Laura Sutton

Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events

Context Guidelines recommend adding long-acting -agonists to regimens of patients with asthma that is not controlled on inhaled corticosteroids alone. Is this safe? Contribution This meta-analysis summarizes 66 GlaxoSmithKline trials involving 20966 patients with persistent asthma. Trials compared twice-daily salmeterol, 50 g, plus inhaled corticosteroids with inhaled corticosteroids alone. Combination therapy did not appear to alter risk for asthma-related hospitalizations but did decrease risk for severe exacerbations requiring systemic corticosteroids. The only cases of asthma-related death and intubation occurred in patients receiving combination therapy. Caution Most trials were short and originally designed to assess lung function rather than clinical outcomes. The Editors Asthma is a chronic disease affecting nearly 20 million people in the United States and approximately 300 million people worldwide (1). In response to the growing burden of uncontrolled asthma, evidence-based guidelines were released in the early 1990s to bridge the gap between research and practice, with the objective of improving management. National and international asthma guidelines recommend that all patients with persistent asthma receive regular treatment with anti-inflammatory medication, preferably an inhaled corticosteroid. For patients whose asthma is not controlled by inhaled corticosteroids alone, guidelines recommend adding a long-acting -agonist (1, 2). Recently, concern about the role of long-acting -agonists in asthma management was raised in a randomized, observational study of more than 26000 patients (3). In this study, salmeterol compared with placebo added to usual therapy showed a small but statistically significant increase in severe asthma-related events, including asthma-related death. In contrast, the largest casecontrolled study to date of 532 asthma deaths (4) concluded that use of long-acting -agonists was not associated with increased risk for asthma-related death compared with other therapies. The Cochrane Airways Group has published several meta-analyses of clinical trials that studied the combination of inhaled corticosteroids and long-acting 2-agonists and concluded that exacerbations of asthma were infrequent and occurred at similar or lower rates in participants receiving concurrent long-acting -agonists and inhaled corticosteroids than in those receiving inhaled corticosteroids alone (57). Salpeter and colleagues (8) performed a meta-analysis examining life-threatening or fatal asthma exacerbations in participants using long-acting -agonists. Approximately 50% of the participants did not receive concurrent inhaled corticosteroid therapy, and the results showed that, although rare, asthma-related hospitalization and death occurred more frequently in participants receiving long-acting -agonists than in those receiving placebo. Because asthma guidelines clearly state that long-acting -agonists should be taken concurrently with inhaled corticosteroids (1, 2), we conducted a meta-analysis of published and unpublished GlaxoSmithKline trials that evaluated use of salmeterol and inhaled corticosteroids compared with inhaled corticosteroid monotherapy alone. Methods Data Sources and Searches We reviewed all studies posted as of September 2007 to the GlaxoSmithKline Clinical Trials Registry (ctr.gsk.co.uk/welcome.asp) for the following GlaxoSmithKline drugs: fluticasone propionate/salmeterol (Advair), salmeterol xinafoate (Serevent), and fluticasone propionate (Flovent). This registry is a repository of data from GlaxoSmithKline-sponsored clinical trials. We also searched MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews from 1982 to September 2007. These searches were not restricted to studies published in English. Terms included salmeterol, -agonist, long-acting -agonist, inhaled corticosteroids, fluticasone propionate, budesonide, triamcinolone acetonide, beclomethasone dipropionate, randomized, controlled clinical trial, asthma, Advair, and Seretide. Finally, we supplemented these searches by reviewing references from published reviews. Study Selection Three reviewers perused the GlaxoSmithKline registry and search outputs (titles and abstracts) to identify randomized, controlled trials that compared the use of inhaled corticosteroids plus salmeterol with inhaled corticosteroids alone in patients with asthma. We selected randomized, double-blind, parallel-design, long-term dosing studies (range, 1 to 52 weeks) that used the approved dosage of salmeterol (50 g twice daily) in the United States and had been completed and analyzed by 30 September 2007. We did not exclude any trials on the basis of language. We excluded uncontrolled, open-label studies; single-dose studies; and crossover studies. Data Extraction and Quality Assessment One reviewer extracted information about participants, interventions, and comparisons from trials in the GlaxoSmithKline database, registry, or publications, and a second reviewer doubled-checked this information. One reviewer extracted information about trials that were not sponsored by GlaxoSmithKline. We did not use a specific checklist or scale to assess the quality of the trials: Protocols for the GlaxoSmithKline trials met the International Conference on Harmonisation guidelines. For these trials, a participant could spontaneously report adverse events. Study personnel solicited these participants by regular interviews and asked standardized, open-ended questions about any changes in their health status. The interval for these interviews was defined by the individual protocols but generally did not exceed 4 weeks. All GlaxoSmithKline trials report case narratives of serious adverse events, which include hospitalization, intubation, or death. We sent case narratives of reported serious adverse events that occurred during the randomized, double-blind phase of the GlaxoSmithKline trials to 3 physicians. These physicians, who were blinded to drug assignment in each case, independently reviewed the narratives and adjudicated the asthma relationship for hospitalization, intubation, and death status of each case. Any disagreements about adjudications were resolved through consensus of the 3 physicians. Statistical Analysis We used 2 methods to pool GlaxoSmithKline data on asthma-related hospitalizations and severe asthma-related exacerbations that required systemic corticosteroids. First, we calculated risk differences by using data from GlaxoSmithKline trials that met inclusion criteria (even those without events). We applied a treatment group continuity correction for trials in which at least 1 of the treatment groups had no events. In sensitivity analyses, we used 0.01, 0.001, and 0.0001 continuity corrections (9). Second, we used the Peto odds ratio method, which excludes trials with no events and performs reasonably well when imbalance in trial group size is low, the rate of events is low (1%), and the effect size is small (10, 11). For all estimates, we calculated 95% CIs (12, 13). We used the Cochran Q test and I 2 to evaluate statistical heterogeneity. All analyses were based on fixed-effects models and were conducted with StatsDirect statistical software, version 2.6.6 (Sale, United Kingdom) (14). Role of the Funding Source GlaxoSmithKline sponsored most trials summarized in this review. GlaxoSmithKline also supported data collection, analyses, manuscript preparation, and data interpretation for the review. All authors approved the manuscript for submission. Results Of 1218 reports identified in the combined searches, we found 80 randomized trials that compared salmeterol plus inhaled corticosteroids with inhaled corticosteroids alone (Figure 1). Of these, we excluded 4 short crossover trials that involved a total of 72 participants and 3 open-label trials that included 452 participants. None of the 7 excluded trials reported any asthma-related deaths, intubations, or hospitalizations. One trial (SLGT26) included in the current analysis had 3 groups. We excluded the group that involved 244 participants who were assigned to a dose of salmeterol (100 g twice daily) that exceeded the current recommendation. There were 3 asthma-related hospitalizations but no deaths in this excluded treatment group. Figure 1. Study flow diagram. GSK = GlaxoSmithKline. *Studies could contribute to more than 1 subanalysis. Trial Characteristics Seven trials that were not sponsored by GlaxoSmithKline met eligibility criteria. These trials involved a total of 503 participants (1521). None reported hospitalization, intubation, or death in a participant receiving salmeterol plus inhaled corticosteroids or inhaled corticosteroids alone. Because we did not have access to individual case narratives of adverse events in these trials, we did not include them in the quantitative analyses. The GlaxoSmithKline registry included 66 eligible trials that involved a total of 20966 participants (Appendix Table 1). In these trials, 10400 participants received inhaled corticosteroids plus salmeterol and 10566 received inhaled corticosteroids alone. The median trial duration was 12 weeks (range, 1 to 52 weeks). Sample sizes ranged from 12 to 3416. The mean age of participants was about 38 years. Forty-four percent were men, and 82% were white. Most had moderate to severe persistent asthma. The overall rate of withdrawal for any reason was about 14% among participants receiving inhaled corticosteroids plus salmeterol and about 17% among those receiving inhaled corticosteroids alone. Appendix Table 1. Included Studies Most trials used a lung function measure (FEV1 or peak expiratory flow) as the primary end point. In a few studies, the primary end point was a measure of asthma control, such as exacerbations or symptoms. The largest study (SAM40027) used a composite measure of asthma control that integrated lung function measures as well as symptom control and exacerbations as the primary e

Safety and efficacy of long-term treatment with fluticasone propionate and salmeterol via DISKUS versus fluticasone propionate alone

This 52 week study (ADA109057; ClinicalTrials.gov identifier: NCT00452348) was designed to assess the safety and efficacy of fluticasone propionate (FP)/salmeterol 250/50 mcg via DISKUS (FSC) vs FP 250 mcg in subjects with persistent asthma symptomatic on FP 100 mcg. The objective was to demonstrate superiority in lung function (FEV1) of FSC 250/50 mcg vs FP 250 mcg. Secondary objectives included AM PEF, percentage of symptom-free days, and rate of asthma attacks. Three hundred and ten subjects received FSC 250/50 mcg and 318 subjects received FP 250 mcg, both administered twice daily following a 14–21 days of open-label FP 100 mcg. Treatment with FSC 250/50 mcg resulted in an improvement in lung function vs FP 250 mcg (p = 0.09). Additionally, treatment with FSC 250/50 mcg improved AM PEF and increased the percentage of symptom-free days. The asthma attack rate was similar between treatments, as was the safety profile. FSC 250/50 mcg demonstrated improvements in lung function and asthma control vs FP 250 mcg, although statistically significant differences were not consistent. The differences may be representative of this population with less severe disease at entry. In patients with mild-to-moderate persistent asthma FSC offers improved parameters of asthma control compared with ICS alone.