Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy

Abstract

Background: There is concern that long-acting b agonist (LABA) drugs may increase the risk of asthma mortality. Methods: A meta-analysis was conducted of asthma deaths in randomised controlled clinical trials from the GlaxoSmithKline database that compared salmeterol with a non-LABA comparator treatment in asthma. The Peto one-step method was used to determine the risk overall (all studies) and in derived datasets based on inhaled corticosteroid (ICS) use. Results: There were 35 asthma deaths in 215 studies with 106 575 subjects. Two studies (SMART and SNS) contributed 30/35 (86%) asthma deaths, the overall findings largely reflecting the characteristics of these studies. The odds ratio for risk of asthma mortality with salmeterol was 2.7 (95% CI 1.4 to 5.3). In 54 placebo controlled studies the risk of death from asthma in patients not prescribed ICS was 7.3 (95% CI 1.8 to 29.4). In 127 studies in which patients were prescribed ICS, the risk of asthma death was 2.1 (95% CI 0.6 to 7.9). In 63 studies in which patients were randomised to receive the combination salmeterol/fluticasone propionate inhaler or ICS, there were no asthma deaths among 22 600 patients. Conclusions: Salmeterol monotherapy in asthma increases the risk of asthma mortality and this risk is reduced with concomitant ICS therapy. There is no evidence that combination salmeterol/fluticasone propionate therapy is associated with an increased risk of asthma mortality, although this interpretation is limited by the low statistical power of available studies.The role of long-acting b agonist (LABA) drugs in asthma mortality represents the latest chapter in a long running debate about the safety of inhaled b agonist drugs in the treatment of asthma. 1-10Evidence for a possible increased risk of asthma mortality with LABA therapy was first raised in 1993 with publication of the Salmeterol Nationwide Surveillance Study (SNS).9 This study reported a statistically non-significant threefold increased risk of death in subjects treated with salmeterol compared with regular salbutamol, but no increase in hospital admissions or life-threatening events. These findings led to the Salmeterol Multicentre Asthma Research Trial (SMART), which reported a statistically significant fourfold increase in asthma mortality with salmeterol compared with placebo.10 In subgroup analyses, there was no increased risk in asthma mortality for salmeterol in subjects prescribed concomitant ICS therapy. Although limited by low power, this finding raised the possibility that the mortality risk was restricted to salmeterol as monotherapy and that concomitant use of ICS therapy may protect against the risk.This interpretation was supported by the findings of the large UK-based case-control study in which there was no evidence of any positive association between LABAs and asthma death. 11As almost all patients in the UK during the period of the study who were prescribed LABA therapy were co-prescribed ICS therapy, 12 these findings provided evidence that the use of LABAs with c...

24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids

“…Our data support the overall conclusion that doses of VI up to 50 mg have limited side-effects. Clearly, the influence of VI on rare events such as asthma-related worsening or mortality [25,26] cannot be addressed in a study of this nature and therefore must be monitored in future long-term trials.…”

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

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Asthma phenotyping, therapy, and prevention: what can we learn from systems biology?

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