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18th Annual Congress of the European Respiratory Society

Berlin, Germany / October 4-8, 2008

Chronic obstructive pulmonary disease (COPD) is already a major health concern and current trends suggest that its importance will increase. Thus, while the death rate from heart disease has decreased, the death rates from COPD have increased over the last three decades. The economic cost of COPD is also rising. Clearly, improved management of the disease could yield substantial benefits for both patients and society as a whole.

COPD: A Heterogeneous Disease

One of the problems of COPD management is that “people with COPD are grouped together even though they have very different systemic manifestations,” explained Dr. Stephen Rennard, University of Nebraska Medical Center, Omaha. “The understanding is that inflammation starts in the lungs, for whatever reason, such as smoking, and this leads to systemic inflammation, which can lead to muscle weakness, cardiovascular disease and osteoporosis.”

It is often these extrapulmonary manifestations that are responsible for increased mortality—the most common cause of death in patients with moderate COPD is heart disease, and even among patients with severe COPD, heart disease remains the biggest individual cause of mortality. Nevertheless, these patients with systemic disease are usually excluded from clinical trials. “Clinical trials assess groups of patients, whereas clinicians care for individuals and must treat the ‘whole patient,’” according to Dr. Rennard. In a patient bothered by muscle weakness, it may be more important to treat that weakness rather than dyspnea.

As part of this shift towards treating the “whole patient,” it is vital to take into consideration the needs of the patients themselves. “If we don’t find out what they want, our research might be off target, our care might be off target, and we won’t select the best treatment for our patients,” claimed Dr. Martyn Partridge, Chair of Respiratory Medicine, Imperial College London, Charing Cross Hospital, London, UK.

This involves trying to break from the paternalistic attitude that often permeates the physician-patient relationship and moving towards a patient-centred approach. When this is done, it transpires that the main worries of patients are of the coming dependence, and fear of hospitalization and exacerbations (Haughney et al. Eur Respir J 2005;26(4):623-9).

The Importance of Morning Symptoms

Although COPD management has understandably focussed on disease and exacerbation prevention and preservation of lung function, a careful assessment of actual patient needs suggests that morning symptoms may be a major concern. Mornings have been described as “a nightmare” by some patients because their sense of dependence is heightened at this time or because “I need to get up at least two hours before I go anywhere because I function so slowly.”

The problems first thing in the morning can be explained by the lungs being in a suboptimal condition with diminished basal ventilation, mucociliary clearance, and relative hypoventilation, and no coughing during the night to clear secretions. Then, on getting up, patients engage in a prolonged period of concentrated activity. Indeed, a couple of studies have found that lung function variables follow circadian cycles (Calverley et al. Thorax 2003;58(10):855-60; van Noord et al. Chest 2006;129(3):509-17).

It has been hypothesized that certain agents, in particular a corticosteroid with a fast-acting b-agonist, will give a better start in the morning than other agents. Corticosteroid/b-agonist combinations may act in a complimentary manner because cortisone and adrenaline—the natural molecules on which these drugs are based—are the two main hormones released in response to stress.

Three studies are currently being conducted or analyzed that focus specifically on morning symptoms. The first study, pending the final analysis, compared tiotropium therapy (once daily) and added budesonide/formoterol (b.i.d.) in a double-blind, placebo control study on morning FEV1 (primary end point) and symptoms and quality of life (QoL) (secondary end points). The second study is comparing the effect on exercise tolerance of a budesonide/formoterol combination vs. formoterol alone and the third is comparing budesonide/formoterol (b.i.d.) with salmeterol/fluticasone (b.i.d.), with the hypothesis that the faster onset of action of budesonide/formoterol will be beneficial to morning symptoms. The results may help clarify the role of morning symptoms in COPD and which agents may best alleviate such symptoms.

Exacerbations and Decline in Lung Function

“Exacerbations are important to patients, they are a source of anxiety, but they also represent an important driver of disease progression,” stated Dr. David Halpin, Department of Respiratory Medicine, Royal Devon and Exeter Hospital, UK. Erdosteine, an effective treatment in COPD patients both during stable periods and exacerbations, was shown to prolong time to first exacerbation compared to placebo, with a hazard ratio of 0.639 (95% CI, 0.416-0.981) in patients with severe COPD, according to a study presented here by Ballabio et al. The effect was particularly marked in patients with most severe disease.

Budesonide/formoterol has also been shown to be effective at prolonging time to exacerbation in a large, randomized controlled study compared budesonide/formoterol, budesonide alone, formoterol alone, and placebo over a 12-month period in patients with severe COPD (Calverley et al. Eur Respir J 2003;22(6):912-9). The benefit of the combination in terms of time to first exacerbation was marked. “The median time is 96 days for placebo vs. 254 days for combination therapy and I believe that is a really important delay in people with relatively short life expectancies,” noted Dr. Halpin. A sub-analysis of the Chinese patient cohort in that study by Zhong et al., presented at here in Berlin, highlighted how the combination treatment yielded consistent benefit in terms of FEV1 compared to monotherapy and placebo and QoL, as assessed by the Saint George’s Respiratory Questionnaire (-8.4 vs. placebo, -3.2 vs. budesonide and -2.6 vs. formoterol).

Managing Exacerbations in the Primary Healthcare Setting

If a patient finally does experience an exacerbation, oral corticosteroids are often added to intensified bronchodilator treatment with b2-agonists and anticholinergics. However, even short courses of oral prednisolone are associated with significant side effects, and the cumulative steroid dose in patients with frequent exacerbations may be high. Ställberg et al. presented a study which tested the hypothesis that inhaled budesonide/formoterol would be as effective as a two-week course of prednisolone and inhaled formoterol in the management of exacerbations not requiring immediate hospitalization. The primary end point of this double-blind randomized study was change in FEV1. The study was able to demonstrate non-inferiority for the primary end point. The authors concluded that, in patients not requiring immediate hospitalization, inhaled budesonide/formoterol might be a viable alternative for physicians in primary healthcare centres.

Summary

The concepts of COPD management are changing. Prevention and exacerbation control remains a cornerstone of that management, but a greater focus on the actual needs of the patient suggests other areas deserving of attention. We should recognize that COPD is a broad term that covers a number of different systemic presentations of the disease, and our approach should take into account these systemic factors closely linked to the underlying pulmonary inflammation. Another area deserving of attention is a fast-acting strategy beneficial to morning symptoms. Ongoing trials should elucidate the impact of morning symptoms on QoL, and also, which treatments may be most helpful for the patients in this setting.