Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

16th Annual Congress of the European Respiratory Society

Munich, Germany / September 2-6, 2006

Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder that is one of the most important causes of death among elderly patients in industrialized countries. Progressive breathlessness from diminishing lung function leads to increasing limitation in daily activities and an unfavourable change in quality of life (QOL). Restrictions in daily activity may, in turn, contribute to health problems in other systems, such as cardiovascular health. The most commonly used therapeutic options for symptom control are long-acting b-agonists (LABAs), inhaled corticosteroids (ICS) and, most recently, the long-acting anticholinergic agent tiotropium. Typically, clinical studies with these agents have focused on improvements in lung function, but interest in better measuring clinical benefits has increased the emphasis on evaluating outcomes important to patients, particularly functional capacity.

Quality of Life: Key Measure of Treatment Success

Dyspnea is the major symptom of COPD, but impaired QOL is the major result. According to Dr. François Maltais, Director, Respiratory Research Unit, Centre hospitalier universitaire de Laval, Quebec City, it is important to not only evaluate the effect of treatment on lung function but also to assess the ability of treatment to provide and maintain improvements in exercise tolerance. In a study of 261 patients with COPD who were randomized to once daily tiotropium 18 µg or placebo and evaluated over 42 days, the benefits of the anticholinergic relative to placebo were observed from the first day of treatment and were sustained over the course of the study.

Specifically, dyspnea intensity was significantly decreased on all test days (P=0.002), while exercise endurance time at 75% of maximal work capacity was significantly increased after the first dose and was maintained for the remainder of the study. Dr. Maltais reported that the significant increase in endurance time was accompanied by a significant reduction in the intensity of dyspnea at the point of symptom limitation on all test days, with improved inspiratory capacity and shorter periods of discomfort. Due to the fact that those improvements were still evident eight hours after dosing, they covered the periods during which patients are most likely to perform important daily activities.

Exacerbations and Mortality

According to Dr. David Halpin, Royal Devon and Exeter Hospital, UK, another important measure of the efficacy of current treatments is their ability to attenuate the risk of exacerbations. As COPD progresses, frequent exacerbations contribute to a reduced QOL by accelerating the decline in lung function and health status.

Exacerbations are the most frequent cause of medical visits and hospital admissions in COPD. Moreover, they are associated with increased mortality, proving fatal in up to 40% of patients 12 months after an exacerbation. As Dr. Halpin explained, “We do have effective treatments but a significant burden still remains, so prevention of exacerbations is an important treatment goal. Most initial trials of disease modifications in COPD concentrated mainly on lung function and symptom improvement; only recently has the importance of exacerbations been recognized and studies designed to look primarily at treatment for exacerbations.”

Dr. Halpin’s analysis of the effects of tiotropium on lung function involved data from nine studies of at least six months’ duration with 6171 patients and demonstrated substantial effects. “The long-acting bronchodilator reduced the rate of exacerbations leading to treatment with oral corticosteroids by 25% or antibiotics by 18%.” The reduction in the risk of COPD exacerbations was independent of whichever subsequent treatment was needed and demonstrated that exacerbation reduction was robust across severity, ICS use and age groups.

Identifying COPD Patients

One of the major challenges for improving the QOL of COPD patients is simply to make the diagnosis so that effective bronchodilators can be offered. Although the onset of symptoms can be insidious, questions about lung function should be posed routinely to patients in the age range when COPD typically develops, particularly if they have a history of smoking.

According to Dr. Gunnar Johansson, Department of Public Health and Caring Sciences, Uppsala University, Sweden, “More than two-thirds of individuals with undiagnosed mild COPD will say they have symptoms of breathlessness, cough and dyspnea when asked, but still do not seek treatment. That is lamentable because early diagnosis and effective treatment in the milder stages of COPD are vital for preventing lung function decline.” To evaluate pharmacologic therapy in early-stage COPD, he and colleagues tested the long-acting anticholinergic agent tiotropium in 224 patients with mild COPD (defined as post-bronchodilator forced expiratory volume in one second [FEV1] ³60% predicted).

Results demonstrated significant improvement in all lung function assessments compared with placebo, and improvements were equivalent to those achieved in patients with moderate to severe COPD. The most frequently reported adverse reaction was dry mouth, which was usually mild and often resolved spontaneously. Active treatment significantly improved FEV1 area under the curve and trough FEV1 by 8.4% and 6%, respectively, (P<0.0001). Improvements were apparent 30 minutes after the first dose and maintained over the 24-hour period and for at least 85 days.

Reducing Mortality

One reason to focus on change in patient function and QOL is that no study has been able to show a mortality benefit. In the most recent study designed to look at this outcome, called TORCH (Towards a Revolution in COPD Health), there was a numerical reduction in mortality at the end of three years among patients randomized to the LABA salmeterol plus the ICS fluticasone when compared to placebo, but the absolute risk reduction was limited to 2.6%, falling short of statistical significance (P=0.052).

The possibility that effective control of symptoms with bronchodilators can block the vicious cycle that leads to progressive lung dysfunction is now a topic of great interest, but larger studies are needed. According to Dr. Peter Calverley, Aintree University Hospital, Liverpool, UK, “I think a lot of the vagueness about statistics in TORCH would have been resolved [by randomizing greater numbers of patients].” Indeed, he remains optimistic about the ability of future studies to show mortality benefits, particularly through use of bronchodilators, including anticholinergic drugs.

Smoking Cessation: Key First Step

In current treatment guidelines, the first step in the management of COPD is smoking cessation. Smoking cessation is the only treatment that has been associated so far with a significant benefit in objective measurements of lung function, particularly rate of decline in FEV1). While smoking drives disease and is an appropriate target for treatment, it is important to recognize that improvement in functional impairments and protection against recurrent exacerbations with bronchodilators also have substantial theoretical benefits on long-term outcome. Studies testing the impact of different strategies for tight symptom control on long-term outcome are underway, but objective measures of lung function will not be the only criterion for benefit. Rather, due to increasing recognition of the broad impact of COPD on the lives of patients, change in exercise capacity, activities of daily living and QOL are expected to be routinely evaluated to establish benefit from the patient perspective.

Summary

The evidence that bronchodilators can greatly improve QOL in patients with COPD needs to be communicated to both patients and physicians. Whether such treatments as tiotropium or LABAs will prove to extend survival remains a focus of future studies, but there is substantial data to support the use of these agents for improving activity levels as the disease progresses. The nihilism with which this disease was often addressed in the past is no longer justified.