Sally Spencer

Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

Abstract Objectives: To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Design: Double blind, placebo controlled study. Setting: Eighteen UK hospitals. Participants: 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV1) 50% of predicted normal. Interventions: Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo. Main outcome measures: Efficacy measures: rate of decline in FEV1 after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. Results: There was no significant difference in the annual rate of decline in FEV1 (P=0.16). Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). Conclusions: Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1. Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.

Bronchodilator reversibility testing in chronic obstructive pulmonary disease

Background: A limited or absent bronchodilator response is used to classify chronic obstructive pulmonary disease (COPD) and can determine the treatment offered. The reliability of the recommended response criteria and their relationship to disease progression has not been established. Methods: 660 patients meeting European Respiratory Society (ERS) diagnostic criteria for irreversible COPD were studied. Spirometric parameters were measured on three occasions before and after salbutamol and ipratropium bromide sequentially or in combination over 2 months. Responses were classified using the American Thoracic Society/GOLD (ATS) and ERS criteria. Patients were followed for 3 years with post-bronchodilator FEV1 and exacerbation history recorded 3 monthly and health status 6 monthly. Results: FEV1 increased significantly with each bronchodilator, a response that was normally distributed. Mean post-bronchodilator FEV1 was reproducible between visits (intraclass correlation 0.93). The absolute change in FEV1 was independent of the pre-bronchodilator value but the percentage change correlated with pre-bronchodilator FEV1 (r=−0.44; p<0.0001). Using ATS criteria, 52.1% of patients changed responder status between visits compared with 38.2% using ERS criteria. Smoking status, atopy, and withdrawing inhaled corticosteroids were unrelated to bronchodilator response, as was the rate of decline in FEV1, decline in health status, and exacerbation rate. Conclusion: In moderate to severe COPD bronchodilator responsiveness is a continuous variable. Classifying patients as “responders” and “non-responders” can be misleading and does not predict disease progression.

Impact of preventing exacerbations on deterioration of health status in COPD

Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St Georges Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent (<1.65 exacerbations·yr−1) and frequent (>1.65 exacerbations·yr−1). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.

Time course of recovery of health status following an infective exacerbation of chronic bronchitis

Background: The magnitude and time course of effect of an acute exacerbation of chronic bronchitis (AECB) on health status are not known. Data from the GLOBE study, a randomised double blind trial of antibiotic therapy, were used to investigate these effects. Methods: 438 patients with AECB received either gemifloxacin 320 mg once daily for 5 days (214 patients) or clarithromycin 500 mg twice daily for 7 days (224 patients) and were followed up for 26 weeks. St George’s Respiratory Questionnaire (SGRQ) scores were obtained at baseline and after 4, 12, and 26 weeks. Results: At presentation during an exacerbation SGRQ scores were worse (Total score difference 5.4 units, 95% CI 1.9 to 8.8, p=0.002) in patients who had a subsequent exacerbation during follow up. The greatest improvement in SGRQ score occurred within the first 4 weeks (mean 8.9 units, 95% CI 6.5 to 11.5, p<0.0001). Subsequently, scores improved more rapidly in patients with no further exacerbations. At 26 weeks the difference between the two groups was 9.6 units (95% CI 5.7 to 13.4, p<0.0001). In patients with no further exacerbations the SGRQ score improved between 4 and 12 weeks by a further 4.1 units (95% CI 2.2 to 5.9, p<0.0001). Conclusions: A single infective AECB has a sustained effect on health status. The recovery period is long even in patients who have no further exacerbations. A second episode within 6 months limits recovery markedly. Treatments that reduce exacerbation frequency could have a significant impact on health status.

Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study

Background: A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent “response” determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV1) after prednisolone, and whether the prednisolone response predicts 3 year changes in FEV1, health status, or number of exacerbations during placebo or fluticasone propionate treatment. Methods: Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV1 after prednisolone were investigated using multiple regression. The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study. Results: The post-bronchodilator FEV1 increased by a mean 60 ml (CI 46 to 74) after prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p<0.001). There was no relationship between the change in FEV1 after prednisolone and the response to inhaled bronchodilators, baseline FEV1, atopic status, age, or sex. The response to prednisolone, however expressed, was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate. Regression to the mean effects explained much of the apparent prednisolone response. The significant effect of treatment on decline in health status was not predicted by the prednisolone response. Conclusion: Patients with COPD cannot be separated into discrete groups of corticosteroid responders and non-responders. Current smoking reduces the FEV1 response to prednisolone. Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients.

Validation of a guideline-based composite outcome assessment tool for asthma control

BackgroundA global definition of asthma control does not currently exist. The purpose of this study was to validate two new guideline-based composite measures of asthma control, defined as totally controlled (TC) asthma and well controlled (WC) asthma.MethodsWe used data from 3416 patients randomised and treated in the multi-centre Gaining Optimal Asthma controL (GOAL) study. The criteria comprising the asthma control measures were based on Global Initiative for Asthma/National Institutes of Health guidelines. This validation study examined the measurement properties of the asthma control measures using data from run-in, baseline, 12 and 52 weeks. Forced expiratory volume in 1 second (FEV1) and the Asthma Quality of Life Questionnaire (AQLQ) were used as the reference criteria in the validation analysis.ResultsBoth measures had good discriminative ability showing significant differences in FEV1 and AQLQ scores between control classification both cross-sectionally and longitudinally (p < 0.001). Overall both of the composite measures accounted for more of the variance in FEV1 after 52 weeks than the individual components of each asthma control measure. Both of the reference criteria were independently related to each asthma control measure (p < 0.0001). The measures also had good predictive validity showing significant differences in FEV1 and AQLQ scores at 52 weeks by control classification at 12 weeks (p < 0.0001).ConclusionThe guideline-based composite asthma control measures of WC asthma and TC asthma have good psychometric properties and are both valid functional indices of disease control in asthma.

Using intermittent self-catheters: Experiences of people with neurological damage to their spinal cord

Abstract Purpose: The aim of this study was to investigate the experiences of using intermittent self-catheters (ISCs) among people with neurological damage to their spinal cord. This study sought to highlight the impact of using specific ISCs on users’ daily lives and to identify key features of product design which affected ease of use. Methods: In-depth interviews were conducted with 16 ISC users to elicit their views and experiences of ISC use. Interviewees were purposively sampled, primarily from the spinal cord injury population, via a variety of sources. Transcripts were analysed using the Framework method. Results: Key product characteristics which influenced ease of use both inside and outside the home were identified (e.g. gauge, rigidity and packaging); preferences were highly personal. ISC users were conscious of health consumer issues such as the financial costs, the environmental costs and the trustworthiness of the manufacturer. Wider self-catheterisation issues such as anxiety, self-image and control over bladder management were also important to interviewees. Conclusions: This study provides new information on key issues associated with experiences of ISC use by people living in a community setting who have neurological damage to their spinal cord. Implications for Rehabilitation Self-catheterisation is a commonly used method of bladder management for people with neurological damage to the spinal cord. Relatively little is known of users’ experiences with, and preferences for, different characteristics associated with intermittent self-catheters and their impact on daily life and well-being. ISC users require products that meet their individual preferences in relation to ease of use and ideology as a health consumer; one product type is unlikely to suit everyone. Product characteristics (e.g. gauge, rigidity and packaging) influence ease of ISC use inside and outside the home. ISC users may opt to choose different products accordingly.

Dual antibiotics for non-cystic fibrosis bronchiectasis

This is a protocol for a Cochrane Review. The objectives are to evaluate the effects of dual antibiotics for treatment of adults and children with non-cystic fibrosis bronchiectasis

Exploring the outcomes in studies of primary frozen shoulder: is there a need for a core outcome set?

PurposeIn our study we explored the need to define a core outcome set for primary frozen shoulder.MethodsWe investigated the outcomes used by studies included in a systematic review of the management of primary frozen shoulder; surveyed which primary outcome measures health care professionals considered important; and re-examined papers previously obtained for a systematic review of patients’ views of interventions for frozen shoulder to investigate their views on outcomes.ResultsThirty-one studies investigated the outcomes range of movement (28 studies), pain (22), function and disability (22), adverse events (13), quality of life (7) and other outcomes (5). Many different types of pain and ranges of movement were measured. Function and disability was measured using fifteen instruments, the content of which varied considerably. Function and disability, pain and range of movement (132, 108 and 104 respondents, respectively) were most often cited by health care professionals as the primary outcome measure that should be used. Searches identified one paper that included patients’ views. Outcomes of importance to patients were pain at night, general pain, reduced mobility (resulting in modification of activities) and the emotional impact of frozen shoulder.ConclusionsWe identified a diverse range of outcomes that have been used or are considered to be important. The development of a core outcome set would improve the design and reporting of studies and availability of data for evidence synthesis. Methods used to develop a core outcome set should be robust, transparent and reflect the views of all stakeholders.

Head-to-head trials of antibiotics for non-cystic fibrosis bronchiectasis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the comparative effects of different antibiotics in the treatment of adults and children with non-cystic fibrosis bronchiectasis.