Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial.

BACKGROUND: Short-acting ß2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD. METHODS: The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 µg, once-daily umeclidinium 62.5 µg or twice-daily salmeterol 50 µg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates. RESULTS: At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59-74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: - 0.56 [p < 0.001]; low: - 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day. CONCLUSIONS: In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome. FUNDING: GlaxoSmithKline (study number 201749 [NCT03034915]).

Consumer segmentation and time interval between types of hospital admission: a clinical linkage database study.

Background: Healthcare policies target unplanned hospital admissions and 30-day re-admission as key measures of efficiency, but do not focus on factors that influence trajectories of different types of admissions in the same patient over time. Objectives: To investigate the influence of consumer segmentation and patient factors on the time intervals between different types of hospital admission. Research design, subjects and measures: A cohort design was applied to an anonymised linkage database for adults aged 40 years and over (N = 58 857). Measures included Mosaic segmentation, multimorbidity defined on six chronic condition registers and hospital admissions over a 27-month time period. Results: The shortest mean time intervals between two consecutive planned admissions were: 90 years and over (160 days (95% confidence interval (CI): 146-175)), Mosaic groups 'Twilight subsistence' (171 days (164-179)) or 'Welfare borderline' and 'Municipal dependency' (177 days (172-182)) compared to the reference Mosaic groups (186 days (180-193)), and multimorbidity count of four or more (137 days (130-145)). Mosaic group 'Twilight subsistence' (rate ratio (RR) 1.22 (95% CI: 1.08-1.36)) or 'Welfare borderline' and 'Municipal dependency' RR 1.20 (1.10-1.31) were significantly associated with higher rate to an unplanned admission following a planned event. However, associations between patient factors and unplanned admissions were diminished by adjustment for planned admissions. Conclusion: Specific consumer segmentation and patient factors were associated with shorter time intervals between different types of admissions. The findings support innovation in public health approaches to prevent by a focus on long-term trajectories of hospital admissions, which include planned activity.

Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins.

BACKGROUND: Low testosterone levels occur in over 40% of men with type 2 diabetes mellitus (T2DM) and have been associated with increased mortality. Testosterone replacement together with statins and phosphodiesterase 5 inhibitors (PDE5I) are widely used in men with T2DM. PURPOSE: To determine the impact of testosterone and testosterone replacement therapy (TRT) on mortality and assess the independence of this effect by adjusting statistical models for statin and PDE5I use. METHODS: We studied 857 men with T2DM screened from five primary care practices during April 2007-April 2009. Of the 857 men, 175/637 men with serum total testosterone ≤ 12 nmol/l or free testosterone (FT) ≤ 0.25 nmol/l received TU for a mean of 3.8 ± 1.2 (SD) years. PDE5I and statins were prescribed to 175/857 and 662/857 men respectively. All-cause mortality was the primary end-point. Cox regression models were used to compare survival in the three testosterone level/treatment groups, the analysis adjusted for age, statin and PDE5I use, BMI, blood pressure and lipids. RESULTS: Compared with the Low T/untreated group, mortality in the Normal T/untreated (HR: 0.62, CI: 0.41-0.94) or Low T/treated (HR: 0.38, CI: 0.16-0.90) groups was significantly reduced. PDE5I use was significantly associated with reduced mortality (HR: 0.21, CI: 0.066-0.68). After repeating the Cox regression in the 682 men not given a PDE5I, mortality in the Normal T/untreated and Low T/treated groups was significantly lower than that in the reference Low T/untreated group. Mortality in the PDE5I/treated was significantly reduced compared with the PDE5I/untreated group (OR: 0.06, CI: 0.009-0.47). CONCLUSIONS: Testosterone replacement therapy is independently associated with reduced mortality in men with T2DM. PDE5I use, included as a confounding factor, was associated with decreased mortality in all patients and, those not on TRT, suggesting independence of effect. The impact of PDE5I treatment on mortality (both HR and OR < 0.25) needs confirmation by independent studies.

Measuring respiratory symptoms in clinical trials of COPD: reliability and validity of a daily diary.

BACKGROUND: Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease. OBJECTIVE: To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT). METHODS: Qualitative: patient focus group and interviews to address content validity. Quantitative: secondary data analyses to test reliability and validity. RESULTS: Qualitative: n=84; mean (SD) age 65 (10) years, FEV1 1.2(0.4) L; 44% male. Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure. Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male. Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough & Sputum, and RS-Chest Symptoms; second-order FA supported a general factor and total score. Reliability (total and subscales): 0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively. VALIDITY: Total scores correlated significantly (p < 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p < 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p < 0.0001 (RS-Cough & Sputum with Symptoms). RS-Breathlessness correlated with rescue medication use (r=0.32, p < 0.0001), clinician-reported mMRC (r=0.33, p < 0.0001), and FEV1% predicted (r=-0.17, p < 0.05). E-RS scores differentiated groups based on chronic bronchitis diagnosis (p < 0.01-0.001), smoking status (p < 0.05-0.001), and rescue medication use (p < 0.05-0.0001). CONCLUSIONS: Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD. Further study of sensitivity to change is warranted.

Maternal and child health after assisted vaginal delivery: five-year follow up of a randomised controlled study comparing forceps and ventouse.

OBJECTIVE: To undertake a five year follow up of a cohort of women and children delivered by forceps or vacuum extractor in a randomised controlled study. DESIGN: Follow up of a randomised controlled trial. SETTING: District general hospital in the West Midlands. POPULATION: Follow up questionnaires were sent to 306 of the 313 women originally recruited at the North Staffordshire Hospital to a randomised controlled study comparing forceps and vacuum extractor for assisted delivery. Two hundred and twenty-eight women responded (74.5%) and all were included in the study; forceps (n = 115) and vacuum extractor (n = 113). MAIN OUTCOME MEASURES: Bowel and urinary dysfunction, child vision assessment, and child development. RESULTS: Maternal adverse symptoms at long term follow up were relatively common. Urinary incontinence of various severity was reported by 47%, bowel habit urgency was reported by 44% (98/225), and loss of bowel control 'sometimes' or 'frequently' by 20% of women (46/226). No significant differences between instruments were found in terms of either bowel or urinary dysfunction. Overall, 13% (20/158) of children were noted to have visual problems. There was no significant difference in visual function between the two groups: ventouse 11/86 (12.8%), compared with forceps 9/72 (12.5%); odds ratio 0.97, 95% CI 0.38-2.50. Of the 20 children with visual problems, a family history was known in 18, and 17/18 (94%) had a positive family history for visual problems. No significant differences in child development were found between the two groups. CONCLUSIONS: There is no evidence to suggest that at five years after delivery use of the ventouse or forceps has specific maternal or child benefits or side effects.

The role of regional anaesthesia in the surgical management of vulval malignancy.

Abstract Surgical excision is the management of choice in vulval cancer however, the patient population are typically elderly and comorbid, for whom general anaesthesia (GA) carries considerable risk. The outcome of 107 procedures were reviewed in order investigate the postoperative complication rates associated with general and regional anaesthesia for the surgical management of vulval cancer. GA was used in 78 (72.9%) cases; 27 (22.9%) had a regional anaesthetic (spinal/epidural/ileoinguinal) and two women had a GA following a failed spinal anaesthetic. Women having a regional anaesthetic were significantly older (p = 0.0198), had a higher ACE (p = 0.0001) and ASA score (p < 0.0001) than those having a GA. There was an association between GA and grade II+ complications, compared with regional techniques (odds ratio, OR 2.72) but this was not significant due to the small number of events. Regional anaesthetic techniques are safe, well-tolerated alternatives to GA for the surgical management of vulval cancer, especially in an elderly and comorbid population.

Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study.

We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1)) <60% predicted. COPD exacerbations were defined by worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate) or hospital admission (severe). Seasonality effect was calculated as the proportion of patients experiencing an exacerbation each month. Exacerbations in the northern and southern regions showed an almost two-fold increase in the winter months. No seasonal pattern occurred in the tropics. Overall, 38% of exacerbations were treated with antibiotics only, 19% with systemic corticosteroids only and 43% with both, while 20% required hospital admission irrespective of the season. Exacerbation frequency was associated with older age, lower body mass index, lower FEV(1) % pred and history of prior exacerbations. Females and patients with worse baseline breathlessness, assessed using the Medical Research Council (MRC) dyspnoea scale, exacerbated more often (rate ratio (RR) for male versus female 0.7, 95% CI 0.7-0.8 (p<0.001); RR for MRC dyspnoea score 3 versus 1 and 2 combined 1.1, 95% CI 1.1-1.2 (p<0.001)). The effect of season was independent of these risk factors. COPD exacerbations and hospitalisations were more frequent in winter.

Properties of the COPD assessment test in a cross-sectional European study.

A short, easy-to-use health status questionnaire is needed in the multidimensional assessment of chronic obstructive pulmonary disease (COPD) in routine practice. The performance of the eight-item COPD assessment test (CAT) was analysed in 1,817 patients from primary care in seven European countries. The CAT has a scoring range of 0-40 (high score representing poor health status). Mean CAT scores indicated significant health status impairment that was related to severity of airway obstruction, but within each Global Initiative for Obstructive Lung Disease stage (I to IV) there was a wide range of scores (I: 16.2 ± 8.8; II: 16.3 ± 7.9; III: 19.3 ± 8.2; and IV: 22.3 ± 8.7; I versus II, p = 0.88; II versus III, p<0.0001; III versus IV, p = 0.0001). CAT scores showed relatively little variability across countries (within ± 12% of the mean across all countries). Scores were significantly better in patients who were stable (17.2 ± 8.3) versus those suffering an exacerbation (21.3 ± 8.4) (p<0.0001); and in patients with no (17.3 ± 8.1) or one or two (16.6 ± 8.2) versus three or more (19.7 ± 8.5) comorbidities (p<0.0001 for both). The CAT distinguished between classes of other impairment measures and was strongly correlated with the St George's Respiratory Questionnaire (r = 0.8, p<0.0001). The CAT is a simple and easy-to-use questionnaire that distinguishes between patients of different degrees of COPD severity and appears to behave the same way across countries.

Sensitivity to change of the cutaneous electrical perceptual threshold test in longitudinal monitoring of spinal cord injury.

STUDY DESIGN: Prospective longitudinal experimental study. OBJECTIVES: The aim of this study was to assess the sensitivity to change of the electrical perceptual threshold (EPT) test during the longitudinal monitoring of neurological changes in patients with incomplete spinal cord injury (SCI). SETTING: National Spinal Injuries Centre, Stoke Mandeville Hospital, Buckinghamshire Hospitals NHS Trust, Buckinghamshire, UK. METHODS: Perceptual threshold to 3 Hz cutaneous electrical stimulation was measured in 11 patients with incomplete SCI at selected American Spinal Injuries Association (ASIA) sensory key points on four occasions. The first three measurements were performed within a 5-day period (baseline) and the fourth measurement (follow-up) at least 9 months later. The results were tested for statistical significance and the effect sizes were calculated. RESULTS: There were no significant differences between the EPT results of the three baseline assessments. When the mean baseline and follow-up EPT results were compared, there were no significant differences in EPT values above the sensory level of lesion, but a significant difference (reduction in threshold values) was found at and below the level of SCI, with medium and large effect sizes, respectively. CONCLUSION: The EPT test showed good sensitivity to change in dermatomes at and directly below the sensory level of the SCI. This makes it a potentially useful quantitative sensory instrument for detecting changes in sensory function during longitudinal monitoring of patients with SCI.

Quantification of dyspnoea using descriptors: development and initial testing of the Dyspnoea-12.

RATIONALE: Dyspnoea is a debilitating and distressing symptom that is reflected in different verbal descriptors. Evidence suggests that dyspnoea, like pain perception, consists of sensory quality and affective components. The objective of this study was to develop an instrument that measures overall dyspnoea severity using descriptors that reflect its different aspects. METHODS: 81 dyspnoea descriptors were administered to 123 patients with chronic obstructive pulmonary disease (COPD), 129 with interstitial lung disease and 106 with chronic heart failure. These were reduced to 34 items using hierarchical methods. Rasch analysis informed decisions regarding further item removal and fit to the unidimensional model. Principal component analysis (PCA) explored the underlying structure of the final item set. Validity and reliability of the new instrument were further assessed in a separate group of 53 patients with COPD. RESULTS: After removal of items with hierarchical methods (n = 47) and items that failed to fit the Rasch model (n = 22), 12 were retained. The "Dyspnoea-12" had good internal reliability (Cronbach's alpha = 0.9) and fit to the Rasch model (chi(2) p = 0.08). Items patterned into two groups called "physical"(n = 7) and "affective"(n = 5). In the separate validation study, Dyspnoea-12 correlated with the Hospital Anxiety and Depression Scale (anxiety r = 0.51; depression r = 0.44, p<0.001, respectively), 6-minute walk distance (r = -0.38, p<0.01) and MRC (Medical Research Council) grade (r = 0.48, p<0.01), and had good stability over time (intraclass correlation coefficient = 0.9, p<0.001). CONCLUSION: Dyspnoea-12 fulfills modern psychometric requirements for measurement. It provides a global score of breathlessness severity that incorporates both "physical" and "affective" aspects, and can measure dyspnoea in a variety of diseases.

Cognitive function in COPD.

In order to characterise the overall clinical picture of chronic obstructive pulmonary disease (COPD) a better understanding of all relevant comorbidities is required. It is increasingly recognised that COPD is a multi-component disease, but little attention has been paid to its effects on cognitive function. Cognitive dysfunction is associated with increased mortality and disability; however, it remains poorly understood in COPD. This review examines mechanisms of injury and dysfunction to the brain and considers the methods used to evaluate cognition, and assembles evidence concerning the nature and level of cognitive impairment in COPD. Our main findings are: 1) there may be a pattern of cognitive dysfunction specific to COPD; 2) cognitive function is only mildly impaired in patients without hypoxaemia; 3) the incidence of cognitive dysfunction is higher in hypoxaemia; 4) hypoxaemia, hypercapnia, smoking and comorbidities (such as vascular disease) are unlikely to account for all of the cognitive dysfunction seen in COPD; 5) there is weak or no association between cognitive function and mood, fatigue or health status; 6) cognitive dysfunction may be associated with increased mortality and disability; and 7) there is limited evidence for a significant effect of treatment on cognitive function.

Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study.

The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400-123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200-241,700) USD compared to 24,200 (15,200-56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.

Childhood evaluation of salmeterol tolerance--a double-blind randomized controlled trial.

Long acting beta(2)-agonists (LABA) are widely used in children with asthma. Data from adults suggest that there is tachyphylaxis particularly to the bronchoprotective effects of LABA. There are no data in children. To determine whether LABA are subject to tachyphylaxis in school-aged children. Children were eligible for participation if they remained symptomatic on 400 microg of beclometasone dipropionate equivalent/day. Participants undertook a 4-wk run in period with open-label fluticasone 100 microg BD via Diskus. Children were then randomized to receive fluticasone 100 microg BD or salmeterol/fluticasone 50/100 microg BD via Diskus in a double-blind manner. Children underwent spirometry, cold air challenge and salbutamol reversibility testing at baseline, 4 and 8 wk. 37/42 children completed the study. There were significant improvements in basal FEV1 (% predicted) in the salmeterol/fluticasone group (n = 21) (+6.4% (95% CI: 2.4-10.5) p = 0.0033) but not in the fluticasone group (n = 16) [+1.2 (95% CI: -3.4 to 5.8) p = 0.5900]. There was a non-significant reduction in fall in FEV1 provoked by cold air in both groups. There was a significant lessening in the acute salbutamol response after 8 wk in the salmeterol/fluticasone group [-11.4% (95% CI: -17.6 to -5.2) p = 0.0010] but not in the fluticasone group [-1.6% (95% CI: -9.8 to 6.6) p = 0.6827]. Salmeterol/fluticasone therapy significantly improves basal FEV(1) in asthmatic children however, there is negligible additional bronchoprotection by week 4 of treatment and there is significant attenuation of salbutamol responsiveness when compared with fluticasone alone. Some of this reduction in salbutamol response may relate to the concurrent improvements in baseline lung function.

Enhancement of the efficacy of a carbamate nematicide against the potato cyst nematode, Globodera pallida, through mycorrhization in commercial potato fields.

Two experiments were conducted over 2 years in commercial potato fields in Shropshire, UK, to evaluate the compatibility of the nematicide aldicarb with commercial inocula of arbuscular mycorrhizal fungi (AMF) in the control of the potato cyst nematode Globodera pallida. The AMF used were Vaminoc (mixed-AMF inoculum), Glomus intraradices (BioRize BB-E) and G. mosseae (isolate BEG 12). In the absence of AMF, the in-soil hatch of G. pallida increased 30% (P < 0.01) from wk-2 to wk-4 after planting. Inoculation of physiologically-aged potato (cv. Golden Wonder) tubers with AMF eliminated this delay in G. pallida hatch by stimulating a mean increase of 32% (P < 0.01) in hatch within 2 wk after planting. In the aldicarb-treated plots in Experiment 1, G. pallida multiplication rate was 38% lower (P < 0.05) in roots of AMF-inoculated than noninoculated plants, but in Experiment 2, this effect was slightly lower (P = 0.07). In these plots, the single AMF inocula showed also a weak trend (P = 0.10) towards greater tuber yields relative to their noninoculated counterparts. Mycorrhization therefore appears to enhance the efficacy of carbamate nematicides against G. pallida and consequently more research is proposed to validate these findings and fully explore the potential of this model.

Simple non-mydriatic retinal photography is feasible and demonstrates retinal microvascular dilation in Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is associated with an increased risk of myocardial infarction and stroke but it remains unclear how to identify microvascular changes in this population. OBJECTIVES: We hypothesized that simple non-mydriatic retinal photography is feasible and can be used to assess microvascular damage in COPD. METHODS: Novel Vascular Manifestations of COPD was a prospective study comparing smokers with and without COPD, matched for age. Non-mydriatic, retinal fundus photographs were assessed using semi-automated software. RESULTS: Retinal images from 24 COPD and 22 control participants were compared. Cases were of similar age to controls (65.2 vs. 63.1 years, p = 0.38), had significantly lower Forced Expiratory Volume in one second (FEV1) (53.4 vs 100.1% predicted; p < 0.001) and smoked more than controls (41.7 vs. 29.6 pack years; p = 0.04). COPD participants had wider mean arteriolar (155.6 ±15 uM vs. controls [142.2 ± 12 uM]; p = 0.002) and venular diameters (216.8 ±20.7 uM vs. [201.3± 19.1 uM]; p = 0.012). Differences in retinal vessel caliber were independent of confounders, odds ratios (OR) = 1.08 (95% confidence intervals [CI] = 1.02, 1.13; p = 0.007) and OR = 1.05 (CI = 1.01, 1.09; p = 0.011) per uM increase in arteriolar and venular diameter respectively. FEV1 remained significantly associated with retinal vessel dilatation r = -0.39 (p = 0.02). CONCLUSIONS: Non-mydriatic retinal imaging is easily facilitated. We found significant arteriole and venous dilation in COPD compared to age-matched smokers without COPD associated with lung function independent of standard cardiovascular risk factors. Retinal microvascular changes are known to be strongly associated with future vascular events and retinal photography offers potential to identify this risk. TRIAL REGISTRATION: clinicaltrials.gov NCT02060292.

Adherence to inhaled therapy, mortality and hospital admission in COPD.

BACKGROUND: Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity. METHODS: Data on drug adherence from a randomised double-blind trial comparing inhaled salmeterol 50 microg + fluticasone propionate 500 microg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study. RESULTS: Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence. CONCLUSION: Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.

Development and first validation of the COPD Assessment Test.

There is need for a validated short, simple instrument to quantify chronic obstructive pulmonary disease (COPD) impact in routine practice to aid health status assessment and communication between patient and physician. Current health-related quality of life questionnaires provide valid assessment of COPD, but are complex, which limits routine use. The aim of the present study was to develop a short validated patient-completed questionnaire, the COPD Assessment Test (CAT), assessing the impact of COPD on health status. 21 candidate items identified through qualitative research with COPD patients were used in three prospective international studies (Europe and the USA, n = 1,503). Psychometric and Rasch analyses identified eight items fitting a unidimensional model to form the CAT. Items were tested for differential functioning between countries. Internal consistency was excellent: Cronbach's alpha = 0.88. Test re-test in stable patients (n = 53) was very good (intra-class correlation coefficient 0.8). In the sample from the USA, the correlation with the COPD-specific version of the St George's Respiratory Questionnaire was r = 0.80. The difference between stable (n = 229) and exacerbation patients (n = 67) was five units of the 40-point scale (12%; p<0.0001). The CAT is a short, simple questionnaire for assessing and monitoring COPD. It has good measurement properties, is sensitive to differences in state and should provide a valid, reliable and standardised measure of COPD health status with worldwide relevance.

Methods for therapeutic trials in COPD: lessons from the TORCH trial.

The TORCH (Towards a Revolution in COPD Health) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease. These include collection of off-treatment exacerbation data, analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids (ICS) prior to randomisation. When effective medications are available to patients who withdraw, inclusion of off-treatment data can mask important treatment effects on exacerbation rates. Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments. The negative binomial model is currently the best approach to statistical analysis of exacerbation rates, while analysis of time to exacerbation can supplement this approach. In the TORCH trial, exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments. Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo, regardless of prior use of ICS before entry to the study. Factorial analysis provides an alternative analysis for trials with combinations of treatments, but assumes no interaction between treatments, an assumption which cannot be verified by a significance test. No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality.

Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results.

Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.

Spasticity, an impairment that is poorly defined and poorly measured.

OBJECTIVE: To explore, following a literature review, whether there is a consistent definition and a unified assessment framework for the term 'spasticity'. The congruence between the definitions of spasticity and the corresponding methods of measurement were also explored. DATA SOURCES: The search was performed on the electronic databases Web of Science, Science Direct and MEDLINE. REVIEW METHODS: A systematic literature search of publications written in English between the years 1980 and 2006 was performed with the following keywords: spasticity and tone. The search was limited to the following keywords: stroke, hemiplegia, upper, hand and arm. RESULTS: Two hundred and fifty references contributed to this review (190 clinical trials, 46 literature reviews, and 14 case reports). Seventy-eight used the Lance definition; 88 equated spasticity with increased muscle tone; 78 provided no definition; and six others used their own definitions for spasticity. Most papers used a single measure and some used more than one. Forty-seven papers used neurophysiological methods of testing, 228 used biomechanical methods of measurement or assessment, 25 used miscellaneous clinical measures (e.g. spasm frequency scales) and 19 did not explicitly describe a measure. CONCLUSION: The term spasticity is inconsistently defined and this inconsistency will need to be resolved. Often, the measures used did not correspond to the clinical features of spasticity that were defined within a paper (i.e. internal validity was compromised). There is need to ensure that this lack of congruence is addressed in future research.