Condições mecânicas do sistema respiratório em adultos com fibrose cística: estudo pela espirometria, pletismografia e técnica de oscilações forçadas

A fibrose cística (FC) é a doença autossômica recessiva mais comum na população branca que leva à redução na expectativa de vida. A doença pulmonar é a maior causa de morbidade e mortalidade. A relevância do presente estudo se dá diante de alguns fatores: aumento drástico da sobrevida média nos últimos 60 anos na FC, a fisiopatologia pulmonar não é bem compreendida, ausência de estudos reportados na literatura, até o momento, utilizando a técnica de oscilações forçadas (TOF) exclusivamente em adultos com FC. Assim sendo os objetivos deste estudo são: analisar as alterações da mecânica respiratória em adultos com FC através da espirometria, pletismografia e TOF; correlacionar os resultados da TOF aos espirométricos e pletismográficos e avaliar a sensibilidade e especificidade da TOF nestes indivíduos. É um estudo de corte transversal descritivo, no qual foram analisados dois grupos de indivíduos: controle (n=23) e FC (n=27). Os resultados foram expressos através média desvio-padrão. As técnicas funcionais respiratórias foram realizadas na seguinte sequência: TOF, espirometria, pletismografia. Na pletismografia foram avaliados os parâmetros: CPT (capacidade pulmonar total), CRF (capacidade residual funcional) e VR (volume residual), CRF/CPT e VR/CPT, resistência (Rva) e condutância específica das vias aéreas (SGva). Na espirometria: volume expiratório forçado no primeiro segundo (VEF1), capacidade vital forçada (CVF), fluxo expiratório entre 25% e 75% (FEF25%-75%) da CVF (FEF25%-75%) e razões VEF1/CVF (%) e FEF/CVF (%). Na TOF: propriedades resistivas do sistema respiratório- R0 (resistência no intercepto), Rm (resistência média) e S (inclinação da reta de resistência) e propriedades reativas: Cdin,sr (complacência dinâmica do sistema respiratório), Xm (reatância média), frequência de ressonância (fr); e o módulo da impedância em 4 Hz (׀Zrs4Hz׀). Na espirometria o distúrbio ventilatório obstrutivo (DVO) com CVF reduzida foi predominante, com marcante redução do FEF25%-75% no grupo FC (p<0,0001) em relação ao controle. Na pletismografia: destacou-se a elevação de VR, na presença de CPT normal e elevação da Rva e redução da SGva no grupo FC. Alterações da TOF ocorridas no grupo FC em relação ao controle: aumento de R0 e Rm (p<0,0001) e fr (p<0,0002), relacionados à obstrução das vias aéreas; redução de S (p<0,0006), Xm (p<0,0001) associadas à não-homogeneidade do sistema respiratório e Cdin,sr (p<0,0001), relacionada à redução da complacência pulmonar; aumento do módulo da impedância em 4 Hz (׀Zrs4Hz׀) (representando a carga mecânica total do sistema respiratório) resultante da interação das demais alterações da TOF citadas. Os parâmetros da TOF apresentaram correlações muito boas com a espirometria e moderadas com a pletismografia. Rm foi o único parâmetro que não se relacionou com nenhuma destas técnicas. A sensibilidade e especificidade da TOF em adultos com FC apresentaram valores elevados, sobretudo nos parâmetros reativos, em especial, Xm (85,2% e 73,9% respectivamente e área sob a curva de 0,86).

Alveolar nitric oxide and its role in pediatric asthma control assessment

Resumen Background: Nitric oxide can be measured at multiple flow rates to determine proximal (maximum airway nitric oxide flux; Jaw(NO)) and distal inflammation (alveolar nitric oxide concentration; CA(NO)). The main aim was to study the association among symptoms, lung function, proximal (maximum airway nitric oxide flux) and distal (alveolar nitric oxide concentration) airway inflammation in asthmatic children treated and not treated with inhaled glucocorticoids. Methods: A cross-sectional study with prospective data collection was carried out in a consecutive sample of girls and boys aged between 6 and 16 years with a medical diagnosis of asthma. Maximum airway nitric oxide flux and alveolar nitric oxide concentration were calculated according to the two-compartment model. In asthmatic patients, the asthma control questionnaire (CAN) was completed and forced spirometry was performed. In controls, differences between the sexes in alveolar nitric oxide concentration and maximum airway nitric oxide flux and their correlation with height were studied. The correlation among the fraction of exhaled NO at 50 ml/s (FENO50), CA(NO), Jaw(NO), forced expiratory volume in 1 second (FEV1) and the CAN questionnaire was measured and the degree of agreement regarding asthma control assessment was studied using Cohen's kappa. Results: We studied 162 children; 49 healthy (group 1), 23 asthmatic participants without treatment (group 2) and 80 asthmatic patients treated with inhaled corticosteroids (group 3). CA(NO) (ppb) was 2.2 (0.1-4.5), 3 (0.2-9.2) and 2.45 (0.1-24), respectively. Jaw(NO) (pl/s) was 516 (98.3-1470), 2356.67 (120-6110) and 1426 (156-11805), respectively. There was a strong association (r = 0.97) between FENO50 and Jaw(NO) and the degree of agreement was very good in group 2 and was good in group 3. There was no agreement or only slight agreement between the measures used to monitor asthma control (FEV1, CAN questionnaire, CA(NO) and Jaw(NO)). Conclusions: The results for CA(NO) and Jaw(NO) in controls were similar to those found in other reports. There was no agreement or only slight agreement among the three measure instruments analyzed to assess asthma control. In our sample, no additional information was provided by CA(NO) and Jaw(NO).

Avaliação do papel do fator de Von Willebrand em pacientes portadores de Doença Pulmonar Obstrutiva Crônica (DPOC)

A doença pulmonar obstrutiva crônica é uma doença que leva à obstrução pulmonar geralmente irreversível e está intimamente relacionada com o hábito de fumar. Ao longo dos anos, ocorre destruição dos septos alveolares com a degradação das fibras elásticas e depósito do colágeno que compõe estes septos. Muito tem se discutido sobre a existência de inflamação sistêmica no paciente com DPOC e sobre as suas possíveis manifestações extra-pulmonares . O processo de aterosclerose pode fazer parte deste espectro inflamatório a partir da presença de dano endotelial. O fator de Von Willebrand é um marcador de dano endotelial e pode ser dosado de forma quantitativa e qualitativa. Este trabalho demonstra uma diferença estatisticamente significativa, qualitativa e quantitativamente, entre os níveis de fator de Von Willebrand em tabagistas e em pacientes com DPOC, quando comparados ao grupo controle. Ao analisarmos os pacientes com DPOC dividindo-os em subgrupos considerando quatro classificações distintas: GOLD 2006 (Anexo A), GOLD 2011 (Anexo B), grau de sintomatologia a partir da escala de dispneia MRC modificada (Anexo C) e número de exacerbações no último ano. Observamos uma diferença estatisticamente significativa, em relação ao nível qualitativo do fator de von Willebrand, apenas quando comparamos pacientes com DPOC sintomáticos e não sintomáticos. Demonstramos ainda uma correlação inversa entre o percentual predito de volume expiratório forçado no primeiro segundo (VEF1%) com os níveis qualitativos de fator de von Willebrand. Desta forma, o fator de von Willebrand está aumentado no paciente com DPOC, sendo um possível marcador sérico de sintomatologia relacionado a esta doença. Apesar de não se conseguir definir gravidade dos pacientes com DPOC pelo GOLD, o fator de von Willebrand estabelece uma correlação inversa com os níveis de VEF1%, sugerindo algum tipo de participação na progressão da doença.

Self-management education for cystic fibrosis

Background: Self-management education may help patients with cystic fibrosis and their families to choose, monitor and adjust treatment requirements for their illness, and also to manage the effects of illness on their lives. Although self-management education interventions have been developed for cystic fibrosis, no previous systematic review of the evidence of effectiveness of these interventions has been conducted. Objectives: To assess the effects of self-management education interventions on improving health outcomes for patients with cystic fibrosis and their caregivers. Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register (date of the last search: 22 August 2013). We also searched databases through EBSCO (CINAHL; Psychological and Behavioural Sciences Collection; PsychInfo; SocINDEX) and Elsevier (Embase) and handsearched relevant journals and conference proceedings (date of the last searches: 01 February 2014 ). Selection criteria: Randomised controlled trials, quasi-randomised controlled trials or controlled clinical trials comparing different types of self-management education for cystic fibrosis or comparing self-management education with standard care or no intervention. Data collection and analysis: Two authors assessed trial eligibility and risk of bias. Three authors extracted data. Main results: Four trials (involving a total of 269 participants) were included. The participants were children with cystic fibrosis and their parents or caregivers in three trials and adults with cystic fibrosis in one trial. The trials compared four different self-management education interventions versus standard treatment: (1) a training programme for managing cystic fibrosis in general; (2) education specific to aerosol and airway clearance treatments; (3) disease-specific nutrition education; and (4) general and disease-specific nutrition education. Training children to manage cystic fibrosis in general had no statistically significant effects on weight after six to eight weeks, mean difference -7.74 lb (i.e. 3.51 kg) (95% confidence interval -35.18 to 19.70). General and disease-specific nutrition education for adults had no statistically significant effects on: pulmonary function (forced expiratory volume at one second), mean difference -5.00 % (95% confidence interval -18.10 to 8.10) at six months and mean difference -5.50 % (95% confidence interval -18.46 to 7.46) at 12 months; or weight, mean difference - 0.70 kg (95% confidence interval -6.58 to 5.18) at six months and mean difference -0.70 kg (95% confidence interval -6.62 to 5.22) at 12 months; or dietary fat intake scores, mean difference 1.60 (85% confidence interval -2.90 to 6.10) at six months and mean difference 0.20 (95% confidence interval -4.08 to 4.48) at 12 months. There is some limited evidence to suggest that self-management education may improve knowledge in patients with cystic fibrosis but not in parents or caregivers. There is also some limited evidence to suggest that self-management education may result in positively changing a small number of behaviours in both patients and caregivers. Authors' conclusions: The available evidence from this review is of insufficient quantity and quality to draw any firm conclusions about the effects of self-management education for cystic fibrosis. Further trials are needed to investigate the effects of self-management education on a range of clinical and behavioural outcomes in children, adolescents and adults with cystic fibrosis and their caregivers.

Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs

BACKGROUND:
A previous retrospective study suggested that a policy of regular anti-pseudomonal antibiotic treatment improved pulmonary function and increased survival in patients with cystic fibrosis chronically infected with Pseudomonas species. The results of a prospective multicentre study to compare the effects on pulmonary function and mortality of three monthly elective anti-pseudomonal antibiotic treatment with conventional symptomatic treatment are reported.

METHODS:
Sixty patients with cystic fibrosis, chronically infected with P aeruginosa, were randomised to the two treatment arms (elective or symptomatic) and followed clinically at yearly reviews. The major end points were changes in forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). Survival was a secondary end point.

RESULTS:
Patients in the symptomatic group received a mean of three antibiotic treatments each year and those in the elective group received four antibiotic treatments during each year of the study. No significant differences in FEV(1) and FVC were found between the two groups after three years. There was a statistically non-significant higher rate of deaths in the elective group (n = 4), three of which were associated with B cepacia infection, compared with the symptomatic group (n = 0).

CONCLUSIONS:
This study did not demonstrate an advantage of a policy of elective antibiotic treatment over symptomatic treatment in patients with cystic fibrosis chronically infected with Pseudomonas species.

Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol

Background: It has been suggested that asthmatic subjects with persisting symptoms despite adequate maintenance therapy should be systematically evaluated to identify factors contributing to poor control. The aims of this study were to examine the prevalence of these factors in a cohort of sequentially referred poorly controlled asthmatics, and to determine if any factor or combination of factors predicted true therapy resistant asthma (TRA).

Methods: Patients were evaluated using a systematic evaluation protocol including induced sputum analysis, psychiatric assessment, ear, nose and throat examination, pulmonary function testing, high resolution CT scan of the thorax, and 24 hour dual probe ambulatory oesophageal pH monitoring; any identified provoking factor was treated. Asthma was managed according to BTS guidelines.

Results: Of 73 subjects who completed the assessment, 39 responded to intervention and 34 had TRA. Subjects with TRA had a greater period of instability, a higher dose of inhaled steroids at referral, more rescue steroid use, and a lower best percentage forced expiratory volume in 1 second (FEV1%). Oesophageal reflux, upper airway disease, and psychiatric morbidity were common (57%, 95%, 49%, respectively) but were not more prevalent in either group. Using multivariate logistic regression analysis, inhaled steroid dose >2000 µg BDP, previous assessment by a respiratory specialist, and initial FEV1% of <70% at referral predicted a final diagnosis of TRA.

Conclusions: In poorly controlled asthmatics there is a high prevalence of co-morbidity, identified by detailed systematic assessment, but no difference in prevalence between those who respond to intervention and those with TRA. Targeted treatment of identified co-morbidities has minimal impact on asthma related quality of life in those with therapy resistant disease.

High concentrations of pepsin in bronchoalveolar lavage from children with cystic fibrosis are associated with high interleukin-8

Background Gastro-oesophageal reflux is common in children with cystic fibrosis (CF) and is thought to be associated with pulmonary aspiration of gastric contents. The measurement of pepsin in bronchoalveolar lavage (BAL) fluid has recently been suggested to be a reliable indicator of aspiration. The prevalence of pulmonary aspiration in a group of children with CF was assessed and its association with lung inflammation investigated. Methods This was a cross-sectional case–control study. BAL fluid was collected from individuals with CF (n=31) and healthy controls (n=7). Interleukin-8 (IL-8), pepsin, neutrophil numbers and neutrophil elastase activity levels were measured in all samples. Clinical, microbiological and lung function data were collected from medical notes. Results The pepsin concentration in BAL fluid was higher in the CF group than in controls (mean (SD) 24.4 (27.4) ng/ml vs 4.3 (4.0) ng/ml, p=0.03). Those with CF who had raised pepsin concentrations had higher levels of IL-8 in the BAL fluid than those with a concentration comparable to controls (3.7 (2.7) ng/ml vs 1.4 (0.9) ng/ml, p=0.004). Within the CF group there was a moderate positive correlation between pepsin concentration and IL-8 in BAL fluid (r=0.48, p=0.04). There was no association between BAL fluid pepsin concentrations and age, sex, body mass index z score, forced expiratory volume in 1 s or Pseudomonas aeruginosa colonisation status. Conclusions Many children with CF have increased levels of pepsin in the BAL fluid compared with normal controls. Increased pepsin levels were associated with higher IL-8 concentrations in BAL fluid. These data suggest that aspiration of gastric contents occurs in a subset of patients with CF and is associated with more pronounced lung inflammation.

A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation

Background:

Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.

Methods:

We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1).

Results:

The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P < 0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P < 0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P < 0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P < 0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P < 0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).

Conclusions:

Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.

Quality of life and healthcare utilisation in cystic fibrosis:A multicentre UK study

The aim of our study was to discover the health status and healthcare utilisation associated with pulmonary exacerbations in cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection.

Patients with CF from five UK CF centres attended two visits, 8–12 weeks apart. They were classified at visit 1 as being in one of the three health states: no current pulmonary exacerbation; “mild” (no hospitalisation) pulmonary exacerbation; and “severe” (hospitalisation) pulmonary exacerbation. All patients completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and EuroQol (EQ-5D) and a clinical form, and forced expiratory volume in 1 s (FEV1) was measured at visits 1 and 2. Annual healthcare utilisation data were collected.

94 patients of mean±sd age 28.5±8.2 yrs and FEV1 58.7±26.8% were recruited. 60 patients had no pulmonary exacerbation, 15 had a mild and 19 had a severe pulmonary exacerbation at visit 1. EQ-5D and CFQ-R data showed that the worse the exacerbation, the poorer the health-related quality of life (HRQoL). There were strong relationships between the CFQ-R and EQ-5D domain scores. The mean rate of pulmonary exacerbations per patient per year was 3.6 (1.5 in hospital and 2.2 at home). The mean length of stay per hospital pulmonary exacerbation was 9 days.

As exacerbation status worsens, patients experience worse HRQoL. There is a significant healthcare burden associated with treatment of pulmonary exacerbation and long-term prophylaxis.

I can't get a breath: experiences of living with advanced chronic obstructive pulmonary disease

This study aims to explore the potential for palliative care among people living with advanced chronic obstructive pulmonary disease (COPD). Individual semi-structured interviews (n=13) were conducted with people who had a diagnosis of advanced COPD and were on optimal tolerated drug therapy, with their breathing volume (forced expiratory volume at less than 30%) or were on long-term oxygen therapy or non-invasion ventilation. Participants raised concerns about the uncertain trajectory of the illness and reported unmet palliative care needs with poor access to palliative care services. For most people, palliative care was associated with end of life; therefore, they were unwilling to discuss the issue. There was a wide acceptance that, medically, nothing more could be done. Findings also suggest that patients had unmet palliative care needs, requiring information and support. The research suggests the need for palliative care to be extended to all (regardless of diagnosis), with packages of care developed to target specific needs.

Lung Clearance Index Is a Repeatable and Sensitive Indicator of Radiological Changes in Bronchiectasis

RATIONALE: In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy.

OBJECTIVES: To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis.

METHODS: Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2).

MEASUREMENTS AND MAIN RESULTS: In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = -0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life.

CONCLUSIONS: The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.

The distribution of COPD in UK general practice using the new GOLD classification

The new Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 document recommends a combined assessment of chronic obstructive pulmonary disease (COPD) based on current symptoms and future risk.

A large database of primary-care COPD patients across the UK was used to determine COPD distribution and characteristics according to the new GOLD classification. 80 general practices provided patients with a Read code diagnosis of COPD. Electronic and hand searches of patient medical records were undertaken, optimising data capture.

Data for 9219 COPD patients were collected. For the 6283 patients with both forced expiratory volume in 1 s (FEV1) and modified Medical Research Council scores (mean¡SD age 69.2¡10.6 years, body mass index 27.3¡6.2 kg?m-2), GOLD 2011 group distributions were: A (low risk and fewer symptoms) 36.1%, B (low risk and more symptoms) 19.1%, C (high risk and fewer symptoms) 19.6% and D (high risk and more symptoms) 25.3%. This is in contrast with GOLD 2007 stage classification: I (mild) 17.1%, II (moderate) 52.2%, III (severe) 25.5% and IV (very severe) 5.2%. 20% of patients with FEV1 o50% predicted had more than two exacerbations in the previous 12 months. 70% of patients with FEV1 ,50% pred had fewer than two exacerbations in the previous 12 months.

This database, representative of UK primary-care COPD patients, identified greater proportions of patients in the mildest and most severe categories upon comparing 2011 versus 2007 GOLD classifications. Discordance between airflow limitation severity and exacerbation risk was observed.

Tiotropium Respimat inhaler and the risk of death in COPD

Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.

Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis

BACKGROUND: Pseudomonas aeruginosa is the most common bacterial pathogen in patients with cystic fibrosis (CF). Current infection control guidelines aim to prevent transmission via contact and respiratory droplet routes and do not consider the possibility of airborne transmission. It was hypothesised that subjects with CF produce viable respirable bacterial aerosols with coughing.

METHODS: A cross-sectional study was undertaken of 15 children and 13 adults with CF, 26 chronically infected with P aeruginosa. A cough aerosol sampling system enabled fractioning of respiratory particles of different sizes and culture of viable Gram-negative non-fermentative bacteria. Cough aerosols were collected during 5 min of voluntary coughing and during a sputum induction procedure when tolerated. Standardised quantitative culture and genotyping techniques were used.

RESULTS: P aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles <or=3.3 microm aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008).

CONCLUSION: During coughing, patients with CF produce viable aerosols of P aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission.

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4)

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.