Pharmacological prevention of COPD exacerbations

Exacerbations of COPD are characterized by changes in the patient’s baseline dyspnoea, cough, and/or sputum that are beyond normal day-to-day variations, that are acute in onset, and that may warrant a change in regular medication. The frequency and severity of exacerbations increase with disease severity and are associated with poorer quality of life and health outcomes, with a greater burden on health care, accelerated decline of lung function, and increased risk of death. For all these reasons, exacerbations are a major target of prevention and treatment in patients with COPD.While exacerbations are increasingly used as primary outcome or secondary pre-specified outcome in clinical trials in COPD, major limitations of the studies on COPD exacerbations are that the definition is based on symptoms and not on objective measurements. Furthermore, the definition varies between studies, and often comorbidities are not adequately taken into account. Worsening of daily respiratory symptoms, particularly dyspnoea, could be associated with respiratory events, such as pneumonia, or non respiratory events, such as heart failure, thromboembolisms, and renal failure, among others. Long-acting bronchodilators alone or in combination with inhaled glucocorticosteroids are the most effective treatment for reducing the number and severity of COPD exacerbations—even though caution is required in interpreting the results of some trials. Suissa and coworkers, in their recent papers on methodological issues, suggest that the results of major randomized controlled clinical trials that evaluate the effect of treatment on COPD exacerbations might be biased by the facts that many patients enrolled in the studies are already receiving inhaled therapy before randomization, and that the results could be influenced by withdrawal from the ongoing effective therapy. Another bias might be that patients included in the trials are often not followed after discontinuation of treatment; considering the different rates of withdrawal between treatments and the different causes of withdrawal, this may severely affect the interpretation of the data. Statistical methods are also critical. A statistical approach that does not weight for the length of the follow-up (unweighted approach), and for the within- and between-subject variability of exacerbations, may lead to false-positive results. In particular, this bias applies to all but two trials examining the effect of inhaled glucocorticosteroids on exacerbations, causing the authors of those studies to conclude that the positive effect of inhaled glucocorticosteroids on exacerbations is not supported by solid evidence. With these limitations, however, randomised controlled trials are and will remain the fundamental tools for evaluating the benefit of COPD treatment, and the data collected so far, albeit with the potential biases, are the only evidence available to support treatment recommendations.In this chapter we review the various classes of medications commonly used in treating COPD. We focus on the most effective medications for preventing exacerbations, such as inhaled long-acting bronchodilators alone or in combination with inhaled glucocorticosteroids. Also, considering their importance in the management of COPD, we briefly discuss the effects of smoking cessation and vaccinations on COPD exacerbations. We do not discuss the effects of treatment of exacerbations on subsequent exacerbations—obviously an important clinical aspect. In fact, short-term therapy with oral glucocorticosteroids after hospitalization for a COPD exacerbation reduces the likelihood of readmission for another exacerbation.