Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent being cardiovascular ...disease, lung cancer, osteoporosis, muscle weakness, and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations, and physical inactivity or inherent factors such as genetic background and ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensin-converting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of so-called spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful.
Summary Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or ...comorbities. The main cause is smoking tobacco, but other factors have been identified. Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli. The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both. Comorbidities include ischaemic heart disease, diabetes, and lung cancer. Bronchodilators constitute the mainstay of treatment: β2 agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids). Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification. Future research should be directed towards the development of agents that notably affect the course of disease.
This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most ...significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed.
In this large, randomized trial, the investigators compared outcomes in patients with chronic obstructive pulmonary disease (COPD) treated with once-daily inhalation of tiotropium or placebo. There ...was no benefit of treatment on the rate of loss of lung function over time, although benefits were observed in some secondary end points.
These investigators compared outcomes in patients with chronic obstructive pulmonary disease treated with once-daily inhalation of tiotropium or placebo. There was no benefit of treatment on the rate of loss of lung function over time, although benefits were observed in some secondary end points.
Prospective studies testing effects on the progression of chronic obstructive pulmonary disease (COPD) through the evaluation of the slope of the forced expiratory volume in 1 second (FEV
1
) have not shown that inhaled short-acting anticholinergic drugs, inhaled corticosteroids, or
N
-acetylcysteine alter this marker of disease progression.
1
–
7
To date, only smoking cessation has prospectively been shown to alter the rate of decline of FEV
1
in patients with COPD.
2
Tiotropium is a once-daily, inhaled anticholinergic drug that provides at least 24-hour improvements in airflow and hyperinflation in patients with COPD.
8
–
10
Clinical trials lasting 6 weeks to . . .
The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. ...Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St George's Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term "minimum worthwhile incremental advantage" to describe this parameter.
OBJECTIVES:To investigate whether a daily exercise session, using a bedside cycle ergometer, is a safe and effective intervention in preventing or attenuating the decrease in functional exercise ...capacity, functional status, and quadriceps force that is associated with prolonged intensive care unit stay. A prolonged stay in the intensive care unit is associated with muscle dysfunction, which may contribute to an impaired functional status up to 1 yr after hospital discharge. No evidence is available concerning the effectiveness of an early exercise training intervention to prevent these detrimental complications.
DESIGN:Randomized controlled trial.
SETTING:Medical and surgical intensive care unit at University Hospital Gasthuisberg.
PATIENTS:Ninety critically ill patients were included as soon as their cardiorespiratory condition allowed bedside cycling exercise (starting from day 5), given they still had an expected prolonged intensive care unit stay of at least 7 more days.
INTERVENTIONS:Both groups received respiratory physiotherapy and a daily standardized passive or active motion session of upper and lower limbs. In addition, the treatment group performed a passive or active exercise training session for 20 mins/day, using a bedside ergometer.
MEASUREMENTS AND MAIN RESULTS:All outcome data are reflective for survivors. Quadriceps force and functional status were assessed at intensive care unit discharge and hospital discharge. Six-minute walking distance was measured at hospital discharge. No adverse events were identified during and immediately after the exercise training. At intensive care unit discharge, quadriceps force and functional status were not different between groups. At hospital discharge, 6-min walking distance, isometric quadriceps force, and the subjective feeling of functional well-being (as measured with “Physical Functioning” item of the Short Form 36 Health Survey questionnaire) were significantly higher in the treatment group (p < .05).
CONCLUSIONS:Early exercise training in critically ill intensive care unit survivors enhanced recovery of functional exercise capacity, self-perceived functional status, and muscle force at hospital discharge.
Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even ...survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications.
The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.
An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards.
We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality.
Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.
Summary Background The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of ...the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD. Methods The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 μg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV1 ) and in postbronchodilator FEV1 , beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov , number NCT00144339. Findings 2739 participants (mean age 64 years SD 9) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV1 of 1·63 L (SD 0·37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV1 was lower in the tiotropium group than in the control group (43 mL per year SE 2 vs 49 mL per year SE 2, p=0·024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV1 did not differ between groups (35 mL per year SE 2 vs 37 mL per year SE 2; p=0·38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p≤0·006 for all timepoints). Time to first exacerbation and time to exacerbation resulting in hospital admission were also longer in the tiotropium group than in the control group (hazard ratio 0·82, 95% CI 0·75–0·90, and 0·74, 0·62–0·88, respectively). Interpretation Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV1 in patients with GOLD stage II COPD. This finding and the other improvements in outcomes suggest that treatment of COPD should begin at an early stage of the disease. Funding Boehringer Ingelheim and Pfizer Pharmaceuticals.
We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in ...the previous 12 months.
In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computer-generated sequence to randomly allocate patients (1:1; stratified by baseline inhaled corticosteroid use, with the balance of treatments maintained at country level) to receive either indacaterol (150 μg) or tiotropium (18 μg) once-daily for 52 weeks. Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate of exacerbations at week 52 (secondary endpoint). Analysis populations for the primary and key secondary endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00845728.
Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium. At week 12, the estimated least squares mean trough FEV1 difference between the groups was -0.011 L (least squares mean with indacaterol n=1450 1.134 L SE 0.008 vs tiotropium n=1467 1.145 L 0.008; one-sided 97.5% CI lower limit -0.026 L; p<0.0001). The lower limit of the 97.5% CI was above the prespecified non-inferiority margin of -0.055 L, suggesting that indacaterol was non-inferior to tiotropium. Indacaterol did not show non-inferiority in terms of annualised exacerbation rates: 0.79 (indacaterol, n=1529) versus 0.61 (tiotropium, n=1543); ratio 1.29 (one-sided 97.5% CI upper limit 1.44). In the safety set, we recorded no between-group difference in the number of patients who had adverse events (indacaterol 1119 65% of 1721 patients vs tiotropium 1065 62% of 1718 patients) or serious adverse events (indacaterol, 263 15% of 1721 patients vs tiotropium, 255 15% of 1718 patients). Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747 43% of 1721 patients and tiotropium, 665 39% of 1718 patients) and serious adverse events (COPD: indacaterol, 147 9% of 1721 patients and tiotropium, 121 7% of 1718 patients).
Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles. Tiotropium afforded greater protection from exacerbations, although the absolute number of events was small and the difference between treatments is of uncertain clinical importance. The present data offer evidence consistent with current guidelines.
Novartis Pharma AG.
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