American Journal of Respiratory and Critical Care Medicine | 2021
Reply to López-Campos et al.: Triple-Therapy Trials for Chronic Obstructive Pulmonary Disease: Methodological Considerations in the Mortality Effect
Abstract
number of events [n=5–8 across groups], preventing meaningful conclusions), and across a broad range of eosinophil counts (1), suggesting that it is highly unlikely that this was a chance finding influenced by confounding. Wedisagreewith the suggestion that theremayhave been a different level of effort in retrieving deaths between groups. Our supplemental follow-up retrieved 52-week vital status for 99.65% of patients in the intent-to-treat population. For the 30 patients whose 52-week vital status remained unknown in the final retrieved dataset (including n=10 on BGF 320 and n=5 on GFF), we reported tipping-point analyses to examine the possible impact of these patients. If all 5 missing patients on GFF were alive and up to 8 of 10 patients on BGF 320 died the day after we last knew they were alive, the treatment comparison would remain significant (1). It is correct that not all retrieved deaths were included in the analysis and that the percentage of excluded deaths varied across groups. This is because the analysis only included deaths up to 52 weeks, and a greater percentage of deaths in the dual-therapy groups occurred within 52 weeks. We performed a sensitivity analysis including all retrieved deaths, regardless of how late they occurred (i.e., 37 deaths for BGF 320 and 64 deaths for GFF); this produced a hazard ratio of 0.46 (95% confidence interval, 0.30–0.71; P=0.0004). Overall, we agree that further trials assessing the benefits of triple therapy on mortality would be welcome. However, there would be substantial practical difficulties in conducting such trials, including the fact that two large studies (IMPACT [Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment] and ETHOS) have now shown a benefit of triple therapy on mortality, raising ethical questions on the appropriateness of randomizing this patient population to longterm dual therapy. As mentioned by Rogliani and Calzetta, clinical trial populations are only partially representative of real-life populations, and any future trials would have this same limitation. Nevertheless, many studies have now provided evidence that triple therapy reduces exacerbations and improves lung function and patient-reported outcomes compared with dual therapies (3). The findings from IMPACT and ETHOS on mortality add support for the benefit of these therapies in improving the lives of patients with chronic obstructive pulmonary disease. n