Mucolytic Agent Reduces COPD Exacerbations

By Todd Neale
GUANGZHOU, China, 14 june 2008 -- For patients with chronic obstructive pulmonary disease, year-long treatment with the mucolytic agent carbocisteine eased symptoms and was well tolerated, a large randomized study showed.
Treatment with carbocisteine -- which is not approved in the U.S. -- reduced the frequency of self-reported exacerbations by 25% compared with placebo (RR 0.75, 95% CI 0.62 to 0.92, P=0.004), Nan-Shan Zhong, M.D., of Guangzhou Institute of Respiratory Disease, and colleagues reported in the June 14 issue of The Lancet.
The reduction remained significant after adjusting for smoking, disease stage, and use of other medications, they said.
Adverse events occurred in similar numbers in each group, and there were no deaths.
The researchers concluded that "mucolytics, such as carbocisteine, should be recognized as a worthwhile treatment for the long-term management of COPD."
Mucolytics are widely used in Europe and Asia for the treatment of respiratory diseases with phlegm production, they said, noting that carbocisteine appears to play a role in antioxidation and anti-inflammation, in addition to mucolysis, which may help alleviate the symptoms of COPD.
Past studies of the agent have been inconclusive because of limitations in study design, the researchers said, so they initiated a randomized, double-blind, placebo-controlled trial at 22 centers in China.
The researchers randomized 354 patients to 1,500 mg of carbocisteine a day and 355 to placebo for one year.
Overall, 79% of the participants were male, the mean age was 65, and the mean baseline forced expiratory volume in one second was 44% of the predicted value.
Symptom exacerbations were defined as at least a two-day persistence of at least two major symptoms -- worsening dyspnea and an increase in sputum purulence, volume, or both -- or of any single major symptom plus more than one minor symptom -- upper airway infection, unexplained fever, and increased wheezing. All symptoms were reported by the participants.
During the study, there were 325 exacerbations in the carbocisteine group and 439 in the placebo group, corresponding to 1.01 exacerbations per patient-year with active treatment versus 1.35 with placebo.
The between-group difference in the rate of exacerbations first became significant at the six-month follow-up, "suggesting that longer use of carbocisteine was more effective for preventing exacerbations of COPD," the researchers said.
At one year, the overall quality-of-life score -- assessed on the St. George's Respiratory Questionnaire -- was significantly improved from baseline in the carbocisteine group (4.06 points, P<0.0001), which the researchers said was clinically relevant, but not in the placebo group.
Scores were significantly better in the carbocisteine group than in the placebo group for both overall score (P=0.046) and symptom score (P=0.015).
Measurements in forced expiratory volume in one second were similar in both groups at the end of the study.
The authors noted that their results may differ from those of other studies because of the ethnicity of the participants.
"The Chinese differ from Europeans in dietary patterns, nutritional status, and lifestyle," they said, "which might specifically affect certain therapies."
The use of mucolytics to treat COPD may be cheaper than using inhaled corticosteroids, long-acting beta-2 agonists, and anticholinergics, they said, which yield better outcomes but cost about six times as much over the course of a year.
"Less-expensive mucolytics such as carbocisteine might be an important option," they said, "especially in low-income countries and regions."
In an accompanying editorial, Paul Albert, M.D., and Peter Calverley, M.D., of the University of Liverpool, pointed out some unanswered questions, including carbocisteine's mechanism of action, which was not addressed in the study.
They also questioned whether similar effects would be found in non-Chinese patients.
"What is clear from [the study] is that rigorous clinical trials of existing drugs can offer new insights into COPD care," they concluded. "These insights should stimulate research into how the effects can be improved in the future, while offering a cost-effective and well-tolerated way of lessening the burden of exacerbations for the increasing numbers of patients in developing countries affected by this chronic and debilitating disorder."
The study was funded by Kyorin Pharmaceuticals, Japan. Study tablets were provided by Baiyunshan Pharmaceutical, China.
One of Dr. Zhong's co-authors won a Best Poster Travel Grant for COPD research from the 2007 European Respiratory Society annual meeting for the study.
Dr. Calverley has led several studies about inhaled bronchodilator or corticosteroid drugs, or both, funded by pharmaceutical sponsors in which exacerbation frequency was an outcome. Dr. Albert declared no conflicts of interest.
Primary source: The LancetSource reference:Zheng J-P, et al "Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomized placebo-controlled study" Lancet 2008; 371: 2013-2018. Additional source: The LancetSource reference: Albert P, Calverley P "A PEACE-ful solution to COPD exacerbations?" Lancet 2008; 371: 1975-1976.