Drug Combo Improves COPD Symptoms But Misses Mortality Endoint

LIVERPOOL, England, Feb. 21 -- A three-year trial of combination therapy for chronic obstructive pulmonary disease did not achieve overall significant survival improvement compared with either drug alone, or even placebo.

But the combination of the inhaled corticosteroid fluticasone proprionate (Flovent) and the long-acting beta2 agonist salmeterol (Serevent) significantly reduced the number of exacerbations and improved the overall health and lung function of patients compared with placebo, according to investigators in the TORCH (TOwards a Revolution in COPD Health) study.

Yet the finding of no survival difference could be a statistical fluke, suggested investigators in the Feb. 22 issue of the New England Journal of Medicine. The TORCH investigators had reported their preliminary findings last October at the annual CHEST meeting in Salt Lake City.

The investigators, led by Peter M.A. Calverley, M.D., of the University Hospital Aintree here, reported in the NEJM that the combination of fluticasone and salmeterol produced a 17.5% relative risk reduction in all-cause mortality, compared with placebo.

The catch was that the relative risk reduction did not meet the statistical significance test, coming in with a P value of 0.052 for the difference, due to a lower than expected number of deaths in the placebo group.

"There are two possible reasons why the reduction in mortality in the combination-therapy group, as compared with the placebo group, did not achieve statistical significance," Dr. Calverley and colleagues wrote. "The first is that there is no effect of salmeterol plus fluticasone propionate on survival. In this scenario, the data would suggest that the observed symptomatic and functional improvement derives from mechanisms other than those that prolong life. It could be that mortality is influenced mainly by factors that are currently unidentified and unresponsive to therapy with salmeterol plus fluticasone propionate."

The other (and more likely) possibility they said, was that the study, despite its relatively large size (6,184 patients randomized), was underpowered to detect a difference between the fluticasone/salmeterol combination, either drug alone, or placebo, and that the large number of dropouts (40%) could have skewed the results against the combination.

At CHEST 2006, Ronald Grossman, M.D., of the University of Toronto said in an interview that the trial is "one of the single most important trials in respiratory medicine that has been in an awfully long time," and noted that the 17.5% effect on mortality is probably "a very, very conservative estimate."

The study evaluated patients on an intent-to-treat basis, he said, so that the large number of patients who dropped out of the placebo arm and moved to more effective treatment were counted as failures.

"It's hard to believe it's not a real effect," he said.

In an editorial accompanying the study, Klaus F. Rabe, M.D., Ph.D, of the Leiden University Medical Center in The Netherlands, said that despite the failure to produce a conclusive outcome, there are important take-home messages for clinicians.

"The interpretation of the data for the primary outcome as published is conservative -- and, in principle, it is correct: the reduction in mortality in the combined- therapy group did not reach the predetermined level of statistical significance," he wrote.

"On further weighing these results, however, I think the treatment with long-acting beta agonists was a winner and that with inhaled corticosteroids was a clear loser. The clinical guidance is obvious: monotherapy with corticosteroids should not be advocated for patients with COPD, monotherapy with a long-acting bronchodilator appears to be safe, and the combination therapy offers no statistically significant additional survival benefit," Dr. Rabe wrote.

The TORCH investigators randomly assigned 6,184 patients to one of four treatment groups: salmeterol 50 ?g plus fluticasone ?g twice daily, salmeterol alone, fluticasone alone, or placebo. The study duration was three years, with the primary outcome being death from any cause for the comparison between the combination regimen and placebo. Secondary measures included the frequency of exacerbations, health status, and spirometric values.

They found that of 6,112 patients in the efficacy population, 875 died within three years after the start of the study treatment. 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.

Compared with placebo, the hazard ratio for the primary endpoint of death in the combination-therapy group was 0.825 (95% confidence interval 0.681 to 1.002; P=0.052, adjusted for the interim analyses). This corresponded to an absolute difference of 2.6 percentage points, or a reduction in the risk of death of 17.5% for patients treated with the combination.

Mortality rates for neither fluticasone alone nor salmeterol alone were significantly different from that of placebo.

The combination regimen was superior to placebo at reducing the annual rate of exacerbations, from 1.13 to 0.85 (P