Guus M. Asijee

Eosinophilia, Frequent Exacerbations, and Steroid Response in Chronic Obstructive Pulmonary Disease

4 Department 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; 5 Department of Metabolic Medicine, University of Modena & Reggio Emilia, Modena, Italy; 6 Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research (DZL), Grosshansdorf, Germany; 7 Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands; 8 Department of Biostatistics and Data Sciences, Boehringer Ingelheim, Bracknell, UK

Health Status and Morbidities in Resident Relatives of Patients With COPD.

OBJECTIVESnResident relatives of patients with chronic obstructive pulmonary disease (COPD) may play a major role in obtaining a healthy lifestyle for patients. Little is known about resident relatives. This study aimed to compare health status, morbidities, care dependency, and mobility between patients with COPD and their resident relatives.nnnDESIGNnCross-sectional study.nnnPARTICIPANTSnStable patients with moderate to very severe COPD (n = 194) and their resident relatives (n = 194) were visited in their home environment.nnnMEASUREMENTSnPost-bronchodilator spirometry was assessed and generic health status was measured using the EuroQol-5 Dimensions and the Assessment of Quality of Life with 8 dimensions. Care dependency was measured using the Care Dependency Scale. Mobility was measured using the Timed Up and Go test (TUG). Morbidities (COPD, hypertension, anxiety and depression, obesity, and muscle wasting) were determined using accepted disease cutoff points and/or receiving specific treatment.nnnRESULTSnAge (patients: 66.0 [8.7], resident relatives: 64.8 [9.7]) and gender (male patients: 53%, male resident relatives: 45%) were comparable. Patients had worse generic health status, higher level of care dependency, and worse mobility. 29% of the resident relatives had airflow limitation based on the Tiffeneau index and 19% based on the lower limit of normal, 33% were current smokers, and 92% had at least one chronic condition. Resident relatives more frequently had hypertension (46% versus 69%).nnnCONCLUSIONnResident relatives of patients with COPD are often current smokers and often have undiagnosed morbidities. Although their health status is better compared with patients, their disease management and health behavior should also be considered when advising patients in obtaining a healthier lifestyle and also when involving them as informal caregivers.

Tiotropium and Salmeterol in COPD Patients at Risk of Exacerbations: A Post Hoc Analysis from POET-COPD®

IntroductionAmong patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events. The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known.MethodsA post hoc analysis of patients at low (≤1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (≥2 exacerbations [oral steroids/antibiotics requirement] or ≥1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD®) database.ResultsCompared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76–0.92; pxa0=xa00.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81–0.99; pxa0=xa00.0383) in patients at high exacerbation risk. With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80–1.00; pxa0=xa00.0478). For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol. With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71–1.07; pxa0=xa00.1968).DiscussionThis analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk.FundingBoehringer Ingelheim and Pfizer.Clinical trial registration number: ClinicalTrials.gov NCT00563381.

Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial

BackgroundPhysical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation.Methods/DesignA prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVCu2009<u20090.7 and FEV1u2009<u200980% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-indexu2009<u20090.6) and who experience a COPD exacerbation will be asked within 56xa0days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients’ perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6xa0weeks, 3, 6, 12 and 24xa0months after inclusion.DiscussionWays to minimise potential problems regarding the execution of this study will be discussed.Trial registrationThe Netherlands National Trial Register NTR1972.

Effects of Tiotropium on Exacerbations in Patients with COPD with Low or High Risk of Exacerbations: A Post-Hoc Analysis from the 4-Year UPLIFT ® Trial

Background: A history of past exacerbations is a predictor of future events for patients with chronic obstructive pulmonary disease (COPD). Very little is known about the effect of pharmacologic therapies on patients with frequent or infrequent exacerbations. Methods: We conducted a post-hoc analysis of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®)trial database. Patients were classified as having a low risk of exacerbations if they experienced ≤1 exacerbation and no COPD-related hospitalization(s) in the year preceding trial entry or as high risk of exacerbations if they had ≥2 exacerbations (courses of oral steroids/antibiotics) or ≥1 COPD-related hospitalization(s) in the year preceding the trial. Results: In patients at low risk or high risk for exacerbations, compared to placebo, tiotropium significantly reduced: 1) the time to first COPD exacerbation (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.74, 0.88; p <0.0001; HR: 0.89; 95% CI: 0.81, 0.97; p=0.0066, respectively); 2) the number of COPD exacerbations (rate ratio [RR]: 0.79; 95% CI: 0.72, 0.86; p<0.0001; RR: 0.88; 95% CI: 0.81; 0.95; p=0.0009). Furthermore, upon treatment with tiotropium, the proportion of patients transitioning from the low- to the high-risk exacerbations group was statistically lower compared to placebo (RR: 0.78; 95% CI: 0.67, 0.92; p=0.0030) Conclusions: This analysis shows that tiotropium reduces the risk of subsequent exacerbation and also prolongs time to first exacerbation, in both the high- and low-risk exacerbator subgroups. It also decreases the proportion of patients who shift from the low- to the high-risk exacerbations group compared to placebo.

Efficacy of a physical exercise training programme COPD in primary care: study protocol of a randomized controlled trial

BackgroundChronic obstructive pulmonary disease (COPD) is recognized as a systemic illness with significant extra-pulmonary features, such as exercise intolerance and muscle weakness. Pulmonary rehabilitation has been shown to be very effective in counteracting these consequences in patients with more advanced COPD. However, limited data is available on the efficacy of a physical exercise training programme in patients with mild to moderate COPD in primary care. Furthermore, it is unknown if improved exercise capacity translates into enhanced daily physical activities. The aim of this paper is to describe the design of a randomized controlled trial to assess the efficacy of a physical exercise training programme in patients with mild to moderate COPD.Methods/designIn this randomized controlled trial situated in the primary care setting, 102 patients with mild to moderate airflow obstruction (FEV1u2009≥u200950% of predicted), dyspnoea and a physically inactive lifestyle will be randomized to an intervention or control group. The intervention group receives a 4-month physical exercise training programme at a local physiotherapy practice, which includes exercise training, resistance training, breathing exercises and advises on how to increase the level of physical activity. The control group receives usual care, i.e. advises on how to increase the level of physical activity and a sham treatment at a local physiotherapy practice of which no physiological training stimulus can be expected. Primary outcome is functional exercise capacity at 4-months measured on the six-minute walk distance. Secondary outcomes include peripheral muscle strength, physical activity in daily life, health related quality of life, Medical Research Council (MRC) dyspnoea score and patients’ perceived effectiveness. Follow-up measurement will take place at 6xa0months after baseline.DiscussionThis will be one of the first studies to evaluate the efficacy of a physical exercise training programme in patients with mild to moderate COPD completely recruited and assessed in primary care. The results of this trial may give a unique insight into the potential of the implementation of an easy, close-to-home rehabilitation programme.Trial registrationThe Netherlands National Trial Register NTR1471.

Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial.

BackgroundChronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials.MethodsRetrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95xa0% CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments.ResultsThe CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alphau2009=u20090.05 two-sided, 90xa0% power) for studies of 1, 2, 3, and 4xa0years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies.ConclusionsA composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo.Trial registrationNCT00144339.