Combination Therapy Reduces Exacerbations In Severe COPD

The research appears in the second issue for January 2007 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Peter Kardos, M.D., of the Respiratory Medicine Section of Maingau Hospital in Frankfurt am Main, Germany, and three associates treated patients with moderate to severe COPD from 92 respiratory centers across Germany. All had less than a 50 percent predicted lung function capability for their age group.

The researchers treated 487 patients with salmeterol, a long-acting bronchodilator, and gave 507 a combination therapy of salmeterol and fluticasone propionate, an inhaled corticosteroid. Of the total cohort, 792 patients completed all phases of the 44-week study.

In the combined therapy group, 324 patients experienced moderate to severe exacerbations, as compared to 464 in the control group. The authors believe that this reduction in exacerbations is likely of clinical importance for patients with severe COPD.

"Exacerbations are a major cause of disease-related problems," said Dr. Kardos. "In particular, they greatly contribute to the decline of the health-related quality of life, increase symptoms and breathlessness, speed progression of the disease and increase the risk of mortality. In addition, exacerbations induce enormous economic costs. They can occur at any stage of the disease, but become more frequent as lung function impairment worsens."

In the United States, COPD is the fourth leading cause of death, killing 122,283 Americans in 2003. In 2004, more than 11 million U.S. adults were estimated to suffer from the disease, which results from chronic bronchitis and emphysema, two lung diseases that frequently co-exist and interfere with normal breathing. Smoking is the primary cause of COPD.

To date, no medication has been effective in halting long-term decline in lung function, which is the hallmark of the disease. Medications can only be used to provide relief from symptoms and prevent complications.

In an editorial on the research in the same issue of the journal, Dennis E. Niewoehner, M.D., and Timothy J. Wilt, M.D., of the Veterans Affairs Medical Center and the University of Minnesota, wrote: "As in all previous large inhaled corticosteroid (ICS) trials, Dr. Kardos administered relatively high doses of flutacasone. High dose ICS causes localized adverse effects in the upper airway and on the skin, but only infrequently do these complications cause discontinuation of therapy."

"Of greater concern is the systemic absorption of small amounts of ICS and the potential for long-term sequelae, particularly involving the bones and eyes," the editorialists continued. "The largely elderly population of patients with COPD may be at greater risk, and, as discussed in a recent review, the extent of the relationship between long-term ICS and bone and eye complications has yet to be fully clarified."

"Dr. Kardos and associates identify an additional safety concern with ICS not mentioned in previous publications. Based on adverse event reporting, 23 cases of pneumonia occurred in the combined-treatment group compared with only seven in the salmeterol arm. This difference is statistically significant and represents an excess pneumonia rate of about 3 per 100 patient years in patients given fluticasone."

The authors noted that similar results were obtained in patients who received fluticasone in TOwards a Revolution in COPD Health (TORCH), a survival study that aimed to determine the impact of salmeterol/fluticasone propionate combination and the individual components on the survival of COPD patients.

"In light of the known immunosuppressive properties of corticosteroids, an excess pneumonia rate from a high local concentration of ICS is not particularly surprising," the editorialists wrote.

The authors also pointed out that only a small minority of patients treated with ICS would achieve "clinically noticeable improvement in health status."

They concluded: "Therefore, decisions to initiate ICS combined with a long-acting beta agonist should focus on severely symptomatic and exacerbation-prone patients and balance the recently demonstrated benefits against increased drug costs and adverse effects."