Lessons Learned from TORCH

Key Point

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SAN FRANCISCO—Due to its large size and international cohort, the Towards a Revolution in COPD Health (TORCH) study may prove to be influential for some time to come. In a lecture at the American Thoracic Society’s 103rd International Conference, various TORCH study authors talked about the general implications of this “landmark” trial (see “TORCH Study Revisited,” page 43) as well as the results of ad hoc analyses focusing on specific patient groups and comorbidities. During the original randomized, double-blind study, a combination salmeterol/fluticasone medication compared favorably with salmeterol alone, fluticasone alone, and placebo in some important outcome measures.

STUDY IMPLICATIONS

“Traditionally, alteration over time in FEV1 has been used as the gold standard of response to COPD therapy,” said Bartolome Celli, MD, member of the TORCH investigative team and Chief of the Pulmonary, Critical Care, and Sleep Medicine Division of the Caritas-St. Elizabeth’s Medical Center in Boston. He cited the seminal 1977 Fletcher and Peto study, which demonstrated that even healthy persons experience increasing lung function decline as they age, but the rate of decline is much faster among smokers with COPD. Among those who quit smoking, the rate of decline slows and eventually returns to normal levels, according to Fletcher and Peto’s research. Until the TORCH study, smoking cessation was the only intervention that had been shown to slow lung function decline in COPD patients.

However, at the end of the three-year TORCH trial, subjects in all active treatment groups experienced slowed FEV1 decline, compared with placebo recipients. The mean change after three years in FEV1 versus placebo was 92 mL in the salmeterol/fluticasone group, 50 mL in the salmeterol-alone group, and 44 mL in the fluticasone-alone group.

“[TORCH] is the first study that demonstrates that bronchotherapy can significantly alter the rate of decline of lung function,” Dr. Celli noted. “All of us who were trained to believe that improvement in FEV1 was the holy grail can now turn to our patients and tell them we are not crazy.”

GEOGRAPHIC DIFFERENCES

Post hoc analysis of the TORCH study results showed that despite differences in baseline characteristics across geographic regions, findings of efficacy were similar, said Christine Jenkins, MD, from the Woolcock Institute of Medical Research, Sydney.

“Although a few critical countries were omitted, participants generally were extensively recruited from all parts of the world,” Dr. Jenkins said. For this analysis, geographic areas were stratified into the following regions: United States, Eastern Europe, Western Europe, Asian Pacific, and “other.” Age was similar across study populations (mean, 65), and the number of participants generally was evenly distributed among regions.

Baseline FEV1 was lowest in participants in the Asian Pacific. “This might be because we didn’t adjust for ethnicity,” Dr. Jenkins noted, as the comparatively smaller average height among persons in the Asian Pacific may affect lung size, and consequently, FEV1 measurements. Exacerbation frequency in the previous year was highest in the population from Eastern Europe and lowest in the US. Participants from the Asian Pacific were the least likely to have used inhaled steroids or long-acting bronchodilators prior to enrollment in the study. Prior use of medication was highest in the Western European population.

There were no significant differences in response to treatment with regard to mortality and exacerbation rate between regions. Change from baseline in health status score was similar across regions, with the exception of the Asian Pacific, which saw disproportionately greater improvement. “This may be a study participation effect,” Dr. Jenkins suggested, particularly in light of the fact that this region had the lowest prestudy medication use.

EYE DISEASE AND BONE DENSITY

“Whenever we have a study such as TORCH, there’s an opportunity to look at how we can impact patient function. But as most of us know, we have to look at safety as well,” said Gary T. Ferguson, MD, of the Pulmonary Research Institute of Southeast Michigan in Livonia.

Dr. Ferguson pointed out that COPD patients typically experience decreased bone density, with the risk of osteoporosis increasing with disease severity. In addition, research suggests that systemic steroids increase risk of osteoporosis, osteopenia, and bone fractures.

“There has been a lot of controversy in the literature about how inhaled steroids affect risk, ranging from no impact to suggestions that they inevitably cause problems over time.” Eye disease—particularly, cataracts, and to a lesser extent, glaucoma—has also been associated with use of inhaled steroids.

In a subset of TORCH participants—dubbed the Ocular and Safety Population (all from the US; n = 658)—bone density tests and eye examinations were performed at baseline and at regular intervals during follow-up. “[At baseline], across all four treatment arms, the prevalence of osteoporosis was significant,” Dr. Ferguson noted.

Specifically, about 70% of all patients had osteopenia or osteoporosis upon entering the study, and although osteoporosis generally is thought of as a women’s disease, the percentage of men who had osteoporosis (50% to 60%) was nearly as high as that of women (60% to 70%), Dr. Ferguson noted. Similarly, for cataracts, “There was a prevalence of disease at the start,” he added. Dr. Ferguson stressed that clinicians should look for and manage these conditions in COPD patients.

At three years, there was no significant between-group difference in change in total hip and lumbar spine bone density; similar findings were observed with regard to the rate of newly diagnosed cataracts or glaucoma. The study authors concluded that long-term use of inhaled corticosteroids does not contribute to bone density reduction or eye problems among COPD patients.            

—Adriene Marshall

Reference
Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.
Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977;1(6077):1645-1648.
Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(2):144-149.
Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of COPD—2006 update. Am J Respir Crit Care Med. 2007 May 16; [Epub ahead of print].

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