke, Tel +44920 264411, Email janelle.yorke@nhs.netPurpose: The modified-Medical Research Council (mMRC) breathlessness scale consists of five grades that contain of a description of different activities. It has wide utility in the assessment of disability due to breathlessness but was originally developed before the advent of modern psychometric methodology and, for example contains more than one activity per grade. We conducted an evaluation of the mMRC structure.Patients and Methods: Cognitive debriefing was conducted with COPD patients to elicit their understanding of each mMRC activity. In a cross-sectional study, patients completed the mMRC scale (grades 0– 4) and an MRC-Expanded (MRC-Ex) version consisting of 10-items, each containing one mMRC activity. Each activity was then given a 4-point response scale (0 “not at all” to 4 “all of the time”) and all 10 items were given to 203 patients to complete Rasch analysis and assess the pattern of MRC item severity and its hierarchical structure.Results: Cognitive debriefing with 36 patients suggested ambiguity with the term “strenuous exercise” and perceived severity differences between mMRC activities. 203 patients completed the mMRC-Ex. Strenuous exercise was located third on the ascending severity scale. Rasch identified the mildest term was “walking up a slight hill” (logit − 2.76) and “too breathless to leave the house” was the most severe (logit 3.42).Conclusion: This analysis showed that items that were combined into a single mMRC grade may be widely separated in terms of perceived severity when assessed individually. This suggests that mMRC grades as a measure of individual disability related to breathlessness contain significant ambiguity due to the combination of activities of different degrees of perceived severity into a single grade.Keywords: psychometrics, Rasch analysis, patient reported outcomes, qualitative, scale development

Hyun-Il Gil,1,* Sungmin Zo,2,* Paul W Jones,3,4 Bo-Guen Kim,2 Noeul Kang,2 Yeonseok Choi,5 Hyun Kyu Cho,6 Danbee Kang,7 Juhee Cho,7 Hye Yun Park,2 Sun Hye Shin2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3Institute For Infection and Immunity, St George’s University of London, London, UK; 4Value Evidence and Outcomes, Global Medical R&D, GlaxoSmithKline, Uxbridge, UK; 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea; 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea; 7Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Sun Hye Shin; Hye Yun ParkDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of KoreaTel +82-2-3410-3429Fax +82-2-3410-3849Email freshsunhye@gmail.com; hyeyunpark@skku.eduPurpose: The chronic obstructive pulmonary disease (COPD) assessment test (CAT) is widely used to assess the impact of COPD symptoms on health status. Whilst the CAT consists of eight different items, details on the distribution of each item are limited. This study aimed to investigate the distribution and clinical implication of each CAT item, stratified by CAT severity group, in stable COPD patients.Patients and Methods: This was a cross-sectional study at a single referral hospital in South Korea. Spirometry confirmed COPD patients with CAT measured at the first clinical visit were retrospectively identified. Patients were categorized into three groups: low (0 ≤ CAT < 10), medium (10 ≤ CAT < 20), and high (20 ≤ CAT ≤ 40) impact group. For the purpose of this analysis, the first four items (cough, sputum, chest tightness, and dyspnea) and the remaining four items (activities, confidence, sleep and energy) were also grouped as “pulmonary” and “extra-pulmonary”, respectively.Results: A total of 815 patients were included, and mean (SD) forced expiratory volume in 1 s (FEV1) was 62.8 (17.4) % pred. Among them, 300 patients (36.8%) were in the high impact group and had a greater exacerbation history and lower lung function. The proportion of “extra-pulmonary” items score was greater in patients with higher total CAT scores, with the activity and confidence items showing higher scores.Conclusion: In our study, in addition to dyspnea, activity limitation is a particular problem in individual patients with higher CAT total scores, for which physicians need to pay more attention. Our study suggests that whilst CAT total score captures the overall impact of COPD, each item of the CAT contains potentially useful information in understanding the patient’s symptom burden.Keywords: COPD, COPD assessment test, patient reported outcome, symptom

Background: Heart rate score (HrSc) ≥70% in cardiac resynchronization therapy defibrillator and implantable cardioverter-defibrillator subjects predicts 5-year mortality risk. A high HrSc suggests few sensed cardiac cycles above the programmed lower rate. Objective: To determine if HrSc is related to chronotropic incompetence (CI) in pacemaker (PM) subjects. Methods: HrSc is the percentage of all atrial-paced and sensed events in the single tallest 10 beats/min histogram bin programmed to DDD 60/min. The prospective LIFE study of PM subjects examined multiple treadmill-based measures of CI. The 1-month postimplant DDD 60/min PM rate histogram prior to treadmill was retrospectively analyzed for HrSc. Measures of CI were applied to submaximal treadmill data in the DDD mode. HrSc was compared to these CI measures and to clinical indications for PM. Results: The 1-month histogram demonstrated HrSc ≥70% in 43% of subjects. HrSc ≥70% correlated with a clinical diagnosis of sick sinus syndrome (P < .001). CI was present in 34%–88% of subjects by treadmill-based measures. Agreement between treadmill-based measures for CI was poor and varied from 39% to 83%. HrSc ≥70%, as a measure of CI, was most highly correlated with unpaced heart rate

OBJECTIVE: Daily inhaled corticosteroid (ICS) and long-acting beta-2-agonist (LABA) combinations comprising either regular maintenance therapy with ICS/LABA plus as-needed short-acting beta-2-agonist (SABA) or ICS-formoterol combinations used as maintenance and reliever therapy (MART) are recommended for moderate asthma. This analysis compares the direct costs of twice-daily fluticasone propionate/salmeterol (FP/salm) and budesonide/formoterol MART in three Southeast Asian countries. METHODS: A literature review identified three randomized trials in patients with asthma (≥ 12 years) comparing regular twice-daily FP/salm with as-needed SABA versus MART in moderate asthma: AHEAD (NCT00242775/17 countries/2309 patients), COMPASS (AstraZeneca study SD-039-0735/16 countries/3335 patients), and COSMOS (AstraZeneca study SD-039-0691/16 countries/2143 patients). Economic analyses, conducted from a healthcare sector perspective (medication costs + healthcare utilization costs), applied unit costs from countries where healthcare costs are publicly available: Indonesia, Thailand and Vietnam. Results are expressed in British pound sterling (GBP/patient/year). RESULTS: Annual exacerbation rates were low and differences between treatment strategies were small (range, FP/salm: 0.31-0.38, MART: 0.24-0.25) although statistically significant in favor of MART. Total average (minimum-maximum) direct costs (in GBP/patient/year) across the three studies were £187 (£137-£284), £158 (£125-£190), and £151 (£141-£164) for those who used FP/salm, and £242 (£217-£267), £284 (£237-£340) and £266 (£224-£315) for MART in Indonesia, Thailand and Vietnam, respectively. On average, total direct costs/patient/year with FP/salm were 22.8%, 44.6% and 43.0% lower than with MART for Indonesia, Thailand and Vietnam, respectively. CONCLUSIONS: In the three countries evaluated, total treatment costs with regular twice-daily FP/salm were consistently lower than with budesonide/formoterol MART due to lower direct healthcare costs.

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD.

BACKGROUND Limited studies are available on the clinical significance of left ventricular (LV) lead polarity in patients undergoing cardiac resynchronization therapy (CRT), with a recent study suggesting better outcomes with LV true bipolar pacing. OBJECTIVE We aimed to determine whether true bipolar LV pacing is associated with reduced mortality in a large, real-life CRT cohort, followed by remote monitoring. METHODS We analyzed de-identified device data from CRT patients followed by the Boston Scientific LATITUDE remote monitoring database system. Patients with LV bipolar leads paced between the LV ring and LV tip were identified as true bipolar and those with LV bipolar leads paced between LV tip or LV ring and right ventricular (RV) coil were identified as extended bipolar. Patients with unipolar leads were identified as unipolar. RESULTS Of the 59 046 patients included in the study, 2927 had unipolar pacing, 34 390 had extended bipolar pacing, and 21 729 had true bipolar pacing. LV true bipolar pacing was associated with a significant 30% lower risk of all-cause mortality as compared to unipolar pacing (hazards ratio [HR] = 0.70, 95% CI: 0.62-0.79, P

Soham Shukla,1 Dhvani Shah,2 Alan Martin,3 Nancy A Risebrough,4 Robyn Kendall,5 Claus F Vogelmeier,6 Isabelle Boucot,3 Lee Tombs,7 Leif Bjermer,8 Paul W Jones,3 Edward Kerwin,9 Chris Compton,3 François Maltais,10 David A Lipson,11,12 Afisi S Ismaila1,13 1Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 2ICON, New York, NY, USA; 3Value Evidence and Outcomes, GSK, Brentford, Middlesex, UK; 4Global Health Economics, and Outcomes Research and Epidemiology, ICON, Toronto, ON, Canada; 5Global Health Economics, and Outcomes Research and Epidemiology, ICON, Vancouver, BC, Canada; 6Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 9Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 10Centre de Pneumologie, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada; 11Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 12Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 13Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Afisi S IsmailaValue Evidence and Outcomes, GlaxoSmithKline 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USATel +1 919 315 8229Email afisi.s.ismaila@gsk.comIntroduction: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data.Methods: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥ 10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results.Results: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (− 0.059, 0.168) with total cost savings of £ 690 (£ 231, £ 1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £ 1336 (£ 1006, £ 2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£ 4/QALY gained) and at the lowest estimate of the St George’s Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£ 12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £ 20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol.Conclusion: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.Keywords: COPD treatment, cost-effectiveness, umeclidinium, salmeterol, umeclidinium/vilanterol

Background In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. Methods The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10−30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21–24, and rescue medication use (puffs/day) over Weeks 1–24. Analyses were conducted across the full range of reversibility (−850–896 mL); however, results are presented for the range −100–400 mL because there were few participants with values outside this range. Results The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. Conclusions FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

Dear Editors,We read with interest the review article by Ritondo et al. on triple therapy in chronic obstructive pulmonary disease (COPD),1 but disagree with some of the points raised by the author...

Key Points Question What are the long-term health outcomes associated with COVID-19 infection 1 year after hospital discharge? Findings In this cohort study of 2433 patients who had been hospitalized with COVID-19, the most common symptoms at 1 year after discharge were fatigue, sweating, chest tightness, anxiety, and myalgia. Patients with severe disease had more postinfection symptoms and higher chronic obstructive pulmonary disease assessment test scores. Meaning This study reported prolonged symptoms of COVID-19 and found that severe disease during hospitalization was a risk factor for more symptoms and higher chronic obstructive pulmonary disease assessment test scores., This cohort study investigates 1-year health outcomes and their associated risk factors among COVID-19 survivors in Wuhan, China., Importance The long-term health outcomes and symptom burden of COVID-19 remain largely unclear. Objective To evaluate health outcomes of COVID-19 survivors 1 year after hospital discharge and to identify associated risk factors. Design, Setting, and Participants This retrospective, multicenter cohort study was conducted at 2 designated hospitals, Huoshenshan Hospital and Taikang Tongji Hospital, both in Wuhan, China. All adult patients with COVID-19 discharged between February 12 and April 10, 2020, were screened for eligibility. Of a consecutive sample of 3988 discharged patients, 1555 were excluded (796 declined to participate and 759 were unable to be contacted) and the remaining 2433 patients were enrolled. All patients were interviewed via telephone from March 1 to March 20, 2021. Statistical analysis was performed from March 28 to April 18, 2021. Exposures COVID-19. Main Outcomes and Measures All patients participated in telephone interviews using a series of questionnaires for evaluation of symptoms, along with a chronic obstructive pulmonary disease (COPD) assessment test (CAT). Logistic regression models were used to evaluate risk factors for fatigue, dyspnea, symptom burden, or higher CAT scores. Results Of 2433 patients at 1-year follow-up, 1205 (49.5%) were men and 680 (27.9%) were categorized into the severe disease group as defined by the World Health Organization guideline; the median (IQR) age was 60.0 (49.0-68.0) years. In total, 1095 patients (45.0%) reported at least 1 symptom. The most common symptoms included fatigue, sweating, chest tightness, anxiety, and myalgia. Older age (odds ratio [OR], 1.02; 95% CI, 1.01-1.02; P

Introduction Smoking may reduce the efficacy of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD), but its impact on bronchodilator efficacy is unclear. This analysis of the EMAX trial explored efficacy and safety of dual- versus mono-bronchodilator therapy in current or former smokers with COPD. Methods The 24-week EMAX trial evaluated lung function, symptoms, health status, exacerbations, clinically important deterioration, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving ICS. Current and former smoker subgroups were defined by smoking status at screening. Results The analysis included 1203 (50%) current smokers and 1221 (50%) former smokers. Both subgroups demonstrated greater improvements from baseline in trough FEV1 at week 24 (primary endpoint) with umeclidinium/vilanterol versus umeclidinium (least squares [LS] mean difference, mL [95% CI]; current: 84 [50, 117]; former: 49 [18, 80]) and salmeterol (current: 165 [132, 198]; former: 117 [86, 148]) and larger reductions in rescue medication inhalations/day over 24 weeks versus umeclidinium (LS mean difference [95% CI]; current: − 0.42 [− 0.63, − 0.20]; former: − 0.25 − 0.44, − 0.05]) and salmeterol (current: − 0.28 [− 0.49, − 0.06]; former: − 0.29 [− 0.49, − 0.09]). Umeclidinium/vilanterol increased the odds (odds ratio [95% CI]) of clinically significant improvement at week 24 in Transition Dyspnea Index versus umeclidinium (current: 1.54 [1.16, 2.06]; former: 1.32 [0.99, 1.75]) and salmeterol (current: 1.37 (1.03, 1.82]; former: 1.60 [1.20, 2.13]) and Evaluating Respiratory Symptoms–COPD versus umeclidinium (current: 1.54 [1.13, 2.09]; former: 1.50 [1.11, 2.04]) and salmeterol (current: 1.53 [1.13, 2.08]; former: 1.53 [1.12, 2.08]). All treatments were well tolerated in both subgroups. Conclusions In current and former smokers, umeclidinium/vilanterol provided greater improvements in lung function and symptoms versus umeclidinium and salmeterol, supporting consideration of dual-bronchodilator therapy in symptomatic patients with COPD regardless of their smoking status. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01855-y., Plain Language Summary Patients with chronic obstructive pulmonary disease (COPD) often require daily medication to control their COPD. Many patients with COPD are smokers, and smoking is one of the most common causes of COPD. This means that it is important to find out whether COPD medications are effective in both smokers and nonsmokers. We analyzed data from a clinical trial (EMAX) that investigated the use of a combination of two bronchodilators, which are inhaled medications that help to open the airways. We compared umeclidinium/vilanterol, a dual-bronchodilator combination, with a single bronchodilator (either umeclidinium or salmeterol) over 6 months. We found that both current and former smokers who were treated with umeclidinium/vilanterol had larger improvements in lung function than those receiving umeclidinium or salmeterol. Current or former smokers who were treated with umeclidinium/vilanterol used their reliever inhaler less than those treated with umeclidinium or salmeterol. Patients treated with umeclidinium/vilanterol were generally less likely to experience disease worsening compared with umeclidinium or salmeterol if they were former smokers, or compared with salmeterol if they were current smokers. Our findings suggest that umeclidinium/vilanterol may be more effective than a single bronchodilator for daily treatment of patients with COPD who are current or former smokers. Physicians should consider prescribing a combination of two bronchodilators to patients who have symptoms, whether or not they currently smoke, as well as encouraging smoking cessation for all patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01855-y.

BACKGROUND Heart rate score (HRSc), the percentage of atrial sensed and paced beats in the largest 10 beat/min bin of a device histogram and mean intrinsic heart rate (MIHR), predicted survival in nonrandomized studies of implantable defibrillator (ICD) patients. We evaluated whether HRSc and MIHR independently predicted mortality and heart failure (HF) hospitalization in the prospective, randomized, controlled INTRINSIC RV trial. METHODS AND RESULTS The INTRINSIC RV trial enrolled 1530 patients receiving dual-chamber ICDs. This analysis involves patients (n = 1471) for whom MIHR and HRSc data were available. Mean follow-up was 10.4 months. The relationship between pre-randomization MIHR and HRSc on the primary endpoint of all-cause mortality and HF hospitalization was assessed using multivariate regression and Cox modeling. As categorical variables, MIHR > 70 bpm and HRSc > 70% were considered high. RESULTS The median baseline MIHR and HRSc were 74 (IQR = 16) and 50% (IQR = 20) respectively. As a continuous variable, for every 1% increase in HRSc, death/HF hospitalization increased by 1% (95%CI: 1.002-1.017; p = 0.01). Regression analysis showed baseline MIHR was associated with HRSc (p = 0.01); for every 1 beat/min increase in MIHR, HRSc increased by 1.8%. A MIHR > 70 bpm and HRSc ≥ 70% predicted, but were independently associated with, the primary endpoint (HR: 1.39; 95%CI: 1.10-1.76, p = 0.005 for MIHR and HR: 1.654; 95%CI: 1.11-2.46, p = 0.01 for HRSc). Male gender (HR: 0.75), history of HF (HR: 1.29), and atrial fibrillation (HR: 1.37) also predicted death/hospitalization in the Cox model. CONCLUSIONS In this large, prospectively studied ICD population, HRSc was a robust and independent predictor of death/HF hospitalization. High MIHR and high HRSc were associated but each predicted outcomes independently.

Nationwide public health restrictions due to the coronavirus disease 2019 (COVID-19) pandemic have disrupted people's routine physical activities, yet little objective information is available on the extent to which physical activity has changed among patients with pre-existing cardiac diseases. Using remote monitoring data of 9,924 patients with pacemakers and implantable cardiac defibrillators (ICDs) living in New York City and Minneapolis/Saint Paul, we assessed physical activity patterns among these patients in 2019 and 2020 from January through October. We found marked declines in physical activity among patients with implantable cardiac devices during COVID-19-related restrictions and the reduction was consistent across age and sex subgroups. Moreover, physical activity among these vulnerable patients did not return to pre-restrictions levels several months after COVID-19 restrictions were eased. Our findings highlight the need to consider the unintended consequences of mitigation strategies and develop approaches to encourage safe physical activity during the pandemic.

Leif Bjermer,1 Isabelle H Boucot,2 François Maltais,3 Edward M Kerwin,4 Ian P Naya,2 Lee Tombs,5 Paul W Jones,2 Chris Compton,2 David A Lipson,6,7 Claus F Vogelmeier8 1Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 2Global Specialty & Primary Care, GSK, Brentford, Middlesex, UK; 3Centre de Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada; 4Clinical Research Institute of Southern Oregon, Medford, OR, USA; 5Precise Approach Ltd, contingent worker on assignment at GSK, Stockley Park West, Uxbridge, Middlesex, UK; 6Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 7Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 8Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Leif BjermerRespiratory Medicine and Allergology, Skane University Hospital, 221 85 Lund, SwedenTel +46 46 17 23 25Email leif.bjermer@med.lu.seIntroduction: Limited prospective evidence is available to guide selection of first-line maintenance therapy in patients with COPD. This pre-specified analysis of the EMAX trial explored the efficacy and safety of dual- versus mono-bronchodilator therapy in maintenance-naïve and maintenance-treated patients.Methods: The 24-week EMAX trial evaluated lung function, symptoms (including rescue medication use), exacerbations, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. Maintenance-naïve and maintenance-treated subgroups were defined by maintenance bronchodilator use 30 days before screening.Results: The analysis included 749 (31%) maintenance-naïve and 1676 (69%) maintenance-treated patients. For both subgroups, improvements from baseline in trough FEV1 at Week 24 (primary endpoint) were greater with umeclidinium/vilanterol versus umeclidinium (mean difference [95% CI]; maintenance-naïve: 44 mL [1, 87]; maintenance-treated: 77 mL [50, 104]), and salmeterol (maintenance-naïve: 128 mL [85, 171]; maintenance-treated: 145 mL [118, 172]), and in rescue medication inhalations/day over 24 weeks versus umeclidinium (maintenance-naïve: − 0.44 [− 0.73, − 0.16]; maintenance-treated: − 0.28 [− 0.45, − 0.12]) and salmeterol (maintenance-naïve: − 0.37 [− 0.66, − 0.09]; maintenance-treated: − 0.25 [− 0.41, − 0.08]). In maintenance-naïve patients, umeclidinium/vilanterol numerically improved scores at Week 24 for Transition Dyspnea Index versus umeclidinium (0.37 [− 0.21, 0.96]) and versus salmeterol (0.47 [− 0.10, 1.05]) and Evaluating Respiratory Symptoms–COPD versus umeclidinium (− 0.26 [− 1.04, 0.53]) and versus salmeterol (− 0.58 [− 1.36, 0.20]), with similar improvements seen in maintenance-treated patients. All treatments were well tolerated across both subgroups.Conclusion: Similar to maintenance-treated patients, maintenance-naïve patients receiving umeclidinium/vilanterol showed greater improvements in lung function and symptoms compared with patients receiving umeclidinium or salmeterol. These findings provide support for the consideration of dual bronchodilator treatment in symptomatic maintenance-naïve patients with COPD.Keywords: COPD treatment, first-line therapy, maintenance-naïve, umeclidinium/vilanterol, umeclidinium, salmeterol

INTRODUCTION Insertable cardiac monitors (ICMs) provide a minimally invasive method of continuous monitoring for abnormal heart rhythms. While the benefits of ICMs are clear, current algorithm performance can be improved. The objective of this study is to assess the performance of a novel adaptive atrial fibrillation (AF) detection algorithm and separately programmable atrial tachycardia (AT) algorithm. METHODS A dual-stage detect-and-verify AF algorithm and separately programmable AT algorithm were developed. Sensitivity and PPV across a range of settings were determined in silico by comparison with an adjudicated Holter data set (n = 1966 with 229 patient days). Finally, the ability to improve performance through simulated remote programming was assessed. RESULTS The dual-stage algorithm detected AF in all true AF patients (76/76) resulting in a patient-level sensitivity of 100%. Episode-level sensitivity and PPV ranged from 97.6% to 100% and 79.1% to 98.5%, respectively. Thirty-six false-positive episodes were observed and 32 (88.9%) of these were corrected with programming changes. Decoupling of AF and AT durations improved PPV from a range of 10%-22% to a range of 95%-100%. CONCLUSIONS AF and AT algorithms were designed with novel features including an adaptive morphology assessment for AF detection and separately programmable durations for AT detection. In silico performance yielded improved PPVs while maintaining high sensitivity across a range of settings. Importantly, programming changes that may be made remotely with this system reduced false positives. These algorithms allow clinicians to individualize arrhythmia detection settings thereby improving data management and reducing clinic burden.

No real-world large database associates lower rate limit (LRL) programming and survival of subjects with cardiac resynchronization therapy-defibrillators (CRT-Ds).The purpose of this study was to test the hypothesis that lower LRL programming is independently associated with survival, and that LRL and heart rate score (HrSc) are associated.All dual-chamber CRT-D devices in the Remote Patient Monitoring (RPM) ALTITUDE database (2006-2011) were queried. Baseline HrSc was defined as the percentage of all atrial sensed and paced beats in the tallest 10-beat histogram bin postimplant. LRL was assessed during repeated RPM uploads. Using a Cox model multivariable analysis, relationships between LRL, survival, HrSc, and other variables were evaluated. Survival was determined by query of death indices.Data analyzed included 61,881 subjects (mean follow-up 2.9 years). LRL ranged from 40 to 85 bpm. Baseline lower LRL was associated with younger age, less atrial fibrillation, female sex, and lower HrSc (P.001 for all covariates). Lower LRL was associated with improved survival, with LRL 40 associated with the largest survival benefit. This was significant for all 3 HrSc subgroups (P .001). An interaction between HrSc and LRL was observed, with the largest survival difference between HrSc groups observed at LRL-40 (P.001).LRL programming and HrSc were associated, and lower values of both were associated with improved survival in a large database of CRT-D subjects. Relationships between survival, LRL programming, and HrSc merit further study.

Claus F Vogelmeier,1 Ian P Naya,2,3 François Maltais,4 Leif Bjermer,5 Edward M Kerwin,6 Lee Tombs,7 Paul W Jones,2 Chris Compton,2 David A Lipson,8,9 Isabelle H Boucot2,10 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Global Specialty & Primary Care, GSK, Brentford, Middlesex, UK; 3RAMAX Ltd, Bramhall, Cheshire, UK; 4Centre De Pneumologie, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Université Laval, Québec, Canada; 5Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 6Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 9Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 10Medical Emerging Markets, GSK, Brentford, Middlesex, UKCorrespondence: Claus F VogelmeierUniversity Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Baldingerstraße, Marburg, 35043, GermanyTel +49 6421/58-66451Email claus.vogelmeier@med.uni-marburg.deIntroduction: This post hoc analysis of the “Early MAXimization of bronchodilation for improving COPD stability” (EMAX) trial investigated whether patients achieving early clinically important improvement (CII) sustained longer-term improvements and lower risk of clinically important deterioration (CID).Methods: Patients were randomized to umeclidinium/vilanterol, umeclidinium, or salmeterol for 24 weeks. The patient-reported outcomes (PROs) Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms, St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were assessed. CII, defined as attaining minimum clinically important differences (MCID) in ≥ 2 PROs, was assessed at Weeks 4, 12 and 24. CID was defined as a deterioration in CAT, SGRQ, TDI by the MCID and/or a moderate/severe exacerbation from Day 30.Results: Of 2425 patients, 50%, 53% and 51% achieved a CII at Weeks 4, 12 and 24, respectively. Patients with a CII at Week 4 versus those without had significantly greater odds of achieving a CII at Weeks 12 and 24 (odds ratio: 5.57 [95% CI: 4.66, 6.66]; 4.09 [95% CI: 3.44, 4.86]). The risk of a CID was higher in patients who did not achieve a CII at Week 4 compared with patients who did (hazard ratio [95% CI]: 2.09 [1.86, 2.34]). Patients treated with umeclidinium/vilanterol versus either monotherapy had significantly greater odds of achieving CII at Weeks 4, 12 and 24.Conclusion: Achieving a CII at Week 4 was associated with longer-term improvement in PROs and a reduced risk of deterioration. Further research is required to investigate the importance of an early response to treatment on the long-term disease course.Keywords: bronchodilator, clinically important improvement, clinically important deterioration, COPD symptoms, early improvement, patient-reported outcomes

This study sought to investigate the temporal association between changes in physiologic heart failure (HF) sensors, atrial fibrillation (AF) progression, and clinical HF in patients with cardiac resynchronization therapy implantable defibrillators (CRT-D) designed to monitor AF and HF daily.AF is a common comorbidity in HF; however, it is unclear if HF triggers AF, or vice-versa. Current implantable cardiac devices have sensors capable of quantifying HF status, which permits a greater understanding of the impact of AF on HF status and may help guide treatment.The MultiSENSE (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) study collected multiple sensor data indicative of HF status in patients with CRT-D followed for up to 12 months. Patients were grouped according to their longest daily AF burden: 1) at least 24 hours of AF (HIGH AF); 2) between 6 minutes and 24 hours (MID AF); and 3)6 minutes (NO AF). Sensor data were aligned to the first qualifying AF event or a randomly selected day for patients in the NO AF group.Among 869 patients with daily AF data available, 98 patients had HIGH AF, 141 patients MID AF, and 630 patients NO AF. At baseline, history of AF, N-terminal pro hormone B-type natriuretic peptide and device-measured S3 were associated with development of AF. HeartLogic index increased before AF onset (Δ HeartLogic = 9.83 ± 2.49; P 0.001). Multivariable time-dependent Cox regression showed an increased risk for HF events following a 24-hour AF episode compared with no 24-hour AF (hazard ratio: 1.96; 95% confidence interval: 1.03-3.74).Device-measured HF indicators worsened before AF onset, whereas clinical HF deterioration only became apparent after AF occurred. Thus, the sensitivity of methods to ascertain AF and HF status appear to influence the direction of perceived causality. (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients [MultiSENSE]; NCT01128166).