TORCH Trial Raises Prospects of COPD Survival

Abstract

SALT LAKE CITY — The combination of inhaled salmeterol and fluticasone propionate is the first-ever drug therapy shown to reduce mortality in patients with chronic obstructive pulmonary disease, according to the results of the landmark Towards a Revolution in COPD Health (TORCH) study. The TORCH findings, presented by Dr. Bartoleme R. Celli at the annual meeting of the American College of Chest Physicians, were well-received by physicians. There was anticipation that the study marks a new era in which COPD—a seriously underdiagnosed disease that's the fourth-leading cause of death—will get greater attention from the public, physicians, and the pharmaceutical industry. Not only did this study “show that patients with COPD live longer with the combination of salmeterol and fluticasone, but they do so with fewer exacerbations and a better quality of life. Now we can add to oxygen therapy and smoking cessation another type of therapy that impacts on mortality,” Dr. Celli said. TORCH was a 3-year, double-blind, four-arm clinical trial involving 6,112 patients with moderate to severe COPD. The mean age of participants was 65 years. They were randomized to b.i.d. placebo, the long-acting bronchodilator salmeterol at 50 mcg, the corticosteroid fluticasone propionate at 500 mcg, or fluticasone/salmeterol 500/50 mcg. The combined therapy is marketed under the brand name Advair in the United States, Viani in Germany, and Seretide elsewhere. The primary end point was all-cause mortality. After 3 years, mortality was 12.6% with fluticasone/salmeterol and 15.2% with placebo, for a 17% relative risk reduction. COPD-related mortality was reduced by 22%; the rates were 4.7% with combination therapy and 6.0% with placebo. Neither salmeterol nor fluticasone alone was significantly better than placebo. Combination therapy worked significantly better on all secondary end points as well. The incidence of moderate to severe exacerbations was reduced by 25% compared with placebo. Health status as measured by the St. George's Respiratory Questionnaire was better than with either drug alone or placebo. And mean forced expiratory volume in 1 second (FEV1) was 91 mm Hg higher in the fluticasone/salmeterol arm than with placebo, added Dr. Celli, professor of medicine at Tufts University, Boston. Nonfatal pneumonia, hoarseness, and oral thrush were significantly more common with combination therapy. But there was no increase in cataracts, nontraumatic fractures, or loss of bone mineral density at the hip compared with placebo. Given the size of the study—the largest-ever COPD clinical trial—along with the strength and consistency of the results, Dr. Celli said he is comfortable in recommending that physicians seriously consider the fluticasone/salmeterol combination in their COPD patients. “To me the signal is strong enough to say that given the inclusion criteria of the study—an FEV1 below 60% of predicted, more than 10 years of smoking, obstruction by spirometry, and no asthma—that person should benefit from the combination,” the pulmonologist said. “TORCH is clearly one of the most important studies in respiratory medicine in a very long time,” said Dr. Ronald F. Grossman, who was not involved in the trial. He shrugged off the borderline significance of the all-cause mortality reduction, P = .052, by intention-to-treat analysis. Most dropouts in the placebo occurred in the first year. A good proportion of them were probably on effective therapy for much of the 3 years, yet they were counted in the placebo group. So if anything, the mortality effect is a very, very conservative estimate,” said Dr. Grossman, professor of medicine at the University of Toronto. Advair is currently Food and Drug Administration-indicated only at a 250/50 mcg formulation. The 500/50 mcg formulation is marketed outside the United States. The company plans to seek FDA approval of the 500/50 mcg formulation. Dr. Celli is a consultant to GlaxoSmithKline, which funded TORCH.