Long-acting Bronchodilators and Mortality in Patients With Stable COPD

Long-acting Bronchodilators and Mortality in Patients With Stable COPD

Abstract and Introduction

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is the 4 leading cause of mortality worldwide. Long-acting bronchodilators are considered first line therapies for patients with COPD but their effects on mortality are not well known. We performed a comprehensive systematic review and meta-analysis to evaluate the effects of long-acting bronchodilators on total mortality in stable COPD.
Methods: Using MEDLINE, EMBASE and Cochrane Systematic Review databases, we identified high quality randomized controlled trials of tiotropium, formoterol, salmeterol, formoterol/budesonide or salmeterol/fluticasone in COPD that had a follow-up of 6 months or longer and reported on total mortality. Two reviewers independently abstracted data from the original trials and disagreements were resolved by iteration and consensus.
Results: Twenty-seven trials that included 30,495 patients were included in the review. Relative risk (RR) for total mortality was calculated for each of the study and pooled together using a random-effects model. The combination of inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA) therapy was associated with reduced total mortality compared with placebo (RR, 0.80; p = 0.005). Neither tiotropium (RR, 1.08; p = 0.61) nor LABA by itself (RR, 0.90; p = 0.21) was associated with mortality.
Conclusions: A combination of ICS and LABA reduced mortality by approximately 20%. Neither tiotropium nor LABA by itself modifies all-cause mortality in COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) affects more than 300 million people worldwide. It is currently the 4 leading cause of mortality accounting for nearly 3 million deaths annually and is the only major cause of mortality that is increasing in both the developed and developing countries. By 2020, it will become the 3 leading cause of death (accounting for 5 million deaths per year) and the 5 leading causing of disability worldwide. Expert guidelines recommend the use of long-acting bronchodilators as first-line therapies for patients with persistent symptoms. However, their effect on mortality remains controversial. A previous meta-analysis suggested that inhaled long-acting anticholinergic bronchodilators had no effect on total mortality. On the other hand, a secondary analysis of the UPLIFT trial suggested a mortality benefit. Similarly, although the TORCH trial suggested a modest mortality benefit with inhaled corticosteroid/long-acting beta-2 agonist combination (ICS/LABA), meta-analyses suggested that they may only reduce mortality when compared to placebo or ICS alone but not to LABA alone. However, there were several limitations to the prior meta-analyses, which may have led to some of the discordant findings. First, the prior meta-analysis on tiotropium did not include data from the recently completed UPLIFT trial. Second, prior meta-analyses did not address the effect of LABA on total mortality, making it difficult to assess whether or not LABA can be used as a reasonable comparator for ICS/LABA. Third, the findings from the ICS/LABA on mortality are dominated by data from one trial (i.e. TORCH), raising doubts about the robustness of the results from previous meta-analyses. Fourth, and most importantly, many of the previous trials of ICS/LABA used a factorial design. However, none of these studies had sufficient power to assess interactions between treatments or to adjust for multiple comparisons. From a methodological perspective, it is essential that the active treatment drugs be compared against one (primary) reference group (and not to each other) unless adjustments are made for multiple comparisons. To address these limitations and to determine the effects of these drugs on total mortality in COPD, we performed a systematic review and meta-analysis with and without TORCH for ICS/LABA and inclusive of UPLIFT for tiotropium. Importantly, to maintain statistical integrity, for trials that used a factorial design, we determined survival effects of the primary active treatment drug against the principal comparator group identified a priori in each of the individual studies.