Chronic Airways Assessment Test: psychometric properties in patients with asthma and/or COPD.

BACKGROUND: No short patient-reported outcome (PRO) instruments assess overall health status across different obstructive lung diseases. Thus, the wording of the introduction to the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) was modified to permit use in asthma and/or COPD. This tool is called the Chronic Airways Assessment Test (CAAT). METHODS: The psychometric properties of the CAAT were evaluated using baseline data from the NOVELTY study (NCT02760329) in patients with physician-assigned asthma, asthma + COPD or COPD. Analyses included exploratory/confirmatory factor analyses, differential item functioning and analysis of construct validity. Responses to the CAAT and CAT were compared in patients with asthma + COPD and those with COPD. RESULTS: CAAT items were internally consistent (Cronbach's alpha: > 0.7) within each diagnostic group (n = 510). Models for structural and measurement invariance were strong. Tests of differential item functioning showed small differences between asthma and COPD in individual items, but these were not consistent in direction and had minimal overall impact on the total score. The CAAT and CAT were highly consistent when assessed in all NOVELTY patients who completed both (N = 277, Pearson's correlation coefficient: 0.90). Like the CAT itself, CAAT scores correlated moderately (0.4-0.7) to strongly (> 0.7) with other PRO measures and weakly (< 0.4) with spirometry measures. CONCLUSIONS: CAAT scores appear to reflect the same health impairment across asthma and COPD, making the CAAT an appropriate PRO instrument for patients with asthma and/or COPD. Its brevity makes it suitable for use in clinical studies and routine clinical practice. TRIAL REGISTRATION: NCT02760329.

Initial heart rate score predicts new-onset atrial tachyarrhythmias in pacemaker patients.

AIMS: Heart rate score (HRSc), the per cent of atrial paced and sensed event in the largest 10 b.p.m. 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. In this study, we evaluated the relationship between pacemaker post-implantation HRSc and the incidence of newly developed atrial tachyarrhythmias (ATAs). METHODS AND RESULTS: Patients with dual-chamber pacemakers, implanted 2013-17, with the LATITUDE remote monitoring data with ≥600 000 beats of histogram data collected at baseline were included (N = 34 543). Heart rate score was determined from the initial 3-month post-implantation histogram data. Patients were excluded if they had ATAs, defined as atrial high-rate episodes >5 min or >1% of right atrial beats >170 b.p.m. during the initial 3 months post-implantation. New ATAs, after the baseline period, were defined by each of the following: >1, >10, or >25% of atrial beats >170 b.p.m. or atrial tachycardia response (ATR) events >24 h. Patients were followed a median of 2.8 (1.0-4.0) years. The incidence of ATAs increased in proportion to HRSc (log-rank P-value <0.001), and the initial HRSc ≥70% was associated with increased ATAs by all definitions. Patients with initial HRSc ≥70% were older, had a higher percentage of right atrium pacing (%RA pacing), had a lower percentage of right ventricular pacing (%RV pacing), and were more likely programmed with rate-response vs. subjects with HRSc <70%. Initial HRSc (hazard ratio: 1.07, 95% confidence interval: 1.05-1.09; P < 0.0001) independently predicted ATAs after adjusting for age, gender, %RV pacing, and rate-response programming. The %RA pacing and initial HRSc were correlated. CONCLUSION: Heart rate score independently predicts any subsequent duration of ATAs in pacemaker patients.

How can the findings of the EMAX trial on long-acting bronchodilation in chronic obstructive pulmonary disease be applied in the primary care setting?

This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care.

Direct healthcare costs associated with management of asthma: comparison of two treatment regimens in Indonesia, Thailand and Vietnam.

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.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial.

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.

Measuring disease activity in COPD: is clinically important deterioration the answer?

Given the heterogeneity of chronic obstructive pulmonary disease (COPD), personalized clinical management is key to optimizing patient outcomes. Important treatment goals include minimizing disease activity and preventing disease progression; however, quantification of these components remains a challenge. Growing evidence suggests that decline over time in forced expiratory volume in 1 s (FEV1), traditionally the key marker of disease progression, may not be sufficient to fully determine deterioration across COPD populations. In addition, there is a lack of evidence showing that currently available multidimensional COPD indexes improve clinical decision-making, treatment, or patient outcomes. The composite clinically important deterioration (CID) endpoint was developed to assess disease worsening by detecting early deteriorations in lung function (measured by FEV1), health status (assessed by the St George's Respiratory Questionnaire), and the presence of exacerbations. Post hoc and prospective analyses of clinical trial data have confirmed that the multidimensional composite CID endpoint better predicts poorer medium-term outcomes compared with any single CID component alone, and that it can demonstrate differences in treatment efficacy in short-term trials. Given the widely acknowledged need for an individualized holistic approach to COPD management, monitoring short-term CID has the potential to facilitate early identification of suboptimal treatment responses and patients at risk of increased disease progression. CID monitoring may lead to better-informed clinical management decisions and potentially improved prognosis.

Development and first validation of a patient-reported experience measure in chronic obstructive pulmonary disease (PREM-C9).

We developed a chronic obstructive pulmonary disease (COPD) patient-reported experience measure (PREM-C9). 174 patients with COPD (86 [49%] with a confirmed diagnosis and 88 [51%] with a self-reported diagnosis of COPD) completed a 38-item list, COPD Assessment Test (CAT) and Hospital Anxiety and Depression Scale (HADS). Hierarchical and Rasch analysis produced a 9-item list (PREM-C9). It demonstrated fit to the Rasch model (χ² p=0.33) and correlated moderately with CAT (r=0.42), HAD-anxiety (r=0.30) and HAD-depression (r=0.41) (p<0.05). A substudy confirmed its ability to detect change prepulmonary and postpulmonary rehabilitation. The PREM-C9 is a simple, valid measure of experience of patients living with COPD, validated in this study population with mild to very severe disease; it may be a useful measure in research and clinical audits.

Outcomes and costs of remote patient monitoring among patients with implanted cardiac defibrillators: An economic model based on the PREDICT RM database.

BACKGROUND: Remote monitoring of implantable cardioverter-defibrillators has been associated with reduced rates of all-cause rehospitalizations and mortality among device recipients, but long-term economic benefits have not been studied. METHODS AND RESULTS: An economic model was developed using the PREDICT RM database comparing outcomes with and without remote monitoring. The database included patients ages 65 to 89 who received a Boston Scientific device from 2006 to 2010. Parametric survival equations were derived for rehospitalization and mortality to predict outcomes over a maximum time horizon of 25 years. The analysis assessed rehospitalization, mortality, and the cost-effectiveness (expressed as the incremental cost per quality-adjusted life year) of remote monitoring versus no remote monitoring. Remote monitoring was associated with reduced mortality; average life expectancy and average quality-adjusted life years increased by 0.77 years and 0.64, respectively (6.85 life years and 5.65 quality-adjusted life years). When expressed per patient-year, remote monitoring patients had fewer subsequent rehospitalizations (by 0.08 per patient-year) and lower hospitalization costs (by $554 per patient year). With longer life expectancies, remote monitoring patients experienced an average of 0.64 additional subsequent rehospitalizations with increased average lifetime hospitalization costs of $2784. Total costs of outpatient and physician claims were higher with remote monitoring ($47 515 vs $42 792), but average per patient-year costs were lower ($6232 vs $6244). The base-case incremental cost-effectiveness ratio was $10 752 per quality-adjusted life year, making remote monitoring high-value care. CONCLUSION: Remote monitoring is a cost-effective approach for the lifetime management of patients with implantable cardioverter-defibrillators.

Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial.

BACKGROUND: Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. METHODS: The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 µg once-daily, umeclidinium 62.5 µg once-daily or salmeterol 50 µg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. RESULTS: Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments. CONCLUSIONS: Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Long-term outcomes following first short-term clinically important deterioration in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by varying trajectories of decline. Information regarding the prognostic value of preventing short-term clinically important deterioration (CID) in lung function, health status, or first moderate/severe exacerbation as a composite endpoint of worsening is needed. We evaluated post hoc the link between early CID and long-term adverse outcomes. METHODS: CID was defined as ≥100 mL decrease in forced expiratory volume in 1 s (FEV1), ≥4-unit increase in St George's Respiratory Questionnaire (SGRQ) score from baseline, and/or a moderate/severe exacerbation during enrollment in two 3-year studies. Presence of CID was assessed at 6 months for the principal analysis (TORCH) and 12 months for the confirmatory analysis (ECLIPSE). Association between presence (+) or absence (-) of CID and long-term deterioration in FEV1, SGRQ, future risk of exacerbations, and all-cause mortality was assessed. RESULTS: In total, 2870 (54%; TORCH) and 1442 (73%; ECLIPSE) patients were CID+. At 36 months, in TORCH, CID+ patients (vs CID-) had sustained clinically significant worsening of FEV1 (- 117 mL; 95% confidence interval [CI]: - 134, - 100 mL; P < 0.001) and SGRQ score (+ 6.42 units; 95% CI: 5.40, 7.45; P < 0.001), and had higher risk of exacerbations (hazard ratio [HR]: 1.61 [95% CI: 1.50, 1.72]; P < 0.001) and all-cause mortality (HR: 1.41 [95% CI: 1.15, 1.72]; P < 0.001). Similar risks post-CID were observed in ECLIPSE. CONCLUSIONS: A CID within 6-12 months of follow-up was consistently associated with increased long-term risk of exacerbations and all-cause mortality, and predicted sustained meaningful loss in FEV1 and health status amongst survivors. TRIAL REGISTRATION: NCT00268216 ; NCT00292552 .

Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease.

BACKGROUND: In clinical trials of inhaled bronchodilators, chronic obstructive pulmonary disease (COPD) guidelines recommend that patient-reported outcomes (PROs) are assessed alongside lung function. How these endpoints are related is unclear. METHODS: Pooled longitudinal data from 23 randomised controlled COPD studies were analyzed (N = 23,213). Treatments included long-acting ß2 agonists, long-acting muscarinic antagonists (LABAs or LAMAs) and the LABA/LAMA combination QVA149. Outcome measures were Transition Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) scores, COPD exacerbation frequency and rescue medication use. Relationships between changes in trough forced expiratory volume in one second (ΔFEV1) and outcomes following treatment were assessed using correlations of data summaries and model-based analysis: generalized linear mixed-effect regression modelling to determine if ΔFEV1 could predict patient outcomes with different treatments. RESULTS: Mean age was 64 years, 73% were male, and most had moderate (45%) or severe (52%) disease. Statistically significant correlations were observed between ΔFEV1 and each outcome measure (exacerbations Rs = 0.05; rescue medication, SGRQ, TDI, r = 0.11-0.16; all p < .001). Patients with greater improvements in trough FEV1 had on average better SGRQ and TDI scores, fewer exacerbations, and used less rescue medication. For SGRQ and TDI scores, minimal clinically important differences were observed over the range of pooled ΔFEV1 values. Model-based predictions confirmed the treatment effect was partly explained by changes in FEV1 from baseline with improvements in PROs observed across all treatments when trough FEV1 improved. Across all endpoints active treatments were better than placebo (p < .0001), and LABA/LAMA treatment resulted in numerically better treatment outcomes than either monocomponent. CONCLUSIONS: These data suggest that FEV1 improvements post-bronchodilation correlate with PRO improvements. Further improvements in patient outcomes may be expected by maximizing lung function improvements. TRIAL REGISTRATION: Registration details for the 23 randomised controlled studies used in this pooled analysis are supplied in Additional File 4.

Propensity score matched comparison of subcutaneous and transvenous implantable cardioverter-defibrillator therapy in the SIMPLE and EFFORTLESS studies.

Aims: Comparison of outcomes between subcutaneous and transvenous implantable cardioverter-defibrillator (S-ICD and TV-ICD) therapy is hampered by varying patient characteristics and complication definitions. The aim of this analysis is to compare clinical outcomes of S-ICD and TV-ICD therapy in a matched cohort. Methods and results: Patients implanted with de novo implantable cardioverter-defibrillators without need for pacing were selected from two studies: SIMPLE (n = 1091 single and n = 553 dual chamber TV-ICDs) and EFFORTLESS (n = 798 S-ICDs). Subcutaneous implantable cardioverter-defibrillator patients were 1:1 matched on propensity score to TV-ICD patients. Propensity scores were calculated using 15 baseline characteristics including diagnosis. The Kaplan-Meier estimates for complications requiring invasive intervention, appropriate shocks, and inappropriate shocks were calculated at 3 years follow-up. The primary analysis yielded 391 patients pairs with balanced baseline characteristics, with mean age 55 ± 14 years, 49% ischaemic cardiomyopathy, mean left ventricular ejection fraction 40%, 71% primary prevention, and 89% of TV-ICDs were single chamber. Follow-up was mean 2.9 years in the S-ICD arm vs. 3.3 in the TV-ICD arm. All-cause complications occurred in 9.0% of S-ICD vs. 6.5% of TV-ICD patients, P = 0.29. Appropriate shocks occurred in 9.9% of S-ICD vs. 13.8% in TV-ICD patients, P = 0.03 and inappropriate shocks in 11.9% in S-ICD vs. 8.9% in TV-ICD patients (P = 0.07). Total shock burden (20 vs. 31, P = 0.05) and appropriate shock burden per 100 patients years (9 vs. 18, P = 0.02) were lower for S-ICD patients, while inappropriate shock burden was equal (11 vs. 13, P = 0.56). Conclusion: The earliest experience of the S-ICD demonstrates similar outcomes as contemporary TV-ICD therapy in a matched comparison with predominately single-chamber devices at 3 years follow-up.

Rescue medication use as a patient-reported outcome in COPD: a systematic review and regression analysis.

BACKGROUND: Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD). To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes. METHODS: A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015. Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint. Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group). Each association was assessed at 6 months and study end. RESULTS: Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation. Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George's Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end. Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028). CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001). The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively. A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations. CONCLUSION: This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes.

Patterns of physical activity and survival following cardiac resynchronization therapy implantation: the ALTITUDE activity study.

AIMS: Cardiac resynchronization therapy with implantable defibrillator backup (CRT-D) improves outcomes, but predictors and markers of response remain limited. Physical activity information collected by CRT devices may provide insights to CRT response and the relationship between activity changes and survival. METHODS AND RESULTS: Patients entered into the LATITUDE remote monitoring system from 2008 to 2012 after receipt of a new CRT-D were eligible. Mean daily activity was calculated from LATITUDE uploads at baseline (first 3-10 days following implant) and 6 months (180-210 days). Pairwise differences for baseline-6-month activity were calculated, and survival according to quintiles of 6-month activity change was assessed. Cox regression was used to examine the adjusted association between survival and baseline-6-month activity change. A total of 26 509 patients were followed for a median of 2.3 years (mean age 70.2 ± 11.0 years, 70.7% male). Mean baseline activity was 66.2 ± 47.7 min/day, with mean paired increase at 6 months of 37.1 ± 48.2 min/day [95% CI (confidence interval), 36.5-37.6, P < 0.0001], though 15.5% of patients did not improve or worsened at 6 months. Survival at 3 years was significantly higher in the largest baseline-6-month activity change quintile vs. the lowest quintile (88.9% vs. 62.1%, log-rank P-value < 0.001). Adjusted for age and gender, higher 6-month activity change was associated with a lower risk of death (adjusted hazard ratios 0.65 per 30 min increase in activity, 95% CI, 0.63-0.67). CONCLUSIONS: Change in physical activity between baseline and 6 months following CRT implantation is strongly associated with survival.

Echocardiographic abnormalities and their impact on health status in patients with COPD referred for pulmonary rehabilitation.

BACKGROUND AND OBJECTIVE: Both patients with cardiac diseases as well as those with COPD report an impaired health status. The frequencies of objectively assessed co-morbid cardiac diseases and their impact on health status in patients with COPD are unknown. We aimed to investigate echocardiographic abnormalities and their impact on health status in a large cohort of patients with COPD referred for pulmonary rehabilitation (PR). METHODS: In this cross-sectional, observational analyses, demographic and clinical characteristics were assessed during an inpatient pre-PR assessment. All patients underwent Doppler echocardiographic evaluation. Health status was assessed using the COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 514 patients (55.3% males, age: 64.1 (9.1) years, forced expiratory volume in 1 s (FEV1 ): 48.6 (20.0) % predicted) were included for analyses. Two hundred and seventy-six patients (53.7%) were diagnosed with one or more echocardiographic abnormalities. Most prevalent were left ventricular (LV) hypertrophy (LVH, 31.0%), increased right ventricular systolic pressure (RVSP, 20.4%) and impaired LV ejection fraction (LVEF, 16.5%). Of the 276 patients, 176 (63.8%) with echocardiographic abnormalities did not have these recorded in their medical history. Patients with echocardiographic abnormalities reported a worse health status as assessed with the SGRQ total score (62.5 (17.1) vs 59.3 (17.6) points, P = 0.044). CCQ and CAT did not differ between groups. CONCLUSION: More than half of the patients referred to PR had echocardiographic abnormalities of which two-third did not have them recorded in their medical history. We detected a limited impact of echocardiographic abnormalities on health status.

White matter lesions characterise brain involvement in moderate to severe chronic obstructive pulmonary disease, but cerebral atrophy does not.

BACKGROUND: Brain pathology is relatively unexplored in chronic obstructive pulmonary disease (COPD). This study is a comprehensive investigation of grey matter (GM) and white matter (WM) changes and how these relate to disease severity and cognitive function. METHODS: T1-weighted and fluid-attenuated inversion recovery images were acquired for 31 stable COPD patients (FEV1 52.1% pred., PaO2 10.1 kPa) and 24 age, gender-matched controls. T1-weighted images were segmented into GM, WM and cerebrospinal fluid (CSF) tissue classes using a semi-automated procedure optimised for use with this cohort. This procedure allows, cohort-specific anatomical features to be captured, white matter lesions (WMLs) to be identified and includes a tissue repair step to correct for misclassification caused by WMLs. Tissue volumes and cortical thickness were calculated from the resulting segmentations. Additionally, a fully-automated pipeline was used to calculate localised cortical surface and gyrification. WM and GM tissue volumes, the tissue volume ratio (indicator of atrophy), average cortical thickness, and the number, size, and volume of white matter lesions (WMLs) were analysed across the whole-brain and regionally - for each anatomical lobe and the deep-GM. The hippocampus was investigated as a region-of-interest. Localised (voxel-wise and vertex-wise) variations in cortical gyrification, GM density and cortical thickness, were also investigated. Statistical models controlling for age and gender were used to test for between-group differences and within-group correlations. Robust statistical approaches ensured the family-wise error rate was controlled in regional and local analyses. RESULTS: There were no significant differences in global, regional, or local measures of GM between patients and controls, however, patients had an increased volume (p = 0.02) and size (p = 0.04) of WMLs. In patients, greater normalised hippocampal volume positively correlated with exacerbation frequency (p = 0.04), and greater WML volume was associated with worse episodic memory (p = 0.05). A negative relationship between WML and FEV1 % pred. approached significance (p = 0.06). CONCLUSIONS: There was no evidence of cerebral atrophy within this cohort of stable COPD patients, with moderate airflow obstruction. However, there were indications of WM damage consistent with an ischaemic pathology. It cannot be concluded whether this represents a specific COPD, or smoking-related, effect.

Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes. Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown. We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome. METHODS: This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations. Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo. The primary end point was mean in-hospital blood glucose concentration. Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool. RESULTS: 52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo). All were included in the primary end point analysis. The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference -0.9 mmol/L, 95% CI -2.1 to +0.3; p=0.273). No significant between-group differences were observed on any of the secondary end points. Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants. CONCLUSION: Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes. TRIAL REGISTRATION NUMBER: ISRCTN66148745 and NCT01247870.

Blood eosinophils and inhaled corticosteroid/long-acting ß-2 agonist efficacy in COPD.

OBJECTIVE: We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. METHODS: Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57-75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. RESULTS: For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. DISCUSSION: Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.

Implantable Cardioverter Defibrillator Programming Characteristics, Shocked Rhythms, and Survival Among Patients Under Thirty Years of Age.

INTRODUCTION: Indications for implantable cardioverter defibrillators (ICDs) in young patients have expanded and differ from those in older adults. We sought to provide descriptive characteristics and data regarding ICD therapy and outcomes among younger and older ICD recipients. METHODS AND RESULTS: Demographics, device type and programming, remotely transmitted data, shock events, and survival were compared among younger (≤30 years) and older (>30 years) cohorts with ICDs from a single manufacturer followed on a remote network. The younger cohort included 904 patients (1.6% of all implants). This group had more females (46% vs. 25%; P < 0.01), single-coil leads (21% vs. 4%; P < 0.01), and single-chamber devices (46% vs. 34%; P < 0.01). Shock incidence was higher (40% younger vs. 32% older at 4 years; P < 0.01) and survival was better over comparable follow-up (88% vs. 72%; P < 0.01). Remote monitoring was associated with improved survival in both groups (93% vs. 86% ≤ 30 years, P < 0.01; 73% vs. 66% > 30 years, P < 0.01). Shock for polymorphic ventricular tachycardia/fibrillation (VT/VF) was more frequent in younger patients (12% vs. 5%; P < 0.01); 39% of all shocks were inappropriate. A 10-fold increased risk of mortality was seen among young patients with shocks for atrial fibrillation/flutter (AF/AFL). CONCLUSIONS: Differences in survival, shock incidence, and prognostic significance of VT/VF and AF/AFL exist between younger and older ICD recipients. These suggest distinct differences in myocardial substrates and diseases that ultimately impact ICD management.