Evaluating the Impact of Triple Therapy on Mortality in Copd: The End is the Beginning?

Mortality has long been one of the two “Holy Grails” of COPD management, the second being the change in the natural history of the disease, as expressed by the rate of decline of FEV 1 . The hype around the role of inhaled corticosteroids (ICS) in mortality reduction has been long-standing, as there is evidence that these drugs reduce exacerbations [1] and the rate of decline of FEV 1 [2]. However, the two mega-trials of combinations of ICS/long-acting β-agonist (LABA) designed to evaluate all-cause mortality as the primary endpoint, were not able to show a mortality benefit for these combinations vs. placebo: the TORCH trial showed a 17.5% reduction in mortality with salmeterol/fluticasone propionate that did not reach statistical significance with the notorious p-value of 0.052 [3], whereas the SUMMIT trial did not show any survival benefit for vilanterol/fluticasone furoate in COPD patients with history of cardiovascular disease or with cardiovascular risk factors [4]. Other trials that were not powered to evaluate mortality have provided con-tradicting results, with the 2-year INSPIRE trial in exacer-bating COPD patients showing a mortality benefit for salmeterol/fluticasone vs. tiotropium [5], whereas that was not the case for the FLAME trial in the comparison of salmeterol/fluticasone and the LABA/long-acting muscarinic antagonist (LAMA) combination of indacaterol/glycopyrro-nium [6], not allowing for firm conclusions. Recently the topic was revisited in the large IMPACT [7] and ETHOS [8] trials, that showed a 28% and 49% reduction in mortality with