American Journal of Respiratory and Critical Care Medicine

While decline in lung function over time is a natural consequence of the aging process of adults, such decline is dramatically accelerated in patients with chronic obstructive pulmonary disease (COPD). A pharmacological treatment that could alter the trajectory of FEV1 decline of patients with COPD could be valuable in preserving lung function and, by extension, life. The search for such disease-modifying drugs in COPD has been intense. Until now, there hasn't been much cause for optimism as the results of the quest for such drugs have been ambiguous at best.

Inhaled corticosteroids have received the greatest attention as to their potential to modify lung function decline in COPD. The first randomized controlled trials of inhaled corticosteroids in COPD found no change in the decline of FEV1 over time compared with placebo. Subsequent randomized trials, all involving inhaled corticosteroids combined with a long-acting β-agonist, reported significant effects on FEV1 but supplied only limited information regarding its decline over time and were ambiguous on the effects of inhaled corticosteroids alone. Paradoxically, two meta-analyses contradicted each other, one finding no improvement in the annual FEV1 decline with inhaled corticosteroids, the other reporting a significant improvement (1, 2). A recent pooled analysis found no improvement with inhaled corticosteroids (3). Such conflicting and ambiguous evidence has made the need for further research even more crucial.

In this issue of the Journal (pp. 332–338), we begin to see the emergence of hopeful signs for patients with COPD. Celli and colleagues report a detailed analysis of the Towards a Revolution in COPD Health (TORCH) trial data on FEV1 decline (4). TORCH is the first mega trial in COPD, randomizing over 6,000 patients with moderate to severe COPD to one of four treatment groups involving either fluticasone, salmeterol, both fluticasone and salmeterol, or placebo, with the patients then followed for 3 years. In addition to mortality as the primary outcome, several secondary outcomes were measured. Using data from over 26,000 measurements of post-bronchodilator FEV1 made during follow-up, this article reports that the rate of decrease in FEV1 between 6 months and 3 years after randomization is significantly lower with the salmeterol/fluticasone combination (39 ml/yr), fluticasone alone, or salmeterol alone (42 ml/yr), compared with placebo (55 ml/yr). While these results are encouraging, their validity must be judged against possible methodological limitations, which may be present even in such a large randomized trial.

The primary limitation of this TORCH report is the absence of a pure intent-to-treat analysis. While TORCH collected information on mortality during the entire follow-up period, it did not do so for the secondary endpoints. The 26,000 measurements of FEV1 were only collected until the patients discontinued treatment, so that around 10,000 measurements were missing for the proper intent-to-treat analysis. As a result, the FEV1 decline as estimated using incomplete follow-up may be biased, as was demonstrated for exacerbations (5). Indeed, the data are clearly not randomly missing: nearly 18% of patients allocated to placebo did not contribute a single FEV1 value, compared with 9% for combination therapy, and there are more missing FEV1 values in the latter part of the follow-up period than earlier on. The authors argue that patients withdrawing before the end of follow-up had steeper FEV1 decline than those who completed the full follow-up period. This, however, does not take into account the possibility that those who were excluded even before any follow-up measurement (such as 18% of placebo patients) likely would have had the worse FEV1 values at the first visit. The slope of decline in the remaining subjects with better FEV1 values at the first visit thus may have been exaggerated as a consequence of regression to the mean.

The second limitation relates to the design requirement to discontinue the use of inhaled corticosteroids and long-acting β-agonists at the time of randomization; this can lead to significant bias (6). Using stratified analyses, the authors show that, among the patients who did not use these drugs prior to randomization, the rate of decrease in FEV1 is practically identical for all three treatment groups at around 39 ml/year, all slower than placebo (52 ml/yr).

Despite these methodological limitations, and the fact that FEV1 was not a primary endpoint, we can nonetheless concur that the TORCH study brings some clarity to the treatment picture, and provides some hopeful signs for patients with COPD. For the first time, we have possible evidence that medications can modify the decline in lung function in COPD. Notwithstanding its methodological limitations, this study demonstrates that no treatment (placebo) is not an option for patients with moderate-to-severe COPD and that any one of the three treatments may slow the accelerated lung function decline of patients with COPD. Moreover, the improvement in the rate of decline by nearly 15 ml/year is impressive, considering the decline of 30 ml/year related to normal aging. Even more important, the slowing of the decline in lung function can be achieved with a single drug alone, avoiding unnecessary risks. Indeed, this analysis suggests that all three drugs result in an equal improvement over placebo, and this is particularly convincing in the analysis restricted to patients who did not have to discontinue treatment at randomization.

Regarding the question of which drug should be preferred, the answer is quite clear: it must be the long-acting β-agonist bronchodilator (7). First, a more complete 2 × 2 factorial analysis of the TORCH data on the independent contribution of each component of the treatment combination on mortality showed that any reduction in mortality was entirely due to the bronchodilator component and not to the inhaled corticosteroid component (6, 8). Moreover, inhaled corticosteroids alone or in combination have been associated with increased risks of glaucoma and possibly osteoporotic fractures (911), and have been shown to increase the risk of cataract and pneumonia, particularly with the high doses currently in use (1216).

On the whole, this study offers two major advances that benefit the patient with COPD. It provides the first possible evidence that lung function decline can be slowed with medications. It also provides further evidence that the use of inhaled corticosteroids, alone or in combination, in COPD is unnecessary and thus inappropriate.

1. Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease: a meta-analysis. Ann Intern Med 2003;138:969–973.
2. Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58:937–941.
3. Soriano JB, Sin DD, Zhang X, Camp PG, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM, Connett JE, et al. A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo. Chest 2007;131:682–689.
4. Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins C, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley PMA. 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.
5. Aaron SD, Fergusson D, Marks GB, Suissa S, Vandemheen KL, Doucette S, Maltais F, Bourbeau JF, Goldstein RS, Balter M, et al.; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Counting, analysing and reporting exacerbations of COPD in randomised controlled trials. Thorax 2008;63:122–128.
6. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of chronic obstructive pulmonary disease. Eur Respir J 2008;31:927–933.
7. Rabe KF. Treating COPD: the TORCH trial, P values, and the dodo. N Engl J Med 2007;356:851–854.
8. La Vecchia C, Fabbri LM. Prevention of death in COPD. N Engl J Med 2007;356:2211–2212.
9. Garbe E, LeLorier J, Boivin JF, Suissa S. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 1997;350:979–982.
10. Hubbard RB, Smith CJ, Smeeth L, Harrison TW, Tattersfield AE. Inhaled corticosteroids and hip fracture: a population-based case-control study. Am J Respir Crit Care Med 2002;166:1563–1566.
11. Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169:83–88.
12. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997;337:8–14.
13. Garbe E, Suissa S, LeLorier J. Association of inhaled corticosteroid use with cataract extraction in elderly patients. JAMA 1998;280:539–543. [Published erratum appears in JAMA 280:1830.]
14. Ernst P, Baltzan M, Deschenes J, Suissa S. Low-dose inhaled and nasal corticosteroid use and the risk of cataracts. Eur Respir J 2006;27:1168–1174.
15. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
16. Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med 2007;176:162–166.

Related

No related items
American Journal of Respiratory and Critical Care Medicine
178
4

Click to see any corrections or updates and to confirm this is the authentic version of record