The 3-year survival of the two cohorts was compared using survival analysis techniques. After adjusting for confounders, the combined users of ICS+LABA had a significant 52% lower mortality (hazard ratio 0.48; 95% CI 0.31–0.73), and the users of ICS only had a significant 38% lower mortality (hazard ratio 0.62; 95% CI 0.45–0.85) than the reference group of other bronchodilator users. Immortal time bias is introduced in the hierarchical definition of exposure, where exposure is first assessed to identify the “exposed” cohort, namely those patients who received ICS+LABA. Only then was the “unexposed” reference group identified from the Inhibitors,research,lifescience,medical remaining patients as those who did not receive

ICS or LABA, but only short-acting bronchodilators. However, many “exposed” subjects had used short-acting bronchodilators prior to their start of ICS+LABA, consistent with the stepped-care approach to COPD treatment. Thus, several subjects from the “exposed” group were in fact “unexposed” before Inhibitors,research,lifescience,medical switching to this exposure

status. More importantly, however, this pre-exposure time during which subjects were “unexposed” is an immortal period since these subjects, in switching from the “unexposed” status to the “exposed” status, will necessarily do so alive. Had they died before switching, Inhibitors,research,lifescience,medical they would by definition have belonged to the unexposed group. Thus, the bias occurs because valid unexposed person-time of follow-up with no deaths is not accounted for in the reference rate of death. This results in an artificial selleckchem increase in the Inhibitors,research,lifescience,medical rate of death of the reference group, leading to a spurious appearance of effectiveness. This bias was illustrated in another cohort of COPD patients, with the hazard ratio changing from a highly significant 0.66 (95% CI 0.57–0.76) Inhibitors,research,lifescience,medical to a non-significant 0.94 (95% CI 0.81–1.09) after properly accounting for this bias.32 The TORCH Randomized Trial In 2007, a large-scale randomized controlled trial was published, comparing an ICS+LABA (fluticasone+salmeterol)

combination with placebo, LABA alone, or ICS alone, over a period of 3 years, on the primary outcome of death from any cause.36 Of the 6,112 randomized patients, all-cause mortality was 12.6% in the ICS+LABA combination group, 15.2% in the placebo group, 13.5% in the LABA group, and 16.0% in the ICS group. The hazard ratio of death for the ICS+LABA combination compared with placebo was 0.82 (95% CI 0.68–1.00), while compared with ICS alone it was 0.77 (95% CI 0.64–0.93). Oxymatrine Moreover, for ICS alone compared with placebo, the hazard ratio was 1.06 (95% CI 0.89–1.27). The authors concluded that the mortality reduction with combination therapy did not reach the predetermined level of statistical significance. As these results were inconclusive, a further analysis of the data as a 2×2 factorial design of ICS (yes/no) and LABA (yes/no) was performed to improve the power and tease out the independent contribution of each component of the combination.