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Issue 6, 2007
HOT TOPICS IN RESPIRATORY MEDICINE
Chronic obstructive pulmonary disease: treatment (Part Two)
| Publ. date: | 2007 |
| ISBN: | 978-88-89881-27-9 |
| ISSN: | 1973-9664 |
| E-ISSN: | 2036-0886 |
| DOI: | 10.4147/HTR-070600 |
Abstract
This issue in the series Hot Topics in Respiratory Medicine provides an updated overview of COPD therapy in 4 intensive chapters. Recent understanding of systemic inflammation associated with COPD has encouraged researchers to investigate the possible mechanisms whereby inhaled corticosteroids (ICS) might reduce systemic as well as airway inflammation. To address this topic, Drs. Sin and Man from St. Paul´s Hospital in Vancouver, Canada, discuss some controversies surrounding the effectiveness of ICS on the inflammatory process in COPD, including steroid insensitivity, the positive effect of ICS on the inflammatory process, its potential action on oxidative stress, and its localized effect on reducing airway hyperresponsiveness. The authors wonder whether inflammatory cell responses might predict clinical responsiveness to ICS. They also discuss the effects of ICS on systemic inflammation in a pragmatic way, showing data from recent clinical trials with reference to FEV1 (forced expiratory volume in 1 second) decline, health status, exacerbations, survival, COPD comorbidities (e.g. myocardial infarction), and potential side effects.
As Dr. Cazzola explains in the second chapter, ICS-long-acting beta agonist (LABA) combinations have a logical role in the treatment of severe to very severe COPD, not only because of the synergistic antiinflammatory action of LABA and ICS observed in vitro, but also because of their positive contributions to lung function leading to improved symptoms and health-related quality of life. In this context the author summarizes the key findings from the most important clinical studies designed to evaluate the impact of combination therapy on the variables previously mentioned. The clinical advantages of ICS/LABA over other combinations and the differences between fluticasone/salmeterol (FSC) and budesonide/formoterol (BFC) are presented. The safety of treatment with ICS/LABA in COPD and the complete results from the latest clinical trials are also presented in this chapter.
The next chapter of this issue addresses one of the most controversial topics related to COPD therapy - Dr. Black comments on the scarcity of evidence in support of the effectiveness of mucolytic agents, on the basis of the available results from small studies and the large BRONCUS study. Finally, Drs. Wood and Stockley expertly highlight what is new in COPD treatment, including novel applications for current medications as well as the newest drugs to target COPD pathogenesis: from anti-inflammatory approaches such as phosphodieterase-4 inhibitors to mediator antagonists such as anti-LTB4, TGF-β, chemokine, and NFκβ inhibitors; antioxidants; proteinase inhibitors; retinoids; anti-TNF-α treatment; nutritional supplementation; and interventions for secondary pulmonary hypertension. We hope that some of these new strategies for treatment will be available in the near future to improve the quality of care of patients with COPD.
Table of contents
Foreword
Treatment of COPD: A Time for Optimism
Chronic Obstructive Pulmonary Disease (COPD) is poised to become a major scourge of the 21st century. Worldwide, it is currently the fifth leading cause of premature mortality and has the dubious distinction of being the only common cause of death that is rising in the ranks, with predictions that it will become the third leading cause of death by the year 2020. The most effective approach in reversing this trend remains prevention - smoking cessation in current smokers and, of greater importance, setting up barriers to smoking initiation by the potential smokers of tomorrow. In addition, reducing exposure to indoor wood smoke, occupational dusts, and chemical sensitizers, and establishing better pollution controls all have the potential to reduce the severity of the coming epidemic.
However, we are still faced with the tremendous challenge of improving the lives of individuals currently afflicted with this disease. Recent research breakthroughs from welldesigned clinical trials have allowed optimism to emerge from the therapeutic nihilism of previous decades. This monograph contains a number of excellent reviews of the progress made over the past few years.
COPD has long been recognized to include a significant component of airway inflammation, but the role of inhaled corticosteroids (ICS) remains undefined. Experimental and research findings that point to primarily neutrophilic inflammation in COPD, as opposed to the eosinophilic inflammation of airways in asthma, previously helped to establish a false belief that these drugs would be ineffective in COPD. This myth was further propagated by the finding that prolonged therapy with ICS failed to delay the decline in FEV1 that is linked to COPD-associated morbidity and mortality [1]. A more recent understanding of the systemic inflammation associated with COPD has led to renewed interest in the possible mechanisms whereby ICS may reduce systemic as well as airway inflammation, thereby leading to improved outcomes in COPD. This topic is reviewed superbly by Sin and Man in this monograph.
The role of long-acting β-agonist (LABA) therapy in COPD has also been controversial. Whereas numerous trials have demonstrated a statistically significant improvement in FEV1 when these drugs are compared to placebo, many researchers have argued that the improvements are too minor to have led to the substantial improvement in the patients’ sense of well-being that was observed in many of these trials. In addition, concerns have been raised about the safety of these medications in an elderly population of COPD patients, many of whom also have cardiac disease [2]. The idea that these drugs may work by reducing dynamic hyperinflation rather than by affecting the traditional parameters of bronchodilation has led to renewed interest in their use in COPD [3]. The many potential benefits of combining a LABA with an ICS in COPD is ably reviewed by Cazzola. The recently published TORCH trial similarly
demonstrates significant reductions in exacerbations, improvements in health related quality of life, and improvements in FEV1 in patients treated with an ICS/LABA compared to those treated with placebo or each component singly [4]. In addition, the very large number of patients treated with a LABA for 3 years should put to rest the concerns about the safety of these medications in a population with COPD.
Chronic cough and sputum production is a frequent complication of smoking and remains a disturbing, not to mention embarrassing, symptom for many ex-smokers. In addition, chronic cough and mucus production may be a risk factor for treatment failure or hospitalization during exacerbations. The use of mucolytics remains controversial, but Black makes a convincing argument that N-acetylcysteine (NAC) has a role to play in the treatment of patients with chronic bronchitis and frequent COPD exacerbations.
Finally, Wood and Stockley review more recent insights into the mechanism of action of some current COPD therapies. They also provide commentary on anti-inflammatory and disease-modifying therapies currently in clinical trials or on the horizon.
There are still many questions that must be answered, including the value of adding long-acting anti-cholinergics to ICS/LABA (addressed, in part, by the OPTIMAL study) [5]; which long-acting bronchodilator is best (this is currently being addressed in the INSPIRE trial); whether there is a role for ICS monotherapy in COPD or only in combination with a LABA; and whether there is any additional benefit in providing NAC to patients who are already taking an ICS. Nonetheless, the results of the recent clinical and experimental research reviewed in this monograph have allowed us to progress from despair to guarded optimism with regard to our pharmacologic treatment of patients with COPD.
REFERENCES
1. Highland KB, Strange C, Heffner JE, et al. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease: a meta-analysis. Ann Intern Med 2003; 138: 969-973.
2. Salpeter SR, Buckley NS, Salpeter EE, et al. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Intern Med 2006;21:1011-1019.
3. O’Donnell DE, Sciurba F, Celli B, et al. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130:647-656.
4. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-789.
5. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007; [Epub ahead of print].
ARTICLES
Inhaled corticosteroids in the treatment of bronchial and systemic inflammation
Shu-Fan Paul Man, Don D. Sin
Combination therapy: long-acting β2-agonists and inhaled corticosteroids
Mario Cazzola
Mucolytics in the treatment of chronic bronchitis and COPD
Peter N. Black
New treatments for COPD
Robert A. Stockley, Alice M. Wood
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Editors-in-chief
Marc Miravitlles - MD
Over the last 15 years there has been a decrease in mortality due to preventable diseases, with the exception of chronic obstructive pulmonary disease (COPD), which is an example that highlights the r...
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