New Hope for COPD?
Abstract & Commentary
By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips reports no financial relationship to this field of study.
Synopsis: Inhaled salmeterol and fluticasone, singly or in combination, reduce the rate of decline of the FEV1 in patients with moderate-to-severe COPD.
Source: Celli BR, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: Results from the TORCH Study. Am J Respir Crit Care Med 2008;178:332-338.
This paper is a report from the Toward a Revolution in COPD Health (TORCH) study, which was funded by GlaxoSmithKline but implemented by six academics.1 The TORCH study was a 3-year, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Eligible patients were stratified by smoking status and randomized to receive by inhalation one of the following 4 regimens twice daily: 50 µg salmeterol + 500 µg fluticasone, 50 µg salmeterol, 500 µg fluticasone propionate, or placebo. All other corticosteroids and inhaled long-acting bronchodilators were stopped for the study, but other COPD medications were allowed.
The primary efficacy endpoint of TORCH was all-cause mortality at 3 years. Other endpoints included exacerbation rate, measures of health status, and post-bronchodilator spirometry. Careful attention was paid to reliability and consistency of spirometric measures.
The study population for TORCH was 6112 patients, but only 5343 (87%) had at least one on-treatment FEV1 and could be included in the analysis. The included patients had a mean age of about 65 years, a mean body mass index (BMI) of about 25 kg/m2, and a baseline FEV1 of about 1235 mL (about 44% predicted); about three-fourths were men. The number of patients was smaller in the placebo group because more patients from the placebo group withdrew within the first 24 weeks. During the study, 187 (3%) patients took tiotropium in addition to the study medication.
The rate of decline of FEV1 was slowest in patients on combined fluticasone + salmeterol, and fastest in those who were randomized to the placebo arm. From week 24 onward, the adjusted rate of decline in FEV1 was 39 mL/yr for fluticasone + salmeterol, 42 mL/yr for single treatment with fluticasone or salmeterol, and 55 mL/yr for placebo. There were statistically significant differences in the rate of decline for any of the three active pharmacologic treatments compared to placebo. Analysis of individual regression slopes or of percent-predicted FEV1 produced similar findings. The effect of treatment on FEV1 occurred regardless of smoking sta-tus, sex, age, baseline FEV1, region of origin, ethnicity, BMI, previous exacerbations, and medication treatment prior to being in the study.
Besides inhaled medication use, other factors were significantly associated with rate of decline of pulmonary function. Those who had quit smoking, women, patients age 65 or older, and those whose FEV1 was < 30% of predicted at baseline also experienced a slower rate of decline of FEV1 in absolute mL/yr. In addition, patients whose BMI was ≥ 25 kg/m2 showed a slower decline in lung function, as did patients who were from the Asia Pacific and Eastern Europe regions. There was also an association between number of exacerbations documented during the study period and the rate of decline of FEV1, with higher rates of decline being evident in patients experiencing more exacerbations.
This study shows, for the first time, that pharmacologic treatment slows the decline in lung function in patients with fairly significant COPD. FEV1 is an important metric, as it predicts many important outcomes, including everything from sleep complaints to mortality. The results of this study are in contrast to several previous studies that failed to demonstrate that pharmacologic treatment affects the decline in pulmonary function in a statistically significant way. The Lung Health Studies 1 and 2,2,3 ISOLDE,4 BRONCHUS,5 and EUROSCOP6 failed to consistently demonstrate important differences in the rate of decline of pulmonary function for those with COPD who received pharmacologic treatment, although they did establish that the rate of decline of FEV1 in older COPD patients is about 60 mL/yr. The TORCH study found a similar rate of decline of FEV1 in the placebo group (about 55 mL/yr), but any of the three active drug treatments essentially cut this rate in half.
In the current study, the authors noted that their findings that higher BMI and region of origin (Asian Pacific and Eastern European) predicted slower deterioration in pulmonary function are novel, and they point out that this may help to explain within-subject variations in FEV1 decline. Their finding that women with COPD lost FEV1 at a slower rate is not new; it confirms work from the Lung Health Study. And, of course, they showed that those who had quit smoking fared better than those who continued to smoke, which has been consistently found in previous work. Prior to this report from the TORCH study, in fact, smoking status was the only modifiable risk factor clearly demonstrated to affect rate of decline of FEV1.
The main result of this trial, i.e., the effect of pharmacologic treatment on mortality, was published last year.1 In that study of 6112 patients, all-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group barely missed statistical significance, but the mortality rates for salmeterol or fluticasone alone did not differ significantly from that for placebo. Further, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P < 0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects among groups, but the probability of pneumonia was higher among patients receiving fluticasone.
In the accompanying editorial, Suissa points out that many FEV1 measurements were missing in this analysis of pulmonary function decline, particularly for the placebo group patients, who dropped out at greater rates than the active treatment patients.8 The editorial also addresses the practical application of this new knowledge. Since fluticasone, salmeterol, or the combination appear to have very similar beneficial effects on the rate of pulmonary function deterioration and exacerbations, which treatment is best to use? Suissa notes that a secondary analysis of the TORCH data on the independent contribution of each component of the treatment showed that any reduction in mortality was due to the bronchodilator (salmeterol) component and not the corticosteroid (fluticasone) component,9 and that inhaled corticosteroids have been associated with increased risk of glaucoma, osteoporosis, cataracts, and pneumonia. COPD is a miserable and prevalent disease. This new information may help us to do a better job in caring for these patients.
1. Calverley PM, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-789.
2. Anthonisen NR, 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;272:1497-1505.
3. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902-1909.
4. Burge PS, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: The ISOLDE trial. BMJ 2000;320:1297-1303.
5. Decramer M, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): A randomised placebo-controlled trial. Lancet 2005;365:1552-1560.
6. Pauwels RA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999;340:1948-1953.
7. Anthonisen NR, et al. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002;166:675-679.
8. Suissa S. Medications to modify lung function decline in chronic obstructive pulmonary disease. Some hopeful signs. Am J Respir Crit Care Med 2008;178:322-323.
9. La Vecchia C, Fabbri LM. Prevention of death in COPD. N Engl J Med 2007;356:2211-2212.