Regular treatment with salmeterol for chronic asthma: serious adverse events

Christopher J Cates; Matthew J Cates

doi:10.1002/14651858.CD006363.pub2

. Author manuscript; available in PMC: 2014 May 9.

Published in final edited form as: Cochrane Database Syst Rev. 2008 Jul 16;(3):CD006363. doi: 10.1002/14651858.CD006363.pub2

Regular treatment with salmeterol for chronic asthma: serious adverse events

Christopher J Cates ¹, Matthew J Cates ²

PMCID: PMC4015854 EMSID: EMS57597 PMID: 18646149

Abstract

Background

Epidemiological evidence has suggested a link between beta₂-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta₂-agonists are safe.

Objectives

The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular salmeterol versus placebo or regular short-acting beta₂-agonists.

Search methods

We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and FDA submissions in relation to salmeterol. The date of the most recent search was August 2011.

Selection criteria

We included controlled parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular salmeterol and were of at least 12 weeks’ duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.

Data collection and analysis

Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second checked them. We sought unpublished data on mortality and serious adverse events.

Main results

The review includes 26 trials comparing salmeterol to placebo and eight trials comparing with salbutamol. These included 62,815 participants with asthma (including 2,599 children). In six trials (2,766 patients), no serious adverse event data could be obtained.

All-cause mortality was higher with regular salmeterol than placebo but the increase was not significant (Peto odds ratio (OR) 1.33 (95% CI 0.85 to 2.08)). Non-fatal serious adverse events were significantly increased when regular salmeterol was compared with placebo (OR 1.15 95% CI 1.02 to 1.29). One extra serious adverse event occurred over 28 weeks for every 188 people treated with regular salmeterol (95% CI 95 to 2606). There is insufficient evidence to assess whether the risk in children is higher or lower than in adults. We found no significant increase in fatal or non-fatal serious adverse events when regular salmeterol was compared with regular salbutamol.

We combined individual patient data from the two largest studies (SNS: n=25,180 and SMART: n=26,355), as all the asthma-related deaths in adults occurred in these studies. In patients who were not taking inhaled corticosteroids, compared to regular salbutamol or placebo, there was a significant increase in risk of asthma-related death with regular salmeterol (Peto OR 6.15 95% CI 1.73 to 21.84). The confidence interval for patients who were taking inhaled corticosteroids is wide and cannot rule in or out an increase in asthma mortality in the presence of an inhaled corticosteroid (Peto OR 2.03 95% CI 0.82 to 5.00).

Authors’ conclusions

In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol. There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies. Although the increase in asthma-related mortality was smaller in patients taking inhaled corticosteroids at baseline, the confidence interval is wide, so we cannot conclude that the inhaled corticosteroids abolish the risks of regular salmeterol. The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied.

Medical Subject Headings (MeSH): Adrenergic beta-Agonists [therapeutic use], Albuterol [administration & dosage; adverse effects; ^*analogs & derivatives; therapeutic use], Anti-Asthmatic Agents [administration & dosage; ^*adverse effects], Asthma [drug therapy; ^*mortality], Bronchodilator Agents [administration & dosage; ^*adverse effects], Cause of Death, Placebos [therapeutic use], Randomized Controlled Trials as Topic

MeSH check words: Adult, Child, Humans

BACKGROUND

Description of the condition

There is currently no universally accepted definition of the term “asthma”. This is in part due to an overlap of asthmatic symptoms with those of other diseases such as chronic obstructive pulmonary disease (COPD), but is also due to the probable existence of more than one underlying pathophysiological process. There are, for example, wide variations in the age of onset, symptoms, triggers, associations with allergic disease and the type of inflammatory cell infiltrate seen in patients diagnosed with severe asthma (Miranda 2004). Patients with all forms and severity of disease will typically have intermittent symptoms of cough, wheeze and/or breathlessness. Underlying these symptoms there is a process of variable, at least partially reversible airway obstruction, airway hyper responsiveness and, in most cases, chronic inflammation.

Airway obstruction

Patients with a history of asthma demonstrate chronic changes within the airways including goblet cell hyperplasia, airway smooth muscle (ASM) hyperplasia and hypertrophy (Ebina 1993;Ordonez 2001; Woodruff 2004) and excess myofibroblasts with increased subepithelial collagen deposition (Brewster 1990). In the acute setting, in patients who have died of status asthmaticus airway obstruction is evident from air-trapping and lung hyperinflation with mucus plugging of the small and large airways (Dunnill 1960; Kuyper 2003). There is also shedding of ciliated bronchial mucosal cells, inflammatory cell infiltrates and submucosal oedema with transudation of fluid into the bronchial lumen (Carroll 1993). It is more difficult to measure the degree of ASM contraction (bronchoconstriction) at post-mortem studies although evidence for a role of bronchoconstriction in airway narrowing comes from other sources.

Airway hyper responsiveness

Patients with asthma typically display a degree of ‘airway hyper responsiveness’ to inhaled allergens (Cockcroft 2006), and to a variety of chemical stimuli including histamine, serotonin, bradykinin, prostaglandins, methacholine and acetylcholine as well as other triggers such as exercise, deep inhalation and inhalation of cold air (Boushey 1980). Bronchoconstriction is implicated as the primary effector mechanism of airway narrowing in these responses. This is because of both the short time frame of the response and because many of these stimuli typically either cause bronchoconstriction directly in vitro or promote bronchoconstriction through interference with the autonomic control of ASM. Further evidence comes from findings that this response can be abolished or diminished by bronchodilator medications such as atropine and beta₂-agonists (Phillips 1990; Simonsson 1967); although beta₂-agonists in particular may have additional mechanisms of action. Whether airway hyper responsiveness relates primarily to an abnormality of ASM, to increased ASM bulk (Wiggs 1990), to aberrant autonomic control or reflex pathways, or to physical damage to the airway epithelium remains to be established. Regular use of salbutamol has, however, been shown to increase airway hyper responsiveness to allergen exposure and produce tolerance to the protective effect of salbutamol against bronchoconstriction induced by both methacholine and allergens (Cockcroft 1993).

Inflammation

It has long been thought that the histological changes described above and the phenomenon of airway hyper responsiveness are due to a combined acute and chronic inflammatory response (Bousquet 2000). Patients with status asthmaticus have increased numbers of inflammatory cells including eosinophils and neutrophils, as well as a variety of pro-inflammatory cytokines and chemokines found in bronchial alveolar lavage (Tonnel 2001). In patients with chronic asthma there is also evidence of increased eosinophil numbers (Bousquet 1990), inflammatory cell adhesion molecules (Vignola 1993) and some evidence of an association between the extent of inflammation, disease severity and hyperreactivity. This association has however been questioned on the background of a number of negative results (Brusasco 1998), although it is made difficult to prove by the lack of a consistent marker of a sequential and variable inflammatory response (Haley 1998).

Description of the intervention

Beta₂-agonists and mortality: an historical perspective

Time trend data and case control studies

Adrenaline was successfully used in the symptomatic treatment of asthma as far back as 1903 (Tattersfield 2006). Initially given subcutaneously, the inhaled route was tried in 1929 to reduce adverse effects but these remained a problem and in 1940 details of a new agent isoprenaline (isoproterenol) were published in Germany (Konzett 1940). Although isoprenaline was more selective for beta- as opposed to alpha-adrenoreceptors, adverse effects including palpitations were still a major problem, particularly with oral administration (Gay 1949) and it first became available as atomizer spray for use in the UK in 1948 (Pearce 2001).

Prior to the 1940s, mortality rates from asthma in a number of countries were stable and low at less than one asthma death per 100,000 people per year (Pearce 2001; Figure 1). During the 1940s and 50s, there was a slight rise in mortality rates and concerns about a possible link to inhaled adrenaline were raised at an early stage (Benson 1948). However, the rise was small and the cause unclear and sales continued to increase with the introduction of aerosol or metered dose inhalers in the early 1960s. During this decade, there was an epidemic of asthma deaths in at least six countries including England, Wales and New Zealand (Figure 1). In all six countries the epidemics coincided with the licensing of an aerosol called ‘Isoprenaline Forte’, which contained five times the dose of isoprenaline per administration than the standard preparation (Stolley 1972). In other countries including the Netherlands where isoprenaline forte was introduced late and sales volumes low and in the US, where isoprenaline forte was not licensed, no increase in asthma mortality occurred. This was despite an approximate trebling in per capita alternative bronchodilator sales between 1962 and 1968 in the US (Stolley 1972). A detailed review of the epidemic in England and Wales concluded it was not due to changes in death certification, disease classification or an increase in asthma prevalence, but instead was most likely due to new methods of treatment (Speizer 1968). In England and Wales, mortality rates fell following health warnings about the overuse of inhalers and banning of over the counter sales in 1968. It was around this time that more selective beta₂-agonists such as terbutaline (Bergman 1969) and salbutamol (albuterol) (Cullum 1969) were being developed.

(From Blauw 1995. With permission from the Lancet.)

In the late 1970s, a second epidemic of asthma deaths occurred in New Zealand (Figure 1). It was later shown that this epidemic coincided with the introduction and rising sales of fenoterol, a new short-acting beta₂-agonist (Crane 1989; Figure 2). A significant association between mortality and fenoterol use was demonstrated in three consecutive case-control studies, the latter studies addressing criticisms of the first (Crane 1989; Grainger 1991;Pearce 1990). Furthermore, the relative risk of asthma death in patients prescribed fenoterol increased markedly when analysis was restricted to subgroups defined by markers of severity, including previous hospital admission and use of oral corticosteroids. Following the publication of the first case control study, the fenoterol market share in New Zealand fell from 30% in 1988 to 3% in 1991 and by the early 1990s the mortality epidemic appeared to be over (Figure 2). During the gradual decline in mortality in New Zealand from its peak in 1979, total sales of alternative beta₂-agonists, including salbutamol, gradually rose and the use of inhaled corticosteroids also increased during the latter half of the 1980s (Pearce 2007).

The introduction of long-acting beta₂-agonists

Given the relatively short-lived action of beta₂-agonists such as salbutamol, in the late 1980s efforts were made to develop longer-acting compounds. Subsequently, the long-acting beta₂-agonists (LABAs), salmeterol and formoterol were released by Glaxo-SmithKline (GSK) and Novartis, respectively. Both drugs cause bronchodilation that lasts for more than 12 hours, although formoterol has a faster onset of action (Kemp 1993; Ringdal 1998). Given previous concerns about the safety profile of some of the short acting beta₂-agonists, salmeterol and formoterol were subject to randomised controlled trials on larger numbers of patients. Using these trials, several Cochrane reviews have addressed the efficacy of LABAs in addition to inhaled corticosteroids (Ni Chroinin 2004; Ni Chroinin 2005), in comparison with placebo (Walters 2007), short-acting beta₂-agonists (Walters 2002), leukotriene-receptor antagonists (Ducharme 2006), and increased doses of inhaled corticosteroids (Greenstone 2005). The beneficial effects of LABAs on lung function, symptoms, quality of life and exacerbations requiring oral steroids have been demonstrated. However, with some studies demonstrating an associated increase in mortality, concerns about the safety profile of LABAs have heightened and there has been much debate about the potential protective role of inhaled corticosteroids.

How the intervention might work

We have outlined the pharmacology of beta₂-agonists in detail in Appendix 1. Since the early epidemics in asthma mortality, a number of potential mechanisms have been proposed to explain a relationship to the use of beta₂-agonists. We discuss these mechanisms in detail in Appendix 2; they include direct toxicity, tolerance, delay in seeking help and reduction in use of inhaled corticosteroids.

Why it is important to do this review

We have taken a different approach from Salpeter 2006, in that we have not assumed a class effect of long-acting beta₂-agonists, but we have considered trials comparing regular salmeterol to placebo or regular salbutamol. We have chosen not to include results from trials on formoterol in this review, as there are known differences in the pharmacology properties of salmeterol and formoterol (Van Noord 1996); however formoterol is the subject of another ongoing review.

In view of the difficulty in ascertaining the causation of deaths and serious adverse events (SAEs), we have considered all-cause fatal and non-fatal SAEs as the main outcomes of this review, with asthma-related and cardiovascular events as secondary outcomes.

OBJECTIVES

The aim of this review is to assess the risk of mortality and non-fatal serious adverse events in trials which randomised patients with chronic asthma to salmeterol alone

METHODS

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of parallel design, with or without blinding, in which salmeterol alone was randomly assigned to patients with chronic asthma. We excluded studies on people with acute asthma and exercise-induced bronchospasm.

Types of participants

We included patients with a clinical diagnosis of asthma of any age group, unrestricted by disease severity, previous or current treatment.

Types of interventions

We included trials that randomised participants to receive inhaled salmeterol twice daily for a period of at least 12 weeks, at any dose and delivered by any device (metered dose inhalers (MDIs) with chlorofluorocarbons (CFCs) or hydrofluoroalkane (HFAs), or dry powder inhalers (DPIs). We included studies that used comparison groups with placebo or short-acting beta₂-agonists, and co-intervention with leukotriene receptor antagonists; inhaled or oral corticosteroids or theophylline was allowed as long as they were not part of the randomised intervention, and were therefore not systematically different between groups. We excluded studies that compared different doses of salmeterol or different delivery devices or propellants (with no placebo arm). We excluded studies in which salmeterol was randomised together with an inhaled steroid (in separate inhalers or a combined inhaler), but these studies were included in a separate review (Cates 2009).

Types of outcome measures

Primary outcomes

All-cause mortality
All-cause non-fatal SAEs

Secondary outcomes

Asthma-related mortality
Asthma-related non-fatal SAEs
Respiratory-related mortality
Respiratory-related non-fatal SAEs
Cardiovascular-related mortality
Cardiovascular-related non-fatal SAEs
Asthma-related non-fatal life-threatening events (intubation or admission to intensive care)
Respiratory-related non-fatal life-threatening events (intubation or admission to intensive care)

We did not sub-divide outcomes according to whether the trial investigators considered them to be related to trial medication.

Search methods for identification of studies

Electronic searches

We identified trials using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts (see Appendix 3 for details). All records in the Specialised Register coded as ‘asthma’ were last searched in August 2011 using the following terms: (((beta* and agonist*) and (long-acting or “long acting”)) or ((beta* and adrenergic*) and (long-acting or “long acting”)) or (bronchodilat* and (long-acting or “long acting”)) or (salmeterol or formoterol or eformoterol or advair or symbicort or serevent or sere-tide or oxis)) AND (serious or safety or surveillance or mortality or death or intubat* or adverse or toxicity or complications or tolerability)

Searching other resources

We checked reference lists of all primary studies and review articles for additional references. We checked websites of clinical trial registers for unpublished trial data and FDA submissions in relation to salmeterol.

Data collection and analysis

Selection of studies

Both authors (CJC, MJC) independently assessed studies identified in the literature searches by examining titles, abstract and keywords fields. We obtained studies that potentially fulfilled the inclusion criteria in full text. We independently assessed these full text trial reports for inclusion. We resolved disagreements by consensus. We kept a record of decisions.

Data extraction and management

We extracted data using a prepared checklist before being entered into RevMan 2011. Data included characteristics of included studies (methods, participants, interventions, outcomes) and results of the included studies. We contacted authors of included studies for unpublished adverse event data, and searched manufacturers’ websites for further details of adverse events. We recorded all-cause SAEs (fatal and non-fatal) and in view of the difficulty in deciding whether events were asthma related, we noted details of the cause of death and SAEs where they were available.

Assessment of risk of bias in included studies

Both authors assessed the included studies for bias protection (including sequence generation for randomisation, allocation concealment, blinding of participants and assessors, loss to follow-up, completeness of outcome assessment and other possible bias prevention) as either high, low or unclear risk of bias in line with recommendation in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008). We resolved disagreements by consensus. We contacted study authors and sponsors to seek clarification where bias protection was unclear.

Assessment of heterogeneity

We explored heterogeneity on the basis of the subgroup and sensitivity analyses outlined below.

Assessment of reporting biases

We inspected funnel plots to assess publication bias.

Data synthesis

The outcomes of this review were dichotomous, and we recorded the number of participants with each outcome event, by allocated treated group. We planned to conduct the primary analysis, mortality, using risk difference, as many studies did not have any deaths in either arm. However, revisions to the Handbook (Higgins 2008) since the protocol was written advise against this approach. Therefore, the risk differences were only used to estimate the absolute impact of treatment. The Peto odds ratio has advantages when events are rare as no continuity correction for zero cells is required, and although it can perform less well with unbalanced treatment arms and large effect sizes, the updated review has now used Peto odds ratio for all primary analyses, and the Mantel-Haenszel random effects model has been used for sensitivity analysis.

Subgroup analysis and investigation of heterogeneity

We conducted subgroup analyses on the basis of dose of salmeterol (usual dose versus high dose), age (adults versus children), severity of asthma, reported corticosteroid use at baseline, comparator used and ethnic groups. We compared subgroups using tests for interaction (Altman 2003).

RESULTS

Description of studies

Results of the search

The initial search in October 2007 found 512 abstracts, which we reduced to 504 after removing duplicates. Of these, we identified 154 abstracts that related to salmeterol alone (three were from references listed in identified trials and review articles, and one was only published on the GSK website). We included 32 studies in the review (42 references) and excluded 118: 71 were less than 12 weeks in duration (including 26 single-dose studies); eight were not RCTs; five were dose comparison studies; five are ongoing studies; four were on exercise-induced bronchospasm; four compared with theophylline; three were propellant studies; three were cross-over in design; and seven were for other reasons. We reached consensus on all the included studies after inspection of the full text from papers and websites; there was initial disagreement on six abstracts, five of which we subsequently included and one excluded. We identified additional references to the included studies and one unpublished study from other reviews (SLGA 3014). A further search in July 2008 generated 48 new references, of which two were relevant to this review (Inoue 2007; Pascoe 2006), but we excluded both as they were short-term crossover studies. We identified no further new studies by the latest searches in August 2009 (79 references) or August 2011 (191 references).

Included studies

There were 32 included studies which randomised 62,630 participants (Adinoff 1998; Boulet 1997; Boyd 1995; Britton 1992;Busse 1998; Chervinsky 1999; D’Alonzo 1994; D’Urzo 2001;Kavuru 2000; Kemp 1998a; Kemp 1998b; Lazarus 2001; Lenney 1995a; Lenney 1995b; Lundback 1993; Nathan 1999; Nathan 2006; Pearlman 1992; Pearlman 2004; Rosenthal 1999; Russell 1995; Shapiro 2000; Simons 1997; SLGA 3014; SLMF4002;SMART 2006; SNS 1993; Von Berg 1998; Wenzel 1998;Weinstein 1998; Wolfe 2000).

A total of 46,501 (74%) people completed treatment, encompassing more than 19,000 patient years studied. There were only seven studies on 2380 (Lenney 1995a; Lenney 1995b;Simons 1997;SLGA 3014; Von Berg 1998; Weinstein 1998) who completed a total of 921 patient years of treatment (this is not allowing for the nine-month extension to the two Lenney studies). The remaining studies were in adults and adolescents with most studies randomising participants of 12 years and older; however many studies included few adolescent patients (for example 6% of all participants in SNS 1993).

Twenty-six studies (34,781 participants) compared salmeterol to placebo and eight studies (28,532 participants) compared salmeterol to regular salbutamol. Two studies included both a placebo and a salmeterol arm (Pearlman 1992; SLGA 3014). The dose of salbutamol as a comparator varied between trials: four studies used salbutamol 200 μg four times daily (Boulet 1997; Pearlman 1992; SLGA 3014; SNS 1993); one study used the same regimen for the first three months, then 200 μg twice daily for the remaining nine months (Britton 1992); two studies used 200 μg twice daily (Lenney 1995a; Lenney 1995b); and one study used 400 μg of salbutamol delivered by diskhaler four times daily for the first three months and then twice daily for the following nine months (Lundback 1993).

The duration of trials ranged from 12 to 52 weeks, but in some of the 52-week studies the data collection was separated into two periods. Four trials separated the first three months from the subsequent nine months of follow-up (Britton 1992; Lenney 1995a; Lenney 1995b; Lundback 1993), whilst Von Berg 1998 separated data from the first and second six-month periods.

The dose of salmeterol used was 50 μg twice daily (described as 42 μg delivered dose in the studies from the USA) in all studies except two which used 100 μg twice daily in participants with more severe asthma on high doses of inhaled steroids at study entry (Boyd 1995; SLMF4002). Three trials used either 25 μg or 50 μg twice daily in children (Lenney 1995a; Lenney 1995b; SLGA 3014).

Concurrent use of inhaled corticosteroids varied in the included studies from zero to 100%; Table 1 lists the inhaled steroid use by study. Only Rosenthal 1999 and Simons 1997 excluded patients who were using inhaled corticosteroids at baseline. Six trials withdrew inhaled corticosteroids from participants for the duration of the trial (Kavuru 2000; Lazarus 2001; Nathan 1999; Nathan 2006; Pearlman 2004; Shapiro 2000).

Table 1. Baseline use of inhaled corticosteroids.

Study ID	% patients
Adinoff 1998	64
Boulet 1997	74
Boyd 1995	100
Britton 1992	64
Busse 1998	67
Chervinsky 1999	51
D’Alonso 1994	21
D’Urso 2001	93
Kavuru 2000	26 - Withdrawn
Kemp 1998a	43
Kemp 1998b	100
Lazarus 2001	53 - Withdrawn
Lenney 1995	57
Lundback 1993	31
Nathan 1999	57 - Withdrawn
Nathan 2006	100 - Withdrawn
Pearlman 1992	25
Pearlman 2004	37 - Withdrawn
Rosenthal 1999	0
Russell 1995	100
Shapiro 2000	100 - Withdrawn
Simons 1997	0
SLGA 3014	50
SLMF4002	100
SMART 2006	47
SNS 1993	69
Von Berg 1998	52
Weinstein 1998	57
Wenzel 1998	47
Wolfe 2000	33

Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	Regular salmeterol
All-cause mortality - adults and adolescents Follow-up: mean 28 weeks	2 per 1000 ¹	3 per 1000 (2 to 4)	OR 1.33 (0.85 to 2.08)²	29128 (10 studies)	⊕⊕⊕○ moderate³	Two studies (27,266 participants) reported that deaths had occurred, and 96% of these were in the SMART study
All-cause mortality - children	See comment	See comment	Not estimable	1126 (4)	See comment	There were no deaths in children during 793 patient years of observation
All-cause non-fatal serious adverse events - adults and adolescents Follow-up: mean 28 weeks	34 per 1000 ¹	39 per 1000 (34 to 43)	OR 1.14 (1.01 to 1.28)	30,196 (13 studies)	⊕⊕⊕⊕ high	92% of events occurred in the SMART study
All-cause non-fatal serious adverse events - children Follow-up: mean 31 weeks	56 per 1000 ¹	72 per 1000 (46 to 108)	OR 1.3 (0.82 to 2.05)	1333 (5 studies)	⊕⊕⊕○ moderate³
Asthma-related mortality - adults and adolescents Follow-up: mean 28 weeks	Medium risk population		OR 3.49 (1.31 to 9.31)	29,128 (10 studies)	⊕⊕⊕⊕ high	Mean risk of asthma death in placebo arm of trials was 2 in 10,000 and 9 in 10,000 for salmeterol arm of trials
	0 per 1000 ¹	1 per 1000 (0 to 2)	OR 3.49 (1.31 to 9.31)	29,128 (10 studies)	⊕⊕⊕⊕ high
Asthma-related non-fatal serious adverse events - adults and adolescents Follow-up: mean 28 weeks	9 per 1000 ¹	13 per 1000 (7 to 24)	OR 1.43 (0.75 to 2.71)	3841 (12 studies)	⊕⊕○○ low³,⁴
Asthma-related non-fatal serious adverse events - children Follow-up: mean 31 weeks	33 per 1000 ¹	55 per 1000 (33 to 92)	OR 1.72 (1 to 2.98)	1333 (5 studies)	⊕⊕⊕○ moderate⁴

Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	regular salbutamol	Regular salmeterol
All-cause mortality - adults and adolescents Follow-up: mean 16 weeks	2 per 1000 ¹	3 per 1000 (2 to 4)	OR 1.28 (0.79 to 2.05)²	26,463 (4 studies)	⊕⊕⊕○ moderate³
All-cause mortality - children Follow-up: mean 12 weeks	3 per 1000 ¹	0 per 1000 (0 to 9)	OR 0.04 (0 to 2.97)	1152 (3 studies)	⊕⊕○○ low³	A single death occurred in 273 patient-years of observation in children
All-cause non-fatal serious adverse events - adults and adolescents Follow-up: mean 16 weeks	43 per 1000 ¹	41 per 1000 (37 to 47)	OR 0.96 (0.85 to 1.1)	27,002 (5 studies)	⊕⊕⊕○ moderate⁴
All-cause non-fatal serious adverse events - children Follow-up: mean 12 weeks	28 per 1000 ¹	38 per 1000 (20 to 71)	OR 1.37 (0.71 to 2.64)	1181 (3 studies)	⊕⊕⊕○ moderate³
Asthma-related mortality - adults and adolescents Follow-up: mean 16 weeks	Medium risk population		OR 2.36 (0.78 to 7.16)	26,463 (4 studies)	⊕⊕⊕○ moderate³	The mean risk of death from asthma was 2 per 10,000 on the regular salbutamol arms of the trials and 7 per 10,000 on the regular salmeterol arms
	0 per 1000 ¹	0 per 1000 (0 to 1)	OR 2.36 (0.78 to 7.16)	26,463 (4 studies)	⊕⊕⊕○ moderate³
Asthma-related non-fatal serious adverse events - adults and adolescents Follow-up: mean 12 weeks	17 per 1000 ¹	16 per 1000 (6 to 39)	OR 0.94 (0.37 to 2.34)	1155 (3 studies)	⊕⊕○○ low³,⁵
Asthma-related non-fatal serious adverse events - children Follow-up: mean 12 weeks	23 per 1000 ¹	24 per 1000 (11 to 52)	OR 1.04 (0.47 to 2.31)	1186 (3 studies)	⊕⊕○○ low³,⁵

Methods	Study design: parallel group 4 groups, multi centre, 27 in USA (majority primary care) . 4-6 weeks initially, 2 groups weaned from non-steroidal asthma medications, then 36 weeks treatment Randomisation: yes, randomised in blocks 5:5:5:1 Blinding: double blind, double dummy, matching devices Withdrawals/drop outs: 75 withdrawals in total, 61 protocol violations, 5 lack efficacy Compliance: not assessed
Participants	N = randomised 386/completed 311, adult/adolescents, M = 203, F = 183; mean age 36.5 (range 12-85) Baseline severity: stable asthma, severity not stated. Mean FEV₁ 66% predicted Inclusion: diagnosis asthma by ATS criteria, baseline FEV₁ 50%-80% predicted, > 15% FEV₁ reversibility to SABA Exclusion: non-smoker > 1 yr, history life threatening asthma, requiring > 2 canisters SABA/month, oral steroids or RTI < 1 month
Interventions	Intervention: salmeterol 42 μg bd versus (with most patients weaning off nonsteroidal medications during the course of the study) Comparison: placebo bd (half the patients randomised to be weaned off nonsteroidal maintenance treatment) Device: MDI Treatment period: 2-6 weeks weaning, 36 weeks maintenance Rescue: albuterol prn Co-interventions: baseline ICS 64%, cromones 20%, theophylline 77% (only ICS were not weaned in any group)
Outcomes	No website data found for this study. Further information awaited from GSK Paper only reports “no deaths or serious drug-related adverse events occurred”
Notes	Funding: grant from GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, double dummy, matching devices
Selective reporting (reporting bias)	High risk	Not found in GSK trial register

Methods	Setting: multicentre study (14 sites in Canada) Length of intervention period: 12 weeks (2 weeks run-in and 1 week run-out) Randomisation: no details Allocation concealment: no details Design: parallel group Masking: double-blind Excluded: 300 enrolled, 228 randomised (all included in the analysis)
Participants	228 adults and adolescents randomised (12 years old or more). Mean age 38 years. M/F (%): 57/53; mean FEV₁ 66%; previous ICS use 73% Inclusion criteria: medical history of mild-to-moderate asthma that required daily pharmacotherapy for at least 6 months. Prebronchodilator FEV₁ 50%-80% with 15% reversibility following 200 μg salbutamol. Symptoms of asthma on 4/7 in last week of run-in period
Interventions	Run-in period: 2 weeks LABA: salmeterol 50 μg bd with placebo inhaler in between SABA: salbutamol 200 μg qid Device: MDI Treatment period: 12 weeks Co-interventions: ICS use 73%; ICS and cromoglycate allowed if enrolled on these for at least one month and the dose was constant through the study
Outcomes	No website data found for this study; further information awaited from GSK “Adverse events were monitored throughout the study” The paper reports frequent adverse events but does not report fatal or non-fatal adverse events
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	High risk	Not found in GSK trial register

Methods	Multi-centre parallel group study. Double-blind placebo controlled (use of identical placebo)
Participants	119 symptomatic asthmatic adults. All patients were on inhaled corticosteroids. Mean age 47 years. FEV₁ 66% predicted at baseline. Most patients took ICS 1000-2000 μg/day at baseline. At least 15% improvement from baseline in lung function following inhaled salbutamol and at least 2 acute asthma exacerbations in the preceding 18 months were required for inclusion Exclusion criteria: - concurrent uncontrolled systemic disease - having received treatment for an acute respiratory infection in the last 2 weeks - or had a FEV₁ < 40% predicted
Interventions	12 week duration; salmeterol 100 μg twice daily compared with placebo (diskhaler)
Outcomes	No website data found for this study; further information awaited from GSK Paper reports seven patients in each treatment group suffered a serious adverse event. Salmeterol 5 respiratory, one leg injury, one abdominal pain and fever. Placebo 4 respiratory tract and 3 hospitalised for unrelated surgical procedures. No mention of fatal events
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	Sequence generation by computer generated random numbers and allocation concealment using numbered coded inhalers supplied by pharmacy
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind placebo controlled (use of identical placebo)
Selective reporting (reporting bias)	Low risk	Not found in GSK trial register, but all cause serious adverse events were described by treatment group in the paper

Methods	A randomised, double-blind, parallel-group study 62 centres in 13 European countries: Austria (2), Belgium (3),Denmark (6), Finland (4), France (3), Germany (6), Ireland (5), Italy (5), Netherlands (3), Norway (4), Sweden (9), Switzerland (2), United Kingdom (10) Sequence generation: unknown Allocation concealment: unknown 06 Apr 1988 to 19 Oct 1989
Participants	Patient characteristics: median age 49 years (range 18 to 81). FEV₁ 2.14 L. 23% were in no steroids, 27% ICS under 1000 μg/day, 36% ICS over 1000 μg/day and 14% on regular oral steroids Asthmatic subjects > 18 years of age with either FEV₁ or daily PEFR > 50% of predicted values, reversibility in FEV₁. 15% 15 minutes following the inhalation of salbutamol 200 μg, and on > 4 of 7 days in the second week of run-in period 2 either asthma symptom scores for > 2 or a diurnal variation in PEFR. 15% were eligible for study participation. Subjects were excluded if they required a maintenance dose of oral prednisolone > 20 mg/day, had a clinical or laboratory history of serious systemic disease, or were treated with beta-receptor antagonists
Interventions	Salmeterol 50 μg (25 μg/actuation) bd viaMDI (N = 334); salbutamol 200 μg (100 μg/actuation) QID via MDI (N = 333) Co-interventions: 23% were on no steroids, 27% ICS under 1000 μg/day, 36% ICS over 1000 μg/day and 14% on regular oral steroids Subjects entered 2 consecutive 1-week run-in periods during which they used a salbutamol inhaler when necessary for the relief of symptoms. Subjects were then randomised to receive either salbutamol 200 μg QID or salmeterol 50 μg bd, along with a placebo inhaler bd for 3 months. At the end of 3 months, subjects randomised to salmeterol 50 μg bd continued the same treatment for a further 9 months. Subjects randomised to salbutamol had their dosage reduced to 200 μg bd. All subjects also received salbutamol inhalers to be used when necessary for the relief of symptoms during the study
Outcomes	Paper reports “Two patients died during the year of the study, one from a stroke caused by a glioma in the left midbrain after 10 months of salmeterol and one from septicaemia and renal failure following an oesophagectomy for an adenocarcinoma after six months treatment with salbutamol” Website: SLGT02. Data on the initial 3 month period on-therapy. One fatal adverse event in salmeterol group (glioma) and one in salbutamol group (adenocarcinoma).Nonfatal serious adverse events occurred in 33 subjects in the salmeterol group and 39 in the salbutamol group
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Study design: parallel group, multicentre (55), USA, 2 weeks run in/ 12 weeks treatment Randomisation: randomised treatment, no method given Blinding: double-blind, double dummy, matching devices Withdrawals/drop outs: 95 withdrawals, 47 active, 48 placebo
Participants	N = randomised 538, completed 443. M = 51; F = 68, adults, mean age 36 (range 12-80) Baseline severity: moderate persistent asthma. FEV₁ 62% Inclusion: non-smoking. Diagnosis asthma by ATS criteria, used SABA daily during 6 weeks or more. Baseline FEV₁ 40-80% predicted. > 15% FEV₁ reversibility to SABA. Symptomatic in run in ASS >= 2 Exclusion: URTI/LRTI < 4 weeks, COPD, CF, unstable asthma, pregnancy, lactation, Use of OS < 1 month
Interventions	Long-acting beta agonist: salmeterol 42 μg bd Placebo: bd Device: MDI Treatment period: 12 weeks Rescue: Salbutamol 100 μg prn Co-interventions: ICS 65%, cromones 7%, theophyllines 30% - all fixed doses
Outcomes	No website data found for this study. Further information awaited from GSK Paper reports “Serious adverse events (asthma exacerbation, deep vein thrombosis, respiratory tract infection) developed in 2 patients treated with salmeterol; however, these were not considered by the investigator to be potentially related to treatment.” Drug-related adverse events shown in Table 3
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, double dummy, matching devices
Selective reporting (reporting bias)	Low risk	Not found in GSK trial register, but all-cause serious adverse events reported in paper

Methods	Study design: three treatment parallel group, multicentre (11) study in USA, 1-2 weeks run in/12 weeks treatment Randomisation: yes, but method not given Blinding: double-blind, double dummy, with 2 matching inhalers Withdrawals: 42/322 , by groups - 15 in salmeterol, 16 in albuterol, 11 in placebo Confounders: differential rates of ICS and cromone use in regular and prn group, use of theophyllines in run in period
Participants	N =322: albuterol = 108, placebo = 108, salmeterol = 106 Age: means - albuterol 31 (14), placebo 28 (12), salmeterol 29 (12) Severity of asthma: baseline FEV₁ 65% predicted Inclusion: diagnosis asthma by ATS criteria, requiring daily drug treatment for > 6 months. Baseline FEV₁ 50%-70% predicted, > 15% FEV₁ reversibility to SABA Exclusion: smokers
Interventions	Long-acting beta agonist: salmeterol 42 μg bd Short-acting beta agonist: albuterol 180 μg qid Placebo: qid Device: MDI Period:12 weeks Rescue: albuterol 90 μg prn Co-interventions: ICS - used by 20% on placebo , 24% on albuterol, 21% on salmeterol Oral steroids - not at randomisation Cromones - used by 9% on placebo , 6% on albuterol, 10% on salmeterol Theophyllines - used only during run in by 46% on placebo, 50% on albuterol, 43% on salmeterol Ooral beta agonists - not permitted
Outcomes	No website data found for this study. Further information awaited from GSK Paper reports common adverse events thought to be related to treatment, but no serious adverse event data
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, double dummy, with 2 matching inhalers
Selective reporting (reporting bias)	High risk	Not found in GSK trial register, and no SAE data in paper

Methods	A multicenter, randomised, double-blind, parallel-group trial to evaluate the long-term efficacy and safety of inhaled salmeterol 50 μg bd compared to short-acting beta₂-agonists as-needed in adult patients with asthma 15 December 1994 - 30 September 1996
Participants	Location: 253 centres in Canada 911 subjects 18 years of age and older with documented asthma who required regular anti-inflammatory treatment and used inhaled beta₂-agonists to control symptoms more than twice daily whom the physician believed would benefit from a long-acting beta₂-agonist were included in this study. Females of child-bearing potential could participate if they were using adequate contraceptive methods, were not pregnant or lactating, and did not plan to become pregnant during the study. Exclusions included subjects with serious pulmonary or systemic disease, subjects who had received prior salmeterol, subjects receiving beta-blockers, and subjects with known hypersensitivity to salmeterol
Interventions	24 weeks of one of the following double-blind study treatments: Salmeterol 50 μg (2 puffs 25 μg) via MDI (CFC) bd (N = 455) Placebo 2 puffs via MDI bd (N = 456) Co-interventions: 93% patients were on ICS and 5% oral steroids (165 under 500 μg/day, 535 on 500 to 1000 μg/day, and 209 on more than 1000 μg per day or prednisone)
Outcomes	Paper publication reports “During the course of the study there were three deaths reported: two in the salmeterol group (one with congestive heart failure, and one with undetermined cause at autopsy, although the subject had a history of abdominal pain) and one in the placebo group (myocardial infarction leading to anoxic encephalopathy) . All deaths were judged to be unrelated to study medication” Website: SLGQ94 (521/180). Salmeterol group: 2 fatal SAEs (chronic obstructive lung disease/congestive heart failure and abdominal pain). Placebo arm: 1 fatal SAE (respiratory distress, also secondary lung edema, myocardial infarction and encephalopathy anoxia). Salmeterol 24 non-fatal SAEs, and placebo 22 non-fatal SAEs
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	This document presents the combined results of GSK studies from the USA in which salmeterol was compared with placebo in randomised controlled trials. Trials lasted from one to 52 weeks
Participants	63 trials involving 17,000 patients with chronic asthma included in Phase II to IV clinical trials in the USA (but results have only been used in this review for patients randomised to salmeterol without ICS)
Interventions	Salmeterol (with or without additional randomised inhaled corticosteroids) versus placebo
Outcomes	Respiratory and cardiac serious adverse events
Notes	Full details are available from http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_01_01-GSK-Serevent.pdf
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No details of individual studies given
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No details of individual studies given
Selective reporting (reporting bias)	Unclear risk	No details of individual studies given

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All-cause mortality	20		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
1.1 Salmeterol versus placebo	14	30254	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.33 [0.85, 2.08]
1.2 Salmeterol versus salbutamol	7	27615	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.22 [0.76, 1.96]
2 Non-fatal serious adverse events (adults and children)	25		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
2.1 Salmeterol versus placebo	18	31529	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [1.02, 1.29]
2.2 Salmeterol versus salbutamol	8	28183	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.96 [0.81, 1.14]
3 Non-fatal serious adverse events in adults	18		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
3.1 Salmeterol versus placebo in adults	13	30196	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.14 [1.01, 1.28]
3.2 Salmeterol versus salbutamol in adults	5	27002	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.79, 1.11]
4 Non-fatal serious adverse events in children	7		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
4.1 Salmeterol versus placebo in children	5	1333	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.30 [0.82, 2.05]
4.2 Salmeterol versus salbutamol (from first 3 months of Lenney)	3	1181	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.37 [0.71, 2.64]
4.3 Salmeterol versus salbutamol (data from Lenney 9 month trial extensions)	3	1130	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.71, 1.94]
5 Non-fatal adverse events in adults and children (SNS sensitivity analysis)	25		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
5.1 Salmeterol versus placebo	18	31529	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.15 [1.02, 1.29]
5.2 Salmeterol versus salbutamol	8	28188	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.86, 1.11]
6 Fatal and non-fatal serious adverse events in adults and children	25		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
6.1 Salmeterol versus placebo	18	31529	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.16 [1.03, 1.30]
6.2 Salmeterol versus salbutamol	8	28183	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.99 [0.84, 1.16]
7 Asthma mortality	2	51535	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.94 [1.41, 6.14]
7.1 Salmeterol versus placebo	1	26355	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.49 [1.31, 9.31]
7.2 Salmeterol versus salbutamol	1	25180	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.36 [0.78, 7.16]
8 Asthma mortality (within study subgroups by ICS use at baseline)	2	46650	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.90 [1.38, 6.13]
8.1 ICS used at baseline	2	26969	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.49 [0.54, 4.11]
8.2 Not on ICS at baseline	2	19681	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.43 [2.13, 19.42]
9 Asthma mortality (within study subgroups by any steroid at baseline)	2	47550	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.95 [1.41, 6.14]
9.1 ICS or oral steroids used at baseline	2	27869	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.03 [0.82, 5.00]
9.2 Not any steroids at baseline	2	19681	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.15 [1.73, 21.84]
10 Cardiovascular mortality	19		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
10.1 Salmeterol versus placebo	13	29920	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.75 [0.32, 1.77]
10.2 Salmeterol versus salbutamol	6	27281	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.22 [0.64, 2.34]
11 Adults and Children non-fatal asthma-related serious adverse events	22		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
11.1 Salmeterol versus placebo	17	5174	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.59 [1.05, 2.41]
11.2 Salmeterol versus salbutamol	6	2341	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.99 [0.54, 1.81]
12 Adults and children non-fatal cardiovascular serious adverse events	21		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
12.1 Salmeterol versus placebo	15	30579	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.73, 1.31]
12.2 Salmeterol versus placebo (US trial results)	1	9275	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.90 [0.27, 2.97]
12.3 Salmeterol versus salbutamol	5	26794	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [0.67, 1.68]
13 Proportion of participants with serious asthma exacerbations in relation to dose of ICS	1	911	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.99 [0.71, 1.39]
13.1 ICS under 500 mcg per day	1	165	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.04 [0.42, 2.61]

Methods	Setting: multicentre study, USA Length of intervention period: 12 weeks Randomisation: yes (method not stated) Allocation concealment: not stated Design: parallel group Masking: double blind Excluded: yes Withdrawals: stated
Participants	527 adults and adolescents screened, 356 randomised (four arm study; placebo: N = 82; salmeterol: N = 92), age range: 12-67; mean baseline FEV₁ (% predicted): placebo: 64; salmeterol: 64. Therapy @ baseline: placebo: ICS - 55%, SAL - 66% Patient characteristics: mean age 36 years, FEV₁ 64% predicted Inclusion criteria: >/= 12 years of age; medical history of asthma (ATS criteria); at least 6 months duration; FEV₁ between 40%-85% predicted; >/= 15% reversibility post SABA; participants treated with ICS prior to enrolment had to have been treated with BDP 252-420 μg/d (6-10 puffs/d), TAA 600-1000 μg/d (6-10 puffs/d); flunisolide: 1000 μg/d (250 QID); fluticasone propionate 176 μg/d (44 QID) for at least 1 month prior to enrolment without change in regimen; If participants using SAL, they had to do so for at least 1 week prior to screening, and demonstrated FEV₁ </= 85% predicted post SABA and not received concurrent ICS for 1 month prior to screening; provision of signed consent Exclusion criteria: female participants had negative pregnancy test, and were sterile, post-menopausal or using acceptable birth control measures; history of life-threatening asthma; hypersensitivity to ICS or beta-agonists; smoking history (> 10 pack years); use of oral, inhaled (external to guidelines above) or IM corticosteroid therapy, intranasal corticosteroids (except for ‘Flonase’); use of OCS in previous 6 months; use of over the counter medicines that might affect course of asthma; abnormal chest x-ray; abnormal ECG; significant concurrent disease. During screening period, participants not eligible if they had > 3 awakenings requiring asthma during 7 days immediately preceding randomisation. ICS patients not eligible if using > 12 puffs SABA per day for more than 3 days, SAL patients not eligible using > 6 puffs SABA per day for more than 3 days
Interventions	Salmeterol 50 μg bd versus placebo Inhaler device: Diskus. Single-blind run-in with a placebo (2 weeks) Co-interventions: baseline ICS 26%. Group 1 (250 participants) all had ICS before enrolment, Group 2 (86 participants) had not used ICS for at least a month but had used salmeterol for at least a week. Protocol suggests that none of the salmeterol or placebo groups continued on ICS as this was a randomised treatment for the other arms
Outcomes	Serious adverse events reported in paper: salmeterol - one asthma exacerbation and one fever. Placebo - one asthma exacerbation. (None were considered related to study medication by the investigator.) Website SFCA 3002 - SAE data: no fatal SAE. One asthma SAE confirmed in salmeterol and placebo groups. The one patient with fever appears to have also had D & V, abdominal discomfort, weight loss, dizziness and anaemia
Notes	Funding: supported by a grant from GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	Low risk	Full information on GSK trials register

Methods	Study design: two Parallel group, multicentre studies, 15 centres USA, 12 weeks. Randomisation: yes, no method stated Blinding: double-blind, double dummy, matching inhalers Withdrawals/drop outs: 41 described after randomisation Compliance: > 70% reported for all but 7 subjects
Participants	N = 451 randomised (149 salmeterol, 150 albuterol, 152 placebo). Adults, M = 262 F = 189 mean age 31 (SD 14) Baseline severity: persistent/symptomatic FEV₁ 65% predicted; 43% on ICS at baseline Inclusion: diagnosis asthma by ATS criteria. Baseline FEV₁ 50%-80% predicted, > 15% FEV₁ reversibility to SABA. Requiring daily drug treatment for > 6 months. Exclusion: smoking.
Interventions	Long-acting beta agonist: salmeterol 50 μg bd Short-acting beta agonist: albuterol 180 μg qid Placebo: qui Device: MDI & dry powder device Treatment period: 12 weeks Rescue: albuterol 100 μg prn Co-interventions: ICS 55%-70 %. Cromones 7%-12%
Outcomes	No website data found for this study. Further information awaited from GSK
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, double dummy, matching inhalers
Selective reporting (reporting bias)	High risk	Not found in GSK trial register, and all cause SAE data absent from paper

Methods	Design: parallel-group, multicenter (44 centres in USA)
Participants	506 symptomatic asthmatic adults and adolescents. Mean age 42 years, baseline FEV₁ 63% predicted Eligibility criteria: average daytime symptom score of 1 on a 0 to 3-point scale over a 2-week screening period - use of a short-acting bronchodilator on a daily basis - FEV₁ of 40% to 80% predicted - >= 15% improvement from baseline in FEV₁ following inhaled albuterol - use of one of the following inhaled corticosteroids on a daily basis at a fixed dose that is within package insert guidelines for a minimum of 6 weeks prior to the screening visit: beclomethasone (300-900 μg/day), flunisolide (1000-2000 μg/day), triamcinolone (600-1600 μg/day) Exclusion criteria: concurrent tobacco use - oral corticosteroid therapy - immunotherapy requiring dosage change - inability to withdraw asthma/allergy medication before PFTs at screening or clinic visits throughout the study - cystic fibrosis, COPD, any significant uncontrolled disease state other than asthma - any other significant illness - pregnancy or lactation - contraindication to study medications - unstable asthma requiring albuterol >= 12 puffs/day or 12 puffs for > 3 days/week - hospitalisation for asthma within 3 months - mechanical ventilation during an asthma exacerbation within 2 years or > 2 albuterol (or equivalent) inhalers/month within 3 months of screening
Interventions	12 weeks of treatment with salmeterol 50 μg twice daily or placebo. Usual ICS continued
Outcomes	No website data found for this study. Further information awaited from GSK Paper reports that “One salmeterol treated patient experienced a serious adverse event (respiratory failure) that the investigators judged to be possibly due to the study drug.” No report of fatal events
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	Randomised by computer generated sequence, (assignment by opaque consecutive numbered envelopes)
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, identical placebo
Selective reporting (reporting bias)	High risk	Not found in GSK trial register, and all cause SAE data absent from paper

Methods	Setting: multicentre study (6 sites in USA). Feb 1997 to Jan 1999 Length of intervention period: 16 weeks (6 weeks run-in and run-out) Randomisation: stratified online randomisation Allocation concealment: random block size. Remote allocation Design: parallel group Masking: triple blind Excluded: 422 enrolled. 361 completed run-in. 339 eligible for run in. 175 patients who were not well controlled during run in were entered into the SLIC study (Lemanske 2001). 164 randomised in this trial Withdrawals: 12 withdrawn in the salmeterol and placebo arms during the randomised treatment period (placebo 5 withdrew consent. Salmeterol 5 withdrew consent, 1 adverse event. TAA 1 lost to follow-up)
Participants	164 adults and adolescents randomised. Total of 16 participants aged less than 18 years old. Mean age 31 years M/F (%): 35/65; Caucasian: 70%; mean FEV₁ 93%; previous ICS use 53% Inclusion criteria: ATS definition of asthma who met recommended treatment criteria for an ICS
Interventions	Run-in period: 6 weeks, during which all patients received triamcinolone 400 μg bd. Enrolled if they were objectively defined as well controlled. LABA: salmeterol 42 μg bd Placebo: placebo 2 puffs bd Device: MDI Treatment period: 16 weeks Co-interventions: nil
Outcomes	One serious non-fatal adverse event (not asthma related) occurred in the salmeterol group. There was no mention of deaths in the paper but the authors confirmed none had occurred (data in paper publication and confirmed by study authors)
Notes	Funding from National Heart, Lung, and Blood Institute
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	Stratified online randomisation. Random block size. Remote allocation
Blinding (performance bias and detection bias) All outcomes	Low risk	Triple-blind
Selective reporting (reporting bias)	Low risk	Data obtained from authors

Methods	This was a multi-centre, multi-national, double-blind, randomised, 3-limbed, parallel-group study This study was divided into a 3-month safety and efficacy period followed by a 9-month safety only period. This is the report of the 3-month efficacy and safety study Study Period: 01 Aug 1990 to 28 Mar 1991
Participants	This study was conducted in 42 centres in 9 countries: Germany (4); Ireland (1); Israel (6); Italy (5); Portugal (2); South Africa (5); Spain (2); Switzerland (1); United Kingdom (16) Subjects aged 4 to 16 years with a history of RAO, who demonstrated at least 15% reversibility of either PEFR or FEV₁ 15 minutes following a standard dose of salbutamol (200ìg), and who required regular or, as required, inhaled beta₂-agonist treatment for control of their asthma symptoms prior to the start of study. Subjects who required a change in asthma medication, or who had had an acute lower respiratory tract infection or a hospital admission for their airways disease in the four weeks preceding the study and subjects who required a maintenance dose of oral steroids were excluded from the study
Interventions	The objectives of the study were to compare the efficacy and safety of inhaled salmeterol 25 μg and 50 μg bd with salbutamol 200 μg bd delivered from pressurised inhalers over a 3-month period Subjects were randomly assigned to receive 1 of the following 3 treatments via pressurised inhalers: salmeterol 25 μg bd (N = 122), salmeterol 50 μg bd (N = 130), or salbutamol 200 μg bd (N = 122). Prior to randomisation subjects completed a 2-week run-in period where they took salbutamol, as needed (prn). Co-interventions: 58% were on ICS at baseline
Outcomes	Paper makes no mention of serious adverse events or mortality Website: SLPT01 (first 3 months). No fatal SAEs. Non-fatal SAEs 5 with salmeterol 25 μg, 9 with salmeterol 50 μg, 8 with salbutamol 200 μg. SMS40093 provides data on the 9-month follow-up period in which there was one patient on salbutamol who died of an asthma attack with circulatory arrest
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	This was a multicenter, multinational, double-blind, randomised, 3-limbed parallel-group study This study was divided into a 3-month safety and efficacy period followed by a 9-month safety only period. This is the report of the 3-month efficacy and safety study 12 Sep 1990 to 10 Apr 1991
Participants	This study was conducted in 54 centres in 13 countries: Austria (3); Belgium (8); Denmark (6); Finland (2); France (5); Germany (2); Ireland (1); Italy (3); Netherlands (4); Norway (4); Sweden (11); Switzerland (1); United Kingdom (4) Subjects aged 4 to 16 years of age with a history of RAO were recruited into the study. Subjects demonstrated at least 15% reversibility of either PEFR or FEV₁ 15 minutes following a standard dose of salbutamol (200 μg). Subjects required regular or, as required, inhaled beta₂-agonist treatment for control of their asthma symptoms prior to the start of study. Subjects had an asthma symptom score of 2 or more on at least five days/nights of the run-in or had diurnal variation in PEFR of > 15% on at least 7 days of the run-in or had required symptomatic bronchodilator use on at least 7 days in the run-in period Subjects were excluded if they had required a change in asthma medication or had been admitted to hospital for their airways disease or had experienced an acute lower respiratory tract infection in the 4 weeks preceding the study. Also excluded were patients requiring maintenance oral steroids or beta-adrenergic antagonists Mean age 10 years
Interventions	Subjects were randomly assigned to receive 1 of the following 3 treatments: salmeterol 25 μg bd (N = 157), salmeterol 50 μg bd (N = 160), or salbutamol 200 μg bd (N = 156) via the Diskhaler® dry powder inhaler Co-interventions: 58% were on ICS at baseline
Outcomes	Paper makes no mention of serious adverse events or mortality Website: SLPT02. No fatal SAE. Subjects with non-fatal SAE: 4 salmeterol 25 μg, 6 salmeterol 50 μg, 2 salbutamol 200 μg. The number withdrawn due to adverse events were 5, 2, and 1 respectively 9-month data provided for these patients by GSK
Notes	Funding: sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel group, multicentre (25) USA, 2 week run-in/26 weeks treatment
Participants	386 adult/adolescents. Mean age 30, with a diagnosis of asthma by ATS criteria for at least 3/12, baseline FEV₁: 65%-90% predicted. > 15% FEV₁ reversibility Exclusion: exacerbation asthma, 1 month, use of ICS/OS < 6mths, smoker, requiring > 12 puffs/day rescue SABA in run in 4/7
Interventions	Salmeterol 50 mcg twice daily versus placebo Device: MDI, no spacer allowed Treatment period: 26 weeks Co-interventions: none permitted (no ICS allowed for the previous 6 months)
Outcomes	No website data found for this study. Further information awaited from GSK Paper reports one patient in each group experienced a serious adverse event (but all judged unrelated to study drug). Salmeterol one overdose and major depressive disorder, placebo one depression. No published information on any deaths
Notes	Funding: grant from GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, double dummy
Selective reporting (reporting bias)	Low risk	Not found in GSK trial register, but all-cause SAE data reported in paper

Methods	Parallel group multicentre study over 12 weeks
Participants	365 adults and adolescents randomised. Age range: 12-82 years, mean FEV₁ 68% predicted. Inclusion criteria: FP440-660 μg/d for at least 3 months prior to study entry; FEV₁ 40%-85%; reversibility >= 15%
Interventions	Combination HFA FP/SAL 110/42 bd (220/84) versus CFC SAL 42 bd (84) versus CFC FP 110 bd (220) versus HFA placebo. Inhaler devices: MDI. Run-in: 2 weeks This review only includes data from the salmeterol and placebo arms Co-interventions: ICS at usual dose was an inclusion criterion, but appears to have been withdrawn in the salmeterol and placebo arms of the study
Outcomes	The paper publication mentions one drug-related SAE (an upper GI bleed from the placebo group) Website: SAS30004. No fatal SAE. One SAE on salmeterol (viral meningitis) and one on placebo (upper GI bleed)
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel-group (3), multicentre (8) in USA
Participants	N = randomised 234; salmeterol N = 78; albuterol (salbutamol) N = 77; placebo N = 79 Patients over 12 years old with asthma (as defined by the American Thoracic Society) and non-smokers. At least 6 months of daily therapy before the start of the study. FEV₁ 50%-80% predicted values
Interventions	Long-acting beta agonist: salmeterol 42 μg bd Short acting beta agonist: albuterol (salbutamol) 180 μg qid Placebo: qid Device: MDI Period treatment: 12 weeks Rescue: albuterol 90 mcg prn Co-interventions: ICS 25%, chromones 10%
Outcomes	No website data found for this study. Further information awaited from GSK No information on serious adverse events reported in the paper
Notes	Funding: grant from GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, placebo controlled using 2 identical inhalers
Selective reporting (reporting bias)	High risk	Not found in GSK trial register, and all-cause SAE data not in paper

Methods	2 parallel group studies, multi-centre (31) USA, 2 week run in/24 weeks treatment/4 weeks run out
Participants	408 adult/adolescents with mean age 28 Inclusion: clinical diagnosis asthma, baseline FEV₁ > 70% predicted, > 15% FEV₁ reversibility to SABA. BHR PD20 < 512 μg or 7.5 mg/mL methacholine Exclusion: URTI/LRTI < 6 weeks hospitalisation < 12 weeks serious uncontrolled systemic disease
Interventions	Salmeterol 50 μg twice daily or placebo (given by MDI) Co-interventions: none permitted (patients were not using inhaled corticosteroids)
Outcomes	No website data found for this study. Further information awaited from GSK The paper publication states that there were seven events requiring hospitalisation in the salmeterol group (respiratory arrest due to alcohol, tonsillitis, mononucleosis, asthma exacerbation with bronchitis, knee ligament tear, fractured leg and anaphylaxis due to acne treatment). It is not reported how many patients suffered a serious adverse event. One patient in the placebo group was hospitalised for status asthmaticus due to pneumonia
Notes	Funding: supported by a research grant from GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, placebo controlled, blinded devices
Selective reporting (reporting bias)	High risk	Not found in GSK trial register, and paper does not report number of patients with SAE

PERMALINK

Regular treatment with salmeterol for chronic asthma: serious adverse events

Christopher J Cates

Matthew J Cates

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

BACKGROUND

Description of the condition

Airway obstruction

Airway hyper responsiveness

Inflammation

Description of the intervention

Beta2-agonists and mortality: an historical perspective

Time trend data and case control studies

Figure 1. Changes in asthma mortality (5-34 age group) in three countries in relation to the introduction of isoprenaline forte in the UK and New Zealand and of fenoterol in New Zealand.

Figure 2. Inhaled fenoterol market share and annual asthma mortality in New Zealand in persons aged 5-34.

The introduction of long-acting beta2-agonists

How the intervention might work

Why it is important to do this review

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

RESULTS

Description of studies

Results of the search

Included studies

Table 1. Baseline use of inhaled corticosteroids.

Risk of bias in included studies

Figure 3. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

Allocation

Blinding

Selective reporting

Other potential sources of bias

Effects of interventions

Primary outcomes

All-cause mortality

Salmeterol versus placebo

Figure 4. Forest plot of comparison: 1 All-cause Mortality, outcome: 1.1 Overall results.

Salmeterol versus salbutamol

Subgroup analyses

SAEs (non-fatal all cause)

Salmeterol versus placebo

Combined data from adults and children

Figure 5. Forest plot of comparison: 1 Regular salmeterol versus placebo or regular salbutamol, outcome: 1.2 Non-fatal serious adverse events (adults and children).

Figure 6. Serious adverse events with salmeterol in comparison to placebo.

Adults with non-fatal SAEs

Figure 7. Forest plot of comparison: 1 Regular salmeterol versus placebo or regular salbutamol, outcome: 1.3 Non-fatal serious adverse events in adults.

Children with non-fatal SAEs

Figure 8. Forest plot of comparison: 1 Regular salmeterol versus placebo or regular salbutamol, outcome: 1.4 Non-fatal serious adverse events in children.

Salmeterol versus salbutamol

Combined data from adults and children

Adults with non-fatal SAEs

Children with non-fatal SAEs

All-cause SAEs (fatal and non-fatal combined)

Secondary outcomes

Mortality by cause of death

Asthma-related mortality

Beta₂-agonists and mortality: an historical perspective

The introduction of long-acting beta₂-agonists

The impact of inhaled corticosteroids on adverse events in relation to long-acting beta₂-agonists

Appendix 1. Pharmacology of beta₂-agonists

Appendix 2. Possible mechanisms of increased asthma mortality with beta₂-agonists

Methods	Multi-centre, double-blind, placebo-controlled, parallel-group study 14 March 1992 to 14 March 1993
Participants	78 centres in the United Kingdom Male and female asthmatic children aged 4 to 16 years, inclusive, who had been taking at least 200 μg daily of BDP or equivalent for at least 6 months and who were symptomatic and demonstrated a mean PEF of 90% or less of predicted normal on at least 4 days of baseline. Subjects excluded were those receiving oral 2-adrenoceptor agonist therapy or maintenance oral corticosteroid therapy or those who had a short course of oral corticosteroids in the two weeks prior to the start of the baseline period. Also excluded were those who had received newly prescribed asthma therapy, or had changed asthma therapy in the two weeks prior to the start of the baseline period
Interventions	The study was designed to assess the efficacy and safety of inhaled salmeterol xinafoate (SAL) 50 μg bd when added to the existing therapy for moderate to severe asthmatic children Subjects remained on their usual prophylactic therapy of at least the maximum licensed dose of BDP or equivalent during the 2-week baseline period, and their usual beta₂-adrenoceptor agonist therapy was replaced by commercially available salbutamol 200 μg Diskhaler (Ventodisks) to be used as required for symptomatic relief. Subjects were then randomised to receive either salmeterol 50 μg bd via the Diskhaler (N = 99) or matching placebo bd (N = 107) in addition to their usual prophylactic therapy for 12 weeks Co-interventions: 100% ICS as this was an inclusion criterion
Outcomes	Paper publication reported serious adverse events in 10 patients on salmeterol and 13 on placebo Website: SALMP/AH91/D89. No fatal SAEs. Salmeterol 10 subjects had non-fatal SAE, placebo 13 subjects
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Setting: multicentre study, USA
Participants	349 adults and adolescents randomised (four treatment arm study; placebo: 93; salmeterol: 88. Data from 13 participants excluded from the analysis due to poor procedure at one site) Inclusion criteria: >/= 12 years; ATS defined asthma of >/= 6 mo duration requiring pharmacotherapy for at least 6 months; FEV₁ between 40% and 85% predicted; >/= 15% increase in FEV₁ 30 minutes after 2 puffs of albuterol; use of ICS 12 weeks prior to the study Exclusion criteria: females with negative pregnancy tests; life-threatening asthma; hypersensitivity to sympathomimetic drugs/steroids; smoking within previous year; smoking history of > 10 pack years; use of oral/injectable steroid therapy within 1 month of study; use of daily oral steroids within 6 months prior to the study; use of any prescription or over the counter medication that could have affected asthma or course of treatment; abnormal CXR; clinically significant abnormal 12-lead ECGs history of concurrent disease
Interventions	Salmeterol 50 μg bd via Diskus inhaler versus placebo. Duration: 12 weeks Co-interventions: baseline 100% ICS (as this was an inclusion criterion). However the ICS appears to have been withdrawn from the salmeterol and placebo arms that we considered
Outcomes	49% completed study in salmeterol arm and 28% in placebo arm Paper reports “no serious drug-related adverse events. Two patients treated with salmeterol withdrew from the study because of adverse events; however, these adverse events were considered by the investigator to be unrelated to study drug (bilateral subcapsular cataracts and postsurgical infection).” Website: SFCA3003: no fatal adverse events. No serious adverse events in placebo arm; three in salmeterol arm (asthma exacerbation, post surgical infection and chest pain)
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias)	All outcomes	Low risk Double blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel group multicentre study from Canada, 2 week run in/52 weeks treatment/2 week run out
Participants	241 children. Mean age 9.3 mths with mild-moderate persistent asthma Inclusion criteria: clinical stable asthma, atopic, well controlled, baseline FEV₁ > 70% predicted, > 10% FEV₁ reversibility to SABA. PC20 methacholine < 8 mg/ml Exclusion: use of ICS/OS for > 4 weeks previously, OS/ICS within 3 mths exacerbation < 12 weeks
Interventions	Salmeterol 50 μg twice daily versus placebo (Diskus). ICS was not permitted as it was used as a third comparison arm in this study
Outcomes	Effect on growth reported as adverse event, but no information in paper on fatal or nonfatal serious adverse events Website: SMS40065 (521/120 [SLPT10]). No fatal SAE. Salmeterol 7 subjects with non-fatal SAE, placebo 3 subjects with non-fatal SAE
Notes	Funding: supported by a grant from GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel group, multicentre (36) USA, 12-week treatment
Participants	449 children aged 4 to 11 years (mean age 8 years) Inclusion: diagnosis asthma by ATS criteria, Baseline FEV₁/PEF 45%-80% predicted Exclusion: not mentioned but reported as similar to Weinstein 1998 (URTI/LRTI/hospitalisation < 4 weeks, OS, anticholinergics, theophyllines, antihistamines, tobacco exposure, serious uncontrolled systemic disease)
Interventions	4 arm study. Salmeterol 50 μg twice daily, salmeterol 25 μg twice daily, albuterol 200 μg four times daily versus placebo (all using dry powder devices - diskus/rotahaler) Co-interventions: ICS around 50%, cromones 25%, immunotherapy continued at same dose
Outcomes	No website information or paper publication Information from FDA submission: no deaths reported during this trial. Serious adverse events were reported in eight patients, one albuterol patient, three 25 μg Diskus patients and four 50 μg Diskus patients. The albuterol patient and three Diskus patients experienced asthma exacerbations
Notes	Funding: sponsored by GSK.
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double-blind, double dummy
Selective reporting (reporting bias)	Low risk	Mortality and SAE reported in FDA submission, results not found on GSK trial register

Methods	Multicentre, randomised, double-blind, placebo-controlled study November 1998 to January 2000
Participants	56 centres in France Main inclusion criteria for entry in run-in period: males and non-pregnant, non-breastfeeding females, aged 18 years or over with asthma currently controlled with ICS (beclometasone 800 to 1200 μg/day or equivalent, or fluticasone 500 μg/day) without change with the last three months; bronchodilator treatment in the previous month as a short-acting beta-₂ agonist (or beta-₂ agonist in combination with anticholinergics) Main inclusion criteria for randomisation were a controlled asthma confirmed during the run-in period, with, during the last week: morning PEF 80% of predicted value, and bronchodilator requirement less than 3 times within one day or within several days, and no more than one day with PEF variation > 20% Main exclusion criteria were: a hospitalisation for asthma exacerbation in the previous year or a lower respiratory tract infection in the previous month or, in the previous month, a treatment with long acting beta-₂ agonist, fixed-dose of short-acting beta-₂ agonist or an anticholinergic, an anti-leukotriene, or theophylline, or, in the last three months, a treatment with corticosteroids by general route, or an extended release corticosteroid
Interventions	Salmeterol 50 μg/inhalation (N = 93), or matching placebo (N = 95) twice daily during 6 months The primary objective was to evaluate the efficacy of sal 100 μg per day in helping maintenance of asthma control when ICS dosage is halved in subjects who were receiving 1000 μg/day of beclometasone or equivalent Co-interventions: ICS 100% as this was an inclusion criterion but the dose was halved as part of the protocol
Outcomes	Unpublished Website: SLMF4002. No subjects with fatal SAE. Non-fatal SAE in 1 subject in the salmeterol group and 4 subjects in the placebo group
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	28 week parallel group study in 6163 centres in the USA
Participants	Randomised: 26,355. Completed 19,128 (73%). Mean age: 39 years Patient characteristics at inclusion: mean PEFR: 355 L/min. Baseline ICS use 47% Inclusion criteria: at least 12 years of age; diagnosis of asthma (clinical investigator); receiving current prescription of asthma medication Exclusion criteria: prior use of LABA; pregnancy or lactation; concurrent disease that may pose a risk to the participant; sensitivity to long-acting beta-agonists; current ß-blocker use
Interventions	Salmeterol 50 μg twice daily verus placebo (MDI) Co-interventions: ICS (47%), methylxanthines, leukotriene agents
Outcomes	Respiratory deaths and life-threatening events Mortality (total, asthma-related, respiratory-related) All cause hospitalisation Combined all-cause death and life-threatening events, asthma-related death and life-threatening events Subgroups identified (post hoc): Caucasian/African American participants; ICS at baseline/no ICS at baseline; predicted PEF above or below 60% Paper report: “Overall, 1093 subjects (4% in each treatment group) had serious adverse events during the study” Website SGLA5011: 580 fatal and non-fatal SAEs with salmeterol and 513 with placebo
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Blinding of participants, personnel and outcomes: placebo MDI used. Morbidity and Mortality Review Committee were blinded to study treatment
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel group, double-blind 16 week study in UK Primary Care (3516 GPs)
Participants	25,180 adults and adolescents (age range 12 to > 60 years) Inclusion: clinical diagnosis of asthma requiring regular bronchodilator Exclusion: beta blocker use, serious uncontrolled diseases, pregnancy
Interventions	Salmeterol 50 μg twice with placebo at noon and early evening versus salbutamol 200 μg four times daily (given by MDI) Co-interventions: ICS 69%, OS 4.7%, theophyllines, chromones, ipratropium - stable doses
Outcomes	Deaths, admission to hospital/life-threatening events. Other serious adverse events and withdrawals. Each outcome was subdivided into respiratory related to asthma and respiratory unrelated to asthma and non-respiratory causes. If patients suffered more than one adverse event they were counted under the most severe category Results expressed as absolute incidence and relative risks Website: SNS-D920619. Data on all mortality and serious adverse events
Notes	Funding: sponsored by GSK. No published inhaled corticosteroid usage in relation to outcomes, but data obtained from GSK for baseline steroid use in those with asthmarelated deaths
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	Computer generated random code, blocks of 6. Prenumbered treatment packs given to the patients as they were allocated the next consecutive study number
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double dummy, matching devices. Independent consultants who reviewed deaths possibly related to asthma were blinded to treatment group
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel group, multicentre (57) in 11 countries, 2 week run in and 52 week treatment with 2 week period off treatment at 6mths to assess BHR
Participants	426 children, mean age 10 years (range 5-15) Inclusion: clinically diagnosed asthma, > 15% FEV₁ reversibility to SABA or diurnal variation PEF > 15%, am PEF< 85% best in run in Exclusion:URTI/LRTI/hospitalisation/changed asthma medication < 4 weeks, requiring OS/anticholinergics/methylxanthines at entry
Interventions	Salmeterol 50 μg twice daily versus placebo (diskhaler) Co-interventions: ICS 50%, cromones 22%
Outcomes	Paper publication mentions frequent and drug-related adverse events but no report of serious adverse events Website SLGB3019 (SLPT09): no fatal adverse events over the entire study period. Data averaged from the two periods so 18 in salmeterol group and 13 in placebo group on average over each six months
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind
Selective reporting (reporting bias)	Low risk	Full SAE data on GSK trials register

Methods	Parallel group, multicentre (11) USA, 1-2 week run in on single blind placebo/12 week treatment
Participants	207 children, mean age 8.4 years (range 4-11) Inclusion: diagnosis asthma by ATS criteria, Baseline FEV₁ 50%-80% predicted, > 15% FEV₁ reversibility to SABA Exclusion: URTI/LRTI/hospitalisation < 4 weeks, OS, anticholinergics, theophyllines, antihistamines, tobacco exposure, serious uncontrolled systemic disease
Interventions	Salmeterol 50 μg twice daily versus placebo Co-interventions: ICS 57%, cromones 32%, immunotherapy continued at same dose
Outcomes	Paper reports “Four salmeterol- and five placebo-treated patients experienced serious adverse events requiring hospitalisation. These included asthma exacerbation (four salmeterol, two placebo), appendicitis (two placebo), and kidney obstruction and dehydration (one placebo)” No website data for this trial on GSK site (SLD390). Listed on FDA site submission from GSK
Notes	Funding: sponsored by GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double dummy
Selective reporting (reporting bias)	Low risk	Not found in GSK trial register, but SAE data given in paper

Methods	Parallel group, multicentre, 40, USA. 12 weeks
Participants	539 adults/adolescents with mean age: 35.4 (range 12 to 83) Inclusion: diagnosis asthma by ATS criteria, requiring daily bronchodilator treatment > 6 weeks. Baseline FEV₁ 40% to 80% predicted, > 15% FEV₁ reversibility to SABA Exclusion: CF, COPD, current smokers, hospitalised by exacerbation asthma < 6 weeks. Use of theophyllines or cromones
Interventions	Salmeterol 50 μg twice daily with placebo twice daily versus salbutamol 200 μg four times daily Co-interventions: ICS 46% (no other details regarding co-interventions)
Outcomes	No website data found for this study. Further information requested from GSK Paper report: “Three patients experienced serious adverse events….Two patients treated with salmeterol experienced status asthmaticus; one event was considered to be potentially related to the study drug while the other was not. The other serious adverse event that occurred in one patient treated with albuterol was antisocial behavior and was not considered to be related to study drug”
Notes	Funding: supported by a grant from GSK
*Risk of bias*
Bias	Authors’ judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, double dummy, matching devices
Selective reporting (reporting bias)	Low risk	Not found in GSK trial register, but all-cause SAE data published in paper