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Clinical Corner

This Editorial has been written by the specialist opinion leader, Paul D Scanlon, MD, Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota and published in the latest issue of the serial publication, Drugs in Context.

For more information, you can download a free-of-charge Quick Reference Guide to the Tiotropium in COPD issue of Drugs in Context which is designed to give you an insight into the numerous key points of information and practical guidance contained in each issue, via carefully selected quotations taken directly from each part of the publication.

CSF Medical Communications publishes Drugs in Context which aims to provide clinicians around the world with a comprehensive, authoritative and independent review of all the significant data on a specific drug, placed in the context of the disease area and today's clinical practice. Each issue comprises four parts - an opening Editorial, a Disease Overview, a Drug Review and finally an Improving Practice section. Each drug is placed within the context of its indications and the clinical practice situation concerned.

In the past, I often introduced lectures and discussions on chronic obstructive pulmonary disease (COPD) with apologies for the lack of effective treatment or positive developments in research. A state of nihilism has long existed among health professionals when it comes to COPD. Patient information materials often began with "Although there is no cure…."

In recent years, however, prospects for COPD have changed. Better understanding of the disease, better approaches to prevention (particularly smoking prevention and cessation), improved guidelines for using currently available therapy, together with the development of new treatments have all brought optimism to healthcare providers and their patients.

COPD is an important but poorly understood disease, both by the lay public and by many health professionals. It is the fourth leading cause of death in the USA with 119,000 deaths in 2000. Among the five leading causes of death in the USA, only COPD is increasing in death rate, particularly among women; while COPD has long been recognized as a disease predominantly afflicting elderly men, since 2000 more women than men have died from COPD.

Despite its importance, COPD research has been poorly funded. Research budgets for cancer, cardiovascular disease and AIDS dwarf the budget for COPD research, whether in absolute dollars or when adjusted for mortality in dollars per death.1 In response to criticism, the leaders of the National Heart Lung and Blood Institute (NHLBI) sought guidance from COPD researchers. In 2002, five recommendations were made for research funding. Since then the National Institutes of Health (NIH) has established a COPD Clinical Research Network and a Lung Tissue Research Consortium. They have sought ideas for research into causes and mechanisms of COPD exacerbations, held a workshop on the use of long-term oxygen therapy and held an additional workshop for further recommendations from researchers.2

Until recently, a common goal for COPD clinical trials was to slow the rate of decline in lung function. However, no therapy other than smoking cessation has ever achieved this convincingly. The negative results of four large multicenter trials of inhaled glucocorticosteroids in 1999-2000 led to a re-evaluation of the goals of therapy. Current clinical trials focus on improved symptoms and quality of life together with reduced exacerbations. Although improved survival appears to be a logical goal, the statistical power of current studies means that this is presently not a realistic target. However, we should remember that it took 14 years of observation to demonstrate improved survival after smoking cessation among the 6000 participants in the Lung Health Study.

There are many effective therapies for COPD. Until recently, the diagnosis and management of COPD was poorly organized, and published guidelines were not widely followed. With the recent revision of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in 2003 and the American Thoracic Society/European Respiratory Society guidelines in 2004, there is now coherence between expert organizations and an organized approach that is available to all practitioners.3,4

So what is effective and recommended? Avoidance of respiratory exposures, particularly tobacco smoke, is by far the most important issue. (Perhaps we should all quit our current practice and work full time on smoking cessation!) Immunization is also effective. Short-acting bronchodilators (i.e. ß2-agonists and anticholinergics) reduce symptoms and improve exercise tolerance. Theophylline is an inexpensive and effective bronchodilator, and reduces exacerbation rates among those who tolerate it. Inhaled glucocorticosteroids improve symptoms and reduce the frequency of exacerbations in moderate-to-severe disease. Systemic steroids reduce treatment failure and shorten hospitalization for severe exacerbations. Treatment for respiratory failure in COPD is improved with non-invasive ventilation. For those with the most severe COPD, oxygen improves survival. Selected patients benefit from lung volume reduction surgery and transplantation.

Long-acting bronchodilators (LABD) are relatively new. Three are currently approved in the USA by the Food and Drug Administration (FDA). Salmeterol xinafoate (Serevent®) and formoterol fumarate (Foradil®) are both twice-daily dry-powder selective ß2-agonists. Tiotropium bromide (Spiriva®) is a once-daily, dry-powder selective muscarinic (M3) cholinergic antagonist. It improves symptoms and exercise tolerance and may reduce exacerbations. In one study - funded by the manufacturer - tiotropium appeared to be superior to salmeterol xinafoate.5

All three of the currently available long-acting bronchodilators are dry powders. However, not all patients can tolerate dry powders, and some are unable to use the devices with which they are administered. Alternative formulations may, therefore, be attractive. Like the other LABDs, tiotropium is moderately expensive - $117 per month (average monthly wholesale cost).6 However, in comparison with ipratropium, it improves health outcomes despite its greater cost.7

There are several issues to be determined in the use of LABDs: when to reach for a LABD, which one to use, and whether there is benefit in the simultaneous use of two LABD's with different mechanisms of action (e.g. salmeterol plus tiotropium). The potential role of tiotropium in asthma and other airway disorders has not been established.8 Long-term safety issues with other medications have been in the headline news. The safety profile of tiotropium has been promising, but further experience is needed. Long after ipratropium was approved for use, one large study raised a concern about the possibility of an increase in arrhythmias among users of ipratropium.9,10 Preliminary results with tiotropium are encouraging in this regard, but a more definitive study that can address this issue is underway.

The increasing mortality from COPD is very concerning news. However, our approach to treatment has improved. Tiotropium is certainly a welcome new arrow in our quiver.

References

1 www.emphysema.net/intro.html
2 Croxton TL, Weinmann GG, Senior RM et al. Clinical research in chronic obstructive pulmonary disease: needs and opportunities. Am J Respir Crit Care Med 2003; 167: 1142-9.
3 www.goldcopd.com
4 www.thoracic.org/copd
5 Brusasco V, Hodder R, Miravitlles M et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003; 58: 399-404.
6 Hutton SF. Tiotropium (Spiriva®) for COPD. Am Fam Physician 2004; 69: 2901-2.
7 Oostenbrink JB, Rutten-van Molken MP, Al MJ, Van Noord JA, Vincken W. One-year cost-effectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease. Eur Respir J 2004; 23: 241-9.
8 O'Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med 1996; 154: 876-80.
9 Anthonisen NR, Connett JE, Kiley JP et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272: 1497-505.
10 Lanes S, Golisch W, Mikl J. Ipratropium and lung health study. Am J Respir Crit Care Med 2003; 167: 801-2.

During 2002-5, Paul D Scanlon, MD, received research funding from Boehringer Ingelheim, Dey Pharmaceuticals, GlaxoSmithKline, LaRoche and ONO Pharmaceuticals. He has no other financial interest in these or any other commercial entity that has an interest in the subject matter of this Editorial.