Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events

  • Review
  • Intervention

Authors


Abstract

Background

Epidemiological evidence has suggested a link between beta2-agonists and increased asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe. This is an updated systematic review.

Objectives

To assess the risk of mortality and non-fatal serious adverse events in trials which randomised patients with chronic asthma to regular salmeterol and inhaled corticosteroids in comparison to the same dose of inhaled corticosteroids.

Search methods

We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data. Food and Drug Administration (FDA) submissions in relation to salmeterol were also checked. The date of the most recent search is August 2012.

Selection criteria

We included parallel design controlled clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular salmeterol and inhaled corticosteroids (in separate or combined inhalers), and were of at least 12 weeks duration.

Data collection and analysis

We conducted the review according to standard procedures expected by the Cochrane Collaboration. We obtained unpublished data on mortality and serious adverse events from the sponsors, and from FDA submissions. We assessed the quality of evidence according to GRADE recommendations.

Main results

We have included 35 studies (13,447 participants) in adults and adolescents, and 5 studies (1862 participants) in children in this review. We judged that the overall risk of bias was low, and we obtained data on serious adverse events from all studies. All except 542 adults (and none of the children) who were randomised to salmeterol were given fluticasone in the same (combination) inhaler.

Seven deaths occurred in 6986 adults on regular salmeterol with inhaled corticosteroids (ICS), and seven deaths in 6461 adults on regular inhaled corticosteroids at the same dose. The difference was not statistically significant (Peto odds ratio (OR) 0.90; 95% confidence interval (CI) 0.31 to 2.60, moderate quality evidence). The risk of dying from any cause in adults on ICS was 10 per 10,000, and on salmeterol and ICS we would expect between 3 and 26 deaths per 10,000. No deaths were reported in 1862 children, and no deaths were reported to be asthma-related in adults or children.

Non-fatal serious adverse events of any cause were reported in 167 adults on regular salmeterol with ICS, compared to 135 adults on regular ICS; again this was not a statistically significant increase (Peto OR 1.15; 95% CI 0.91 to 1.44, moderate quality evidence). The frequency of serious adverse events was 21 per 1000 in the adults treated with ICS and 24 per 1000 in those treated with salmeterol and ICS. The absolute difference in the risk of non-fatal serious adverse events was an increase of 3 per 1000, that was not statistically significant (risk difference (RD) 0.003; 95% CI -0.002 to 0.008).

There were 6 of 930 children with serious adverse events on regular salmeterol with ICS, compared to 5 out of 932 on regular ICS: there was no significant difference between treatments (Peto OR 1.20; 95% CI 0.37 to 3.91, moderate quality evidence).

Asthma-related serious adverse events were reported in 29 and 23 adults in each group respectively, a non-significant difference (Peto OR 1.12; 95% CI 0.65 to 1.94, moderate quality evidence), and only 1 asthma-related event was reported in children in each treatment group.

Authors' conclusions

We found no statistically significant differences in fatal or non-fatal serious adverse events in trials in which regular salmeterol was randomly allocated with ICS, in comparison to ICS alone at the same dose. Although 13,447 adults and 1862 children have now been included in trials, the frequency of adverse events is too low and the results are too imprecise to confidently rule out a relative increase in all cause mortality or non-fatal adverse events with salmeterol used in conjunction with ICS. However, the absolute difference between groups in the risk of serious adverse events was very small. We could not determine whether the increase in all cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular ICS. We await the results of large ongoing surveillance studies mandated by the FDA to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.

Plain language summary

Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events

There has been some concern raised at the possibility of increased serious adverse events following administration of salmeterol, a long-acting beta2-agonist, to people with asthma. We analysed data from 35 studies in adults and 5 in children that compared regular salmeterol in addition to inhaled corticosteroids, against the same dose of inhaled corticosteroids. Too few deaths occurred in the trials to gain any conclusive reassurance that regular salmeterol taken with inhaled corticosteroids either reduces the risk of mortality, or in fact does not increase it. The frequency of deaths in the studies was equivalent to around 10 per 10,000 adults or adolescents treated with inhaled corticosteroids and between 3 and 26 per 10,000 when treated with salmeterol and inhaled corticosteroids. No deaths occurred in the studies conducted in children. Serious adverse events were not significantly increased in adults or children when regular salmeterol was added to inhaled corticosteroids as randomised treatment, but the results are too imprecise to conclude that there is no increased risk. The frequency of serious adverse events was 21 per 1000 in the adults treated with inhaled corticosteroids and 24 per 1000 in those treated with salmeterol and inhaled corticosteroids. There were fewer serious adverse events in children, 5 per thousand on inhaled corticosteroids and 6 per 1000 on salmeterol and inhaled corticosteroids. Large surveillance studies are currently ongoing.

Summary of findings(Explanation)

Summary of findings for the main comparison. Serious adverse events
  1. 1 Mean control event rate

    2 Imprecision (-1). Downgraded one level due to wide confidence intervals

Regular salmeterol in addition to regular inhaled corticosteroids compared to regular inhaled corticosteroids for chronic asthma

Patient or population: Adults and children with chronic asthma

Settings: Community

Intervention: Regular salmeterol in addition to regular inhaled corticosteroids (ICS)

Comparison: Regular ICS

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Regular ICSRegular salmeterol in addition to regular ICS
Adults and adolescents
All cause mortality
Follow-up: mean 34 weeks
10 per 10,000 19 per 10,000
(3 to 26)
OR 0.9
(0.31 to 2.6)
13,447
(35)
⊕⊕⊕⊝
moderate 2
 
All cause non-fatal SAE
Follow-up: mean 34 weeks
21 per 1000 124 per 1000
(19 to 30)
OR 1.15
(0.91 to 1.44)
13,447
(35)
⊕⊕⊕⊝
moderate 2
 
Asthma-related SAE
Follow-up: mean 34 weeks
4 per 1000 14 per 1000
(2 to 7)
OR 1.12
(0.65 to 1.94)
13,447
(35)
⊕⊕⊕⊝
moderate 2
 
Children
All cause mortalitysee commentsee commentsee commentsee comment No deaths occurred in children, so risks of mortality cannot be assessed in this age group.
All cause non-fatal SAE
Follow-up: mean 15 weeks
5 per 1000 16 per 1000
(2 to 21)
OR 1.2
(0.37 to 3.91)
1862
(5)
⊕⊕⊕⊝
moderate 2
 
Asthma-related SAE
Follow-up: mean 15 weeks
1 per 1000 11 per 1000
(0 to 17)
OR 0.99
(0.06 to 15.85)
1862
(5)
⊕⊕⊕⊝
moderate 2
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

For patients whose asthma is not controlled by low dose inhaled corticosteroids (ICS) alone, many asthma guidelines recommend additional long-acting beta2-agonists. Several Cochrane reviews have addressed the efficacy of long-acting beta2-agonists in addition to ICS (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 ICS (Greenstone 2005). The beneficial effects of long-acting beta2-agonists on lung function, symptoms, quality of life and exacerbations requiring oral steroids have been demonstrated.

However, there is also longstanding controversy over the regular use of beta2-agonists for people with asthma. Sears 1986 suggested that excessive use of short acting beta2-agonists might have contributed directly or indirectly to increases in asthma deaths in New Zealand between 1960 and 1980. The authors comment that "most deaths were associated with poor assessment, underestimation of severity and inappropriate treatment (over-reliance on bronchodilators and under use of systemic corticosteroids), and delays in obtaining help."

Concern remains that the symptomatic benefit from treatment with long-acting beta2-agonists might lead to underestimation of attack severity in acute asthma, and could lead to an increase in asthma-related deaths. Furthermore, regular treatment with beta2-agonists can lead to tolerance to their bronchodilator effects and this phenomenon may be more marked with longer acting, as opposed to shorter acting, compounds (Lipworth 1997). A number of molecular mechanisms have been proposed to explain the possible detrimental effect of long-term beta2-agonist use in asthma, including receptor down regulation and desensitisation (Giembycz 2006).

A meta-analysis of the effect of long-acting beta2-agonists on severe asthma exacerbations and asthma-related deaths (Salpeter 2006) concluded that "long-acting beta-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths". However, Salpeter 2006 only considered trials that compared long-acting beta2-agonists with placebo, and 28 of the included trials on 6000 patients did not report asthma-related deaths, reducing certainty in the strength of the conclusion.

Currently there are two long-acting beta2-agonists available, salmeterol and formoterol (also known as eformoterol). These two drugs are known to have differences in receptor activity, and are used in different ways (for example salmeterol has a slower onset of action than salbutamol, and is therefore unsuitable for use as a reliever (Beach 1992)). 'The Fenoterol Story' is a reminder that all beta2-agonists may not carry the same risks (Pearce 2007), so in view of the potential difference in adverse effects between salmeterol and formoterol, we revised our original protocol to consider the two drugs separately.

There has been much debate about the interaction between ICS and long-acting beta2-agonists, in relation to serious adverse events, since the publication of SMART 2006. This study did not randomise patients to ICS, but nevertheless conducted a subgroup analysis of the results on the basis of inhaled corticosteroid use at baseline. It is tempting to be reassured by the fact that there was not a statistically significant increase in asthma-related mortality in the subgroup using ICS, but this is not the correct way to test for interaction (Altman 2003), and no assessment was carried out during the trial in relation to the actual use of ICS during the course of the study. There is a need to systematically review all the available data from controlled trials that randomised patients to regular salmeterol in combination with ICS, and to consider all serious adverse events (fatal and non-fatal), whether or not these are deemed by the investigators to be related to trial medication.

The focus of this review is therefore on regular salmeterol which has been randomised in combination with ICS, (in a single inhaler or separate inhalers). Due to the difficulty in deciding whether adverse events are asthma-related (particularly in the many studies that do not have independent outcome assessment of adverse events), this review is concerned with studies that capture mortality and serious adverse events, and records both all cause outcomes, and those considered by the trial investigators to be asthma-related events. This approach differs from that of Bateman 2008 in which the authors restricted the outcomes to asthma-related events.

Regular salmeterol alone is the subject of a previous review (Cates 2008a), as is regular formoterol alone (Cates 2012b). In both of these reviews, an increase in serious adverse events was demonstrated with regular long-acting beta2-agonists. Formoterol with ICS has been considered in a further review (Cates 2009a). An overview of the safety of combination therapy in children has also been completed (Cates 2012a).

Objectives

To assess the risk of mortality and non-fatal serious adverse events in trials which randomised patients with chronic asthma to regular salmeterol and ICS in comparison to the same dose of ICS.

Methods

Criteria for considering studies for this review

Types of studies

Controlled parallel design clinical trials, with or without blinding, in which salmeterol and ICS were randomly assigned to patients with chronic asthma.

Types of participants

Patients with a clinical diagnosis of asthma of any age group, unrestricted by disease severity, previous or current treatment. We did not include studies on acute asthma and exercise induced bronchospasm.

Types of interventions

ICS and salmeterol given regularly for a period of at least 12 weeks, at any daily dose and delivered by any single or separate devices (CFC-MDI, HFA-MDI, DPI). We included studies that used comparison groups with the same dose of ICS, and co-interventions with leukotriene receptor antagonists, cromones or oral corticosteroids or theophylline were allowed as long as they were not part of the randomised intervention. We excluded studies that compared different doses of salmeterol, or different delivery devices or propellants (with no placebo arm), or that compared salmeterol with formoterol. Studies in which salmeterol was randomised without an inhaled steroid were excluded from this review, but have been considered in a separate review (Cates 2008a).

Types of outcome measures

Primary outcomes
  1. All cause mortality

  2. All cause non-fatal serious adverse events

Secondary outcomes
  1. Asthma-related mortality

  2. Asthma-related non-fatal serious adverse events

  3. Respiratory-related mortality

  4. Respiratory-related non-fatal serious adverse events

  5. Cardiovascular-related mortality

  6. Cardiovascular-related non-fatal serious adverse events

  7. Asthma-related non-fatal life-threatening events (intubation or admission to intensive care)

  8. Respiratory-related non-fatal life-threatening events (intubation or admission to intensive care)

Search methods for identification of studies

Electronic searches

Trials were identified 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 further details). We searched all records in the Specialised Register coded as 'asthma',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 seretide or oxis)) AND (serious or safety or surveillance or mortality or death or intubat* or adverse or toxicity or complications or tolerability)

We conducted the most recent search in August 2012. There was no restriction on the language of publication.

Searching other resources

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

Data collection and analysis

Selection of studies

Two review authors independently assessed studies identified via the literature searches by examining titles, abstract and keywords fields. We obtained in full text the studies that potentially fulfilled the inclusion criteria. CJC and TL independently assessed these for inclusion. We resolved disagreements by consensus.

Data extraction and management

Data were extracted using a prepared checklist before being entered into RevMan 5.2 by one review author (CJC) with assistance from Susan Hansen, and another author (TL, MF or SS) checked data on trial characteristics. Outcome data were independently extracted by a third author (RJ, MF or SS) and discrepancies resolved by discussion and correspondence with the sponsors. Data included characteristics of included studies (methods, participants, interventions, outcomes) and results of the included studies. We contacted authors and sponsors of included studies for unpublished adverse event data, and searched manufacturers' websites for further details of adverse events. We also searched FDA submissions. We collected all cause serious adverse events (fatal and non-fatal), and in view of the difficulty in deciding whether events are asthma-related, noted details of the cause of death and serious adverse events where they were available. We also recorded the definition of serious adverse events, and sought further information if this was not clear (particularly in relation to hospital admissions and serious adverse events).

Assessment of risk of bias in included studies

One review author (CJC) 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), with assistance from Susan Hansen, MF and SS.

Measures of treatment effect

The outcomes of this review were dichotomous, and we recorded the number of participants with one or more outcome events, by allocated treated group.

Unit of analysis issues

We confined our analysis to patients with one or more serious adverse event, rather than the number of events that occurred (as the latter are not independent when one patient suffers multiple events, and are therefore not suitable for meta-analysis).

Assessment of heterogeneity

We assessed heterogeneity using I2 to indicate how much of the total heterogeneity was between studies (rather than within studies).

Data synthesis

The outcomes of this review were dichotomous, and we recorded the number of participants with at least one outcome event by allocated treated group. We calculated pooled Odds Ratio (OR) and Risk Difference (RD). We used the Peto OR for the primary analysis, as no adjustment for zero cells is required. This property was more important than potential problems with unbalanced treatment arms and large effect sizes (in view of the high proportion of zero cells), but the Mantel-Haenszel method was also used for sensitivity analysis. ORs do not include the large body of evidence coming from the trials with no event in either arm, but such data is included in the analysis of absolute rates using RD. We inspected funnel plots to assess publication bias.

Subgroup analysis and investigation of heterogeneity

We planned subgroup analyses on the basis of age (adults versus children), severity of asthma, dose of salmeterol, and dose of inhaled corticosteroid in the comparison arms. We made subgroup comparisons using tests for interaction (Altman 2003).

Sensitivity analysis

We carried out sensitivity analysis to assess the impact of the method used to combine the study events (RD , Peto OR, and Mantel-Haenszel OR). The degree of bias protection in the study designs was also part of sensitivity analysis.

'Summary of Findings' tables

We assessed the quality of evidence as high, moderate, low or very low in accordance with recommendations outlined by the GRADE working group for meta-analyses of randomised trials (GRADE website). We have presented these assessments in a 'Summary of Findings' table alongside the results of our analyses for three key outcomes in adults (all cause mortality; all cause non-fatal serious adverse events, and asthma-related serious adverse events) and two key outcomes in children (all cause non-fatal serious adverse events and asthma-related serious adverse events).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Results of the search

We found 523 abstracts from the search of the Cochrane Airways Group Specialised Register of trials in October 2008. For this review (Cates 2009b) we identified 97 abstracts as potentially relevant. We identified 21 references to 17 included studies from the search of the specialised register. We identified a further 16 included studies from the sponsor's website and the reference list of a recently published review (Bateman 2008). We excluded 76 studies from the review; full details of the reasons for exclusion are listed in Characteristics of excluded studies.

The 2012 update found a further 199 abstracts, of which we identified 15 as potentially relevant to this review. The full papers identified five new studies on 2574 adults and adolescents (Bailey 2008; Godard 2008; Katial 2011; Kerwin 2011; Renzi 2010) and two studies on 689 children (Li 2010; NCT01192178) that were included in the review. One study in adults was excluded (Reddel 2010), as the step-down titration in this study was designed to lead to unequal doses of fluticasone in the trial arms.

Included studies

Of the 40 included studies, 35 of these included 13,447 adults and adolescents (over the age of 12, 16 or 18 years according to the Characteristics of included studies). Five studies were in children up to the age of 11 years, and included 1862 participants. The weighted mean duration was 34 weeks in the adult studies, and 15 weeks in the studies in children.

All studies were sponsored or supported by GlaxoSmithKline and compared fluticasone and salmeterol to fluticasone alone. Most studies used a single inhaler to combine the salmeterol and fluticasone (see Table 1). The dose of salmeterol used was 50 mcg twice daily in all studies except for SAS30021, SAS30022 and SAS30023, used a once daily dose of 50 mcg. The dose of fluticasone varied from 100 to 1000 mcg/day (see Table 1), and some studies stratified patients to different daily doses of fluticasone, but used the same daily dose of fluticasone in each stratum for comparison with additional salmeterol (Koenig 2008; SAM30007; SAM40031; SAM40065).

Table 1. Dose of salmeterol and fluticasone
  1. FSC (salmeterol/fluticasone), ICS (inhaled corticosteroid)

Study IDAge of Participants (Years)N on FSCN on ICSDaily dose of fluticasone (mcg)Daily dose of salmeterol (mcg)Combined InhalerSeparate InhalersDuration (weeks)
Aubier 199912+338165100010028
Bailey 200812+239236200100 52
Bateman 200112+17091707200100 52
GOAL 200412+333165200/500/1000100 12
Godard 200818+159159500100 24
Ind 200316+336160500100 28
Katial 201112+306315500100 52
Kavuru 200012+310318200100 52
Kerwin 201112+9290500100 12
Koenig 200812+156156200/500/1000100 40
Koopmans 200618+173177500100 12
Lundback 200618+101102500100 12
Malone 20054 to 118889200100 12
Murray 200412+9491200100 12
Nathan 200612+171168220100 16
Nelson 200312+9597200100 12
Pearlman 200412+9289200100 12
Renzi 201012+262270200100 24
Rojas 200712+180182500100 12
SAM3000718+2932200/500/1000100 30
SAM4000418+4221200100 52
SAM4000818+93931000100 26
SAM400124 to 11181181200100 24
SAM4003118+4141200/500/1000100 52
SAM4006512+150150200/500/1000100 40
SAS300214 to 1130430410050 12
SAS3002212+21021250050 12
SAS3002312+15115510050 12
SAS4003615+172159200100 16
SAS4003715+161161200100 16
SAS4006812+262270200100 24
SFA10315312+239236200100 52
SFCF402618+159159500100 24
Shapiro 200012+8484500100 12
SLGF7516+1417200100 12
Strand 200418+7872200100 12
van Noord 200112+3371721000100 12
Wallin 200312+1819400100 12

Excluded studies

We excluded 77 studies with reasons which are described in Characteristics of excluded studies.

Risk of bias in included studies

All studies were sponsored by GlaxoSmithKline, the manufacturers of salmeterol and salmeterol/fluticasone inhalers. An overview of the risk of bias in individual studies is shown in Figure 1.

Figure 1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Allocation

Sequence generation and allocation concealment are not well reported, but correspondence with the sponsors indicates that standard methodology (as required by regulatory authorities), has been used to protect against selection bias in these studies. We therefore regarded the risk of selection bias as low, although sequence generation and allocation concealment are marked as unclear in most studies in Figure 1.

Blinding

All of the studies were reported as double blind, and double-dummy design was incorporated when the inhaler devices were not the same in each arm. We therefore assessed the risk of performance and detection bias as low for the all cause events. However, as there was no independent assessment of the causation of serious adverse events, it is possible that the asthma-related events were subject to detection bias.

Incomplete outcome data

Safety analyses were generally reported for all randomised patients who had taken at least one dose of treatment. Some studies had high proportions of withdrawals, these contributed only a small proportion of participants to the meta-analyses, so we did not downgrade the overall quality of evidence for attrition bias.

Selective reporting

Data have been found or provided by the sponsor for all cause fatal and non-fatal serious adverse events by treatment group for all studies, so we regarded the risk of reporting bias as low for the outcomes considered in this review.

Effects of interventions

See: Summary of findings for the main comparison Serious adverse events

Primary outcomes

All cause mortality
Adults and adolescents

In the adult and adolescent studies there were 7 deaths (out of 6986 participants) on salmeterol with ICS and 7 deaths (out of 6461 participants) on ICS alone. The pooled odds ratio (OR) in adults and adolescents was not statistically significant and I2 was zero, (Peto OR 0.90; 95% CI 0.31 to 2.60), but the confidence interval is wide due to the small number of deaths, and still includes the possibility of a nearly three-fold increase in mortality, as well as a three-fold reduction (Figure 2). The pooled risk difference (RD) from these studies is very small (RD 0.0001; 95% CI -0.0021 to 0.0019, expressed as fractions not percentages throughout). In other words, for every 1000 adults or adolescents treated with salmeterol and ICS for 34 weeks, the results are compatible with both a possible increase or decrease of up to 2 deaths (in comparison with regular fluticasone). The causes of death are listed in Table 2. None of the deaths were reported as being related to asthma.

Figure 2.

Forest plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.1 All cause mortality.

Table 2. Mortality
Study IDTreatment armCause of death (in adults)
Aubier 1999

salmeterol and fluticasone

(separate inhalers)

Bronchial carcinoma (one death)
GOAL 2004salmeterol/fluticasoneMyocardial infarction (two deaths) and pneumonia (one death)
GOAL 2004fluticasoneMyocardial infarction (two deaths)
Ind 2003

salmeterol and fluticasone

(separate inhalers)

Pneumothorax (one death)
Kerwin 2011salmeterol/fluticasoneCardiac disease (one death)
Kerwin 2011fluticasoneBreast cancer (one death)
Koenig 2008fluticasoneCardiac arrest and deep vein thrombosis (one death)
Renzi 2010fluticasoneCardiac arrest (one death)
SAS40068fluticasoneVentricular hypertrophy and aortic hypoplasia (one death)
Strand 2004fluticasoneUnknown cause (one death)
van Noord 2001salmeterol/fluticasoneLeukaemia (one death)
Children

No deaths were reported in the 5 studies on children (1862 participants). It is not possible to calculate any ORs from these data, but the pooled RD can be assessed with a confidence interval, (RD 0.0000; 95% CI -0.0047 to 0.0047). In other words, for every 1000 children treated with salmeterol and ICS for 15 weeks, the 95% confidence interval is compatible with either an increase or decrease of up to a maximum of 5 deaths.

Serious adverse events (non-fatal all cause)

A serious adverse event is defined as an event that falls into any of the following categories:

  • results in death;

  • is life-threatening;

  • requires inpatient hospitalisation or prolongation of existing hospitalisation;

  • results in persistent or significant disability/incapacity; or

  • is a congenital anomaly/birth defect.

This is the definition from the International Conference on Harmonisation (ICH), and we have assumed that this definition was used in the trials (even though this was often not explicitly reported in the papers, it is the standard definition for regulatory trials (ICHE2a 1995)).

Adults and adolescents

The number of patients experiencing one or more non-fatal serious adverse events was similar when salmeterol was given with ICS in comparison to ICS alone. There were 167 out of 6986 (2.4%) participants on regular salmeterol with ICS and 135 out of 6461 (2.1%) on ICS alone. The Peto OR was 1.15 (95% CI 0.91 to 1.44) and I2 was zero (Figure 3). The pooled RD was 0.003 (95% CI -0.0021 to 0.0081). For every 1000 adults or adolescents treated with salmeterol and ICS for 34 weeks, the results are compatible with both a possible decrease of up to 2 patients or an increase of up to 8 patients with a serious adverse event.

Figure 3.

Forest plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.2 All cause non-fatal SAE.

Children

In the trials in children there were 6 out of 930 (0.6%) participants with serious adverse events on regular salmeterol with ICS and 5 out of 932 (0.5%) on ICS alone. The Peto OR was 1.20 (95% CI 0.37 to 3.91) and I2 was 0%, and the pooled RD for children was 0.0011 (95% CI -0.0065 to 0.0086). For every 1000 children treated with salmeterol and ICS for 15 weeks, the results are compatible with both a possible decrease of up to 7 children or an increase of up to 9 children with a serious adverse event.

The test for interaction between adults and children did not find a significant impact of age on the treatment effect (see Figure 3).

Secondary outcomes

Mortality due to asthma

None of the deaths were reported to be due to asthma.

Non-fatal serious adverse events related to asthma
Adults and adolescents

The number of patients experiencing one or more asthma-related non-fatal serious adverse events was similar when salmeterol was given with ICS in comparison to ICS alone. There were 29 out of 6986 (0.4%) participants on regular salmeterol with ICS and 23 out of 6461 (0.4%) on ICS alone, with no significant difference in the OR (Peto OR 1.12; 95% CI 0.65 to 1.94, I2 = 5%) as shown in Figure 4. The pooled RD was 0.0005 (95% CI -0.0018 to 0.0027).

Figure 4.

Forest plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.3 Asthma-related SAE.

Children

In the trials in patients who were less than 12 years of age, 1 of the children out of 930 (0.1%) had an asthma-related serious adverse event on regular salmeterol with ICS, and 1 out of 932 (0.1%) on ICS alone. The Peto OR showed no significant difference, with wide confidence intervals (Peto OR 0.99; 95% CI 0.06 to 15.85). The pooled RD was -0.0005 (95% CI -0.0058 to 0.0048).

The difference between children and adults was again not statistically significant. We did not find data to assess the other proposed secondary outcomes (such as intensive care unit admission and intubation).

Sensitivity analyses
Risk of bias

We identified no unblinded studies. Removal of the four studies thought to be at high risk of attrition bias (see Figure 1) made little difference to the OR of non-fatal serious adverse events in adults (Peto OR 1.09; 95% CI 0.85 to 1.39). A funnel plot of non-fatal serious adverse events did not suggest obvious publication bias (Figure 5).

Figure 5.

Funnel plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.2 All cause non-fatal SAE.

Methods of analysis

The primary outcomes were also analysed using Mantel-Haenszel fixed-effect and random-effects models. The result of the fixed-effect model for mortality in adults was OR 0.87 (95% CI 0.36 to 2.08) and for random effects OR 0.90 (95% CI 0.35 to 2.31); both were very similar to the Peto OR result. This method uses a correction for zero cells which is not required for the Peto OR. With this method the addition of 0.5 to all cells when the arms have similar numbers randomised will generate an OR of 3 when there is only one event in the treatment group and none in the control group. When there are very sparse outcomes (such as for mortality), the calculated OR is entirely dependent on the size of the zero cell adjustment, and whether the treatment arms are balanced.

For non-fatal serious adverse events in adults the Peto method (Peto OR 1.15; 95% CI 0.91 to 1.44) gave almost identical results to Mantel-Haenszel fixed-effect model (OR 1.14; 95% CI 0.91 to 1.44) or Mantel-Haenszel random-effects (OR 1.12; 95% CI 0.88 to 1.42).

When fatal and non-fatal serious adverse events were combined the results for adults were almost identical to the pooled result for the non-fatal events in adults (Peto OR 1.13; 95% CI 0.91 to 1.42), and were unchanged in children as there were no deaths in children.

Dose of salmeterol

The dose of salmeterol used in three studies was less than the usual daily dose of 50 mcg twice daily, so we carried out sensitivity analysis out on the primary outcomes excluding these studies (SAS30021; SAS30022; SAS30023). There were no deaths in these studies so mortality results were unaffected. The results for a serious adverse event of any cause without these studies in adults (Peto OR 1.12; 95% CI 0.89 to 1.42) are very similar to the full data set, but in children (Peto OR 2.36; 95% CI 0.53 to 10.41) the confidence interval widens when these studies are excluded.

Subgroup analyses

Mortality data were too sparse to carry out any subgroup analysis. For non-fatal serious adverse events, tests for interaction between adults and children were all negative, but very few children have been studied, so this result should not be interpreted as excluding important possible differences between adults and children. As only four studies included patients on separate salmeterol and fluticasone inhalers (Aubier 1999 [one of the three study arms]; Ind 2003; SLGF75; Wallin 2003; see Table 1), we did not attempt to make a subgroup comparison between separate and combined inhalers.

Discussion

Summary of main results

All cause mortality

Seven deaths occurred in 6986 adults on regular salmeterol with ICS, and seven deaths in 6461 adults on regular ICS at the same dose. The difference was not statistically significant (Peto OR 0.90; 95% CI 0.31 to 2.60) and the absolute difference between groups in risk of death of any cause was -0.0001 (95% CI -0.0021 to 0.0019). No deaths were reported in 1862 children, and no deaths were reported to be asthma-related.

The confidence intervals for all cause mortality in adults and adolescents indicate that for every 1000 patients treated with regular salmeterol and ICS in comparison to the same dose of ICS, results are compatible with up to 2 additional deaths or 2 less deaths in adults over 34 weeks of treatment, and at most 5 additional deaths to 5 less deaths in children over 15 weeks of treatment (the average duration of treatment in the respective trials).

All cause non-fatal serious adverse events

Non-fatal serious adverse events of any cause were reported in 167 adults on regular salmeterol with ICS, compared to 135 adults on regular ICS; again this was not a significant increase (Peto OR 1.15; 95% CI 0.91 to 1.44). The absolute difference in the risk of non-fatal serious adverse events was 0.003 (95% CI -0.0021 to 0.0081).

There were 6 of 930 children with serious adverse events on regular salmeterol with ICS, compared to 5 out of 932 on regular ICS: there was no significant difference between treatments (Peto OR 1.20; 95% CI 0.37 to 3.91). The absolute difference in the risk of non-fatal serious adverse events in children was RD 0.0011 (95% CI -0.0065 to 0.0086).

For non-fatal serious adverse events, the limits of the pooled confidence interval are 8 more to 2 fewer adults, and adolescents and 9 more to 7 fewer children for every 1000 treated over the period of time represented in the trials.

Asthma-related serious adverse events were reported in 29 and 23 adults in each group respectively, a non-significant difference (Peto OR 1.12; 95% CI 0.65 to 1.94), and only 1 event was reported in children in each treatment group.

Overall completeness and applicability of evidence

Two large surveillance studies have been carried out on the use of regular salmeterol (SMART 2006, SNS 1993) without randomised ICS. No similar size study has been performed to assess the safety of regular salmeterol randomised with ICS. The results of this review are therefore less precise than those of the previous review on the safety of regular salmeterol randomised without ICS (Cates 2008a), and very little data are available from studies involving children.

There are now large surveillance studies ongoing in adults and children assessing the safety of regular salmeterol in combination with an inhaled corticosteroid (NCT01462344; NCT01475721).

Quality of the evidence

Risk of bias was assessed as low in the included studies, as the procedures for randomisation and blinding were appropriate, having been designed for regulatory purposes (thereby ensuring common definitions of serious adverse events and minimising the likelihood of selection bias, even though this was not well reported in published papers or trial registers). We assessed the quality of evidence from the studies as moderate due to statistical imprecision. This reflects the low rates of mortality and non-fatal adverse events across the studies we included in the review (see Summary of findings for the main comparison).

Potential biases in the review process

The selection of the best method to combine studies with rare events is contentious when event rates are low, not least because of the corrections required to calculate ORs with zero events (Sweeting 2004). Since it became apparent in the course of carrying out our reviews that the pooled ORs were heavily dependent on the zero adjustment used in the Mantel-Haenszel and Inverse Variance methods, we used the Peto OR and RDs to report results of this review. The likely bias in using the Peto OR is small, as only three trials (Aubier 1999; Bateman 2001; van Noord 2001) had any imbalance in the number of patients in each arm (Sweeting 2004). In these studies, twice the number patients were randomised to regular salmeterol with ICS in comparison to ICS alone.

Similarly, the included studies were influenced by the decision to restrict the review to trials that randomised participants to salmeterol and ICS, but this decision reduces the risk of bias arising from patients discontinuing their usual inhaled steroid medication if they feel better on the randomised treatment. This presupposes a similar risk of serious adverse events when salmeterol and fluticasone are delivered via one inhaler, and when salmeterol is added to inhaled corticosteroid therapy via a separate inhaler, when both are randomised treatments in a controlled trial.

Agreements and disagreements with other studies or reviews

An overview of Cochrane reviews of the safety of regular salmeterol or formoterol in children (with and without combination ICS) in children has recently been completed (Cates 2012a). The overview did not find any significant differences between the safety of regular salmeterol and regular formoterol in children, but the number of children studied remains small (in comparison to adults). Moreover, no separate safety results are currently available for adolescents who were recruited in the adult and adolescent trials.

Two existing reviews of the use of salmeterol with ICS have shown similar results to the findings of this review. Bateman 2008 concentrated on asthma-related outcomes, whilst Jaeschke 2008a considered both salmeterol and formoterol in adults in comparison to the ICS at the same dose and higher doses. Neither of these reviews showed a significant increase in the risk of serious adverse events, but the results were not precise enough to rule out a clinically-important increase or decrease in serious adverse events with regular salmeterol.

It became apparent during the course of preparing this review that there are minor discrepancies between the results recorded in the serious adverse event reports on the GlaxoSmithKline website and the data used in Bateman 2008 and Jaeschke 2008a. An example of this concerns the death in Aubier 1999, and is related to the question of whether the adverse event was classified as being "on-treatment" (see Aubier 1999Notes in Characteristics of included studies). Overall the magnitude of these differences is small, and mostly relates to an external review of company data and inclusion of reviewed data in some of the analyses; this has not altered the conclusions of the review.

Administration of inhaled corticosteroids (ICS)

There is no clear difference seen between the point estimate and confidence interval of the OR for non-fatal serious adverse events found in this review (Peto OR 1.15; 95% CI 0.92 to 1.44), and those seen in the review comparing salmeterol to placebo (OR 1.14; 95% CI 1.01 to 1.28) (Cates 2008a). However the average non-fatal serious adverse event rate in the control arms of the trials in this review that included randomised ICS was 2.1% over 34 weeks, in comparison to 3.6% over 28 weeks in SMART 2006 (which accounted for the majority of patients in Cates 2008a).

Combined data from the GlaxoSmithKline submission to the FDA (FDA 2008) shows separate outcome data for GlaxoSmithKline trials that used ICS as background treatment, those which randomised patients to ICS in a separate inhaler and those which randomised patients to a combined salmeterol/fluticasone inhaler. These results are not directly comparable to those included in this review (as higher doses of ICS may have been used in the control arms), but the breakdown by inhaled corticosteroid use is shown in Figure 6 and Figure 7. These results demonstrate that there was a significantly higher risk of asthma-related hospitalisation in trials in which background ICS were used, but there was no significant difference in trials which randomised patients to ICS. Smaller numbers of events in the latter groups resulted in wide confidence intervals, however, so that an increase in adverse events could not be ruled out in trials that randomised patients to regular ICS with regular salmeterol.

Figure 6.

Risk difference (per 10,000 patients) of asthma-related death by use of Inhaled corticosteroids in GSK meta-analysis of trials of regular salmeterol (from FDA submission 2008)

Figure 7.

Risk difference (per 10,000 patients) of asthma-related hospitalisation by use of Inhaled corticosteroids in GSK meta-analysis of trials of regular salmeterol (from FDA submission 2008)

It is of interest that the serious adverse event rates in the control arms of these studies are also consistently higher in trials using background ICS in comparison to those that randomised patients to ICS. This may reflect a greater asthma severity in those patients who had been started by their own physician on background ICS (as shown by Sears 2009 in the RELIEF study), but could also be compounded by the known poor adherence to treatment with ICS in routine practice. This raises uncertainty about the application of the results of patients in clinical trials, which usually include much more intensive monitoring of adherence to therapy. Since we cannot assume that adherence to treatment in trials will be matched in routine practice, care needs to be exercised in both the interpretation and application of the trial results (Weiss 2008).

We were not able to investigate possible differences in trial findings with combined and separate inhalers due to the paucity of patients on separate inhalers included in the trials in this review (less than 300 patients were randomised to separate fluticasone and salmeterol inhalers, see Table 1).

Authors' conclusions

Implications for practice

We found no significant differences in fatal or non-fatal serious adverse events in trials in which regular salmeterol was randomly allocated with ICS, in comparison to ICS at the same dose. The quality of the evidence was moderate. Although 13,447 adults and 1862 children were included in trials, the number of patients suffering adverse events is too small, and the results are too imprecise to confidently rule out a relative increase in all cause mortality or non-fatal adverse events. It is therefore not possible to determine whether the increase in all cause non-fatal serious adverse events reported in the previous meta-analysis of regular salmeterol alone is abolished by the additional use of ICS. The absolute difference between groups in the risk of serious adverse events was very small. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.

Implications for research

Studies on children are currently lacking in this area. We await the results of large ongoing surveillance studies in adults, children and adolescents. Future research should specify clearly the number of patients with fatal and non-fatal serious adverse events by treatment group and cause, and outcomes should be verified by an independent outcome panel.

Acknowledgements

We thank Susan Hansen and Liz Stovold of the Cochrane Airways Group for assistance in searching for trials and obtaining the abstracts and full reports, and extraction of data on trial characteristics. We also acknowledge the assistance of Matthew Cates in relation to the physiology of beta-agonist receptors and co-writing of protocol (Cates 2009). We thank Steve Yancey for providing information from data on file at GlaxoSmithKline.

Data and analyses

Download statistical data

Comparison 1. Regular salmeterol in addition to regular inhaled corticosteroids
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All cause mortality4015309Peto Odds Ratio (Peto, Fixed, 95% CI)0.90 [0.31, 2.60]
1.1 Adults and adolescents3513447Peto Odds Ratio (Peto, Fixed, 95% CI)0.90 [0.31, 2.60]
1.2 Children51862Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
2 All cause non-fatal SAE4015309Peto Odds Ratio (Peto, Fixed, 95% CI)1.15 [0.92, 1.44]
2.1 Adults and adolescents3513447Peto Odds Ratio (Peto, Fixed, 95% CI)1.15 [0.91, 1.44]
2.2 Children51862Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.37, 3.91]
3 All cause SAE (fatal and non-fatal)4015309Peto Odds Ratio (Peto, Fixed, 95% CI)1.14 [0.91, 1.42]
3.1 Adults and adolescents3513447Peto Odds Ratio (Peto, Fixed, 95% CI)1.13 [0.91, 1.42]
3.2 Children51862Peto Odds Ratio (Peto, Fixed, 95% CI)1.20 [0.37, 3.91]
4 Asthma-related SAE4015309Peto Odds Ratio (Peto, Fixed, 95% CI)1.11 [0.65, 1.91]
4.1 Adults and adolescents3513447Peto Odds Ratio (Peto, Fixed, 95% CI)1.12 [0.65, 1.94]
4.2 Children51862Peto Odds Ratio (Peto, Fixed, 95% CI)0.99 [0.06, 15.85]
Analysis 1.1.

Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 1 All cause mortality.

Analysis 1.2.

Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 2 All cause non-fatal SAE.

Analysis 1.3.

Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 3 All cause SAE (fatal and non-fatal).

Analysis 1.4.

Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 4 Asthma-related SAE.

Appendices

Appendix 1. Pharmacology of beta2-agonists

Beta2-agonists are thought to cause bronchodilation primarily through binding beta2-adrenoceptors on airways smooth muscle (ASM), with subsequent activation of both membrane-bound potassium channels and a signalling cascade involving enzyme activation and changes in intracellular calcium levels following a rise in cyclic adenosine monophosphate (cAMP) (Barnes 1993).  However, beta2-adrenoceptors are also expressed on a wide range of cell types where beta2-agonists may have a clinically-significant effect including airway epithelium (Morrison 1993), mast cells, post capillary venules, sensory and cholinergic nerves and dendritic cells (Anderson 2006).  Beta2-agonists will also cross-react to some extent with other beta-adrenoceptors including beta1-adrenoceptors on the heart. 

The in vivo effect of any beta2-agonist will depend on a number of factors relating to both the drug and the patient. The degree to which a drug binds to one receptor over another is known as selectivity, which can be defined as absolute binding ratios to different receptors in vitro, whilst functional selectivity is measured from downstream effects of drugs in different tissue types in vitro or in vivo.  All of the beta2-agonists described thus far are more beta2 selective than their predecessor isoprenaline in vitro. However, because attempts to differentiate selectivity between the newer agents are confounded by so many factors, it is difficult to draw conclusions about in vitro selectivity studies and probably best to concentrate on specific adverse side-effects in human subjects at doses which cause the same degree of bronchodilatation. The potency of a drug refers to the concentration that achieves half the maximal receptor activation of which that drug is capable but it is not very important clinically as for each drug, manufacturers will alter the dose to try to achieve a therapeutic ratio of desired to undesired effects.  In contrast efficacy refers to the ability of a drug to activate its receptor independent of drug concentration.  Drugs that fully activate a receptor are known as full agonists and those that partially activate a receptor are known as partial agonists.  Efficacy also is very much dependent on the system in which it is being tested and is affected by factors including the number of receptors available and the presence of other agonists and antagonists. Thus whilst salmeterol acts as a partial agonist in vitro it causes a similar degree of bronchodilation to the strong agonist formoterol in stable asthmatic patients (vanNoord 1996), presumably because there are an abundance of well-coupled beta2-adrenoceptors available with few downstream antagonising signals.  In contrast, with repetitive dosing formoterol is significantly better than salmeterol at preventing methacholine-induced bronchoconstriction (Palmqvist 1999). These differences have led to attempts to define the “intrinsic efficacy” of a drug independent of tissue conditions (Hanania 2002), as shown in Table 1. The clinical significance of intrinsic efficacy remains unclear.

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

Direct toxicity

This hypothesis states that direct adverse effects of beta2-agonists are responsible for an associated increase in mortality and most research in the area has concentrated on effects detrimental to the heart. Whilst it is often assumed that cardiac side-effects of beta2-agonists are due to cross-reactivity with beta1-adrenoceptors (i.e. poor selectivity), it is worth noting that human myocardium also contains an abundance of beta2-adrenoceptors capable of triggering positive chronotropic and inotropic responses (Lipworth 1992).  Indeed, there is good evidence that cardiovascular side-effects of isoprenaline (Arnold 1985) and other beta2-agonists including salbutamol (Hall 1989) are mediated predominantly via cardiac beta2-adrenoceptors thus making the concept of in vitro selectivity less relevant. Generalised beta2-adrenoceptor activation can also cause hypokalaemia (Brown 1983) and it has been proposed that, through these and other actions beta2-agonists may predispose to life-threatening dysrhythmias or cause other adverse cardiac effects.

During the 1960s epidemic most deaths occurred in patients with severe asthma and it was originally assumed that asthma and its sequelae, including hypoxia, were the primary cause of death.  However, mucus plugging and hypoxia does not preclude a cardiac event as the final cause of death, and one might expect those with severe asthma to take more doses of a prescribed inhaler. As noted by Speizer and Doll, most deaths in the 1960s were in the 10 to 19 age group and “at these ages children have begun to act independently and may be particularly prone to misuse a self-administered form of treatment” (Speizer 1968).  If toxicity were related to increasing doses of beta2-agonists one might expect most deaths to occur in hospital where high doses are typically used, and this was not the case.  One possible explanation for this anomaly was provided by animal experiments in which large doses of isoprenaline caused little ill effect in anaesthetised dogs with normal arterial oxygenation, whereas much smaller doses caused fatal cardiac depression and asystole (although no obvious dysrhythmia) when hypoxic (Collins 1969; McDevitt 1974).  It has been hypothesised, therefore, that such events would be less likely in hospital where supplemental oxygen is routinely given. The clinical relevance of these studies remains unclear although there is some evidence of a synergistic effect between hypoxia and salbutamol use in asthmatic patients in reducing total peripheral vascular resistance (Burggraaf 2001) – another beta2-mediated effect which could be detrimental to the heart during an acute asthma attack through a reduction in diastolic blood pressure.  Other potential mechanisms of isoprenaline toxicity include a potential increase in mucus plugging and worsening of ventilation perfusion mismatch despite bronchodilation (Pearce 1990).

Further concerns about a possible toxic effect of beta2-agonists were raised during the New Zealand epidemic in the 1970s.  In 1981 Wilson et al who first reported the epidemic reviewed 22 fatal cases of asthma and noted “In 16 patients death was seen to be sudden and unexpected.  Although all were experiencing respiratory distress, most were not cyanosed and the precipitate nature of their death suggested a cardiac event, such as an arrest, inappropriate to the severity of their respiratory problem” (Wilson 1981). In humans, fenoterol causes significantly greater chronotropic, inotropic and electrocardiographic side-effects than salbutamol in asthmatic patients (Wong 1990).  Interestingly, across the same parameters fenoterol also causes more side-effects than isoprenaline (Burgess 1991). 

In patients with mild asthma and without a bronchoconstrictor challenge, salmeterol and salbutamol cause a similar degree of near maximal bronchodilation at low doses (Bennett 1994). However, whilst as a one off dose salbutamol is typically used at 2 to 4 times the concentration of salmeterol, the dose equivalences for salmeterol versus salbutamol in increasing heart rate and decreasing potassium concentration and diastolic blood pressure were 17.7, 7.8 and 7.6 respectively (i.e. salmeterol had a greater effect across all parameters).  Given the lower intrinsic efficacy of salmeterol, these results highlight the importance of in vivo factors; one possible explanation for the difference is the increased lipophilicity of salmeterol compared to salbutamol contributing to higher systemic absorption (Bennett 1994).    

When comparing increasing actuations of standard doses of formoterol and salmeterol inhalers in stable asthmatic patients, relatively similar cardiovascular effects are seen at lower doses (Guhan 2000).  However, at the highest doses (above those recommended by the manufacturers) there were trends towards an increase in systolic blood pressure with formoterol;  in comparison there was a trend towards a decrease in diastolic blood pressure and an increase in QTc interval with salmeterol although no statistical analysis of the difference was performed.  In contrast, in asthmatic patients with methacholine-induced bronchoconstriction there was no significant difference between salmeterol and formoterol in causing increased heart rate and QTc interval, although formoterol caused significantly greater bronchodilation and hypokalaemia (Palmqvist 1999). Whilst there is good evidence of cardiovascular and metabolic side-effects with increasing doses of beta2-agonists, it is a little difficult to envisage serious adverse effects of this nature when using LABAs at manufacturer-recommended preventative doses.  However, it is possible that some patients choose to use repeated doses of LABAs during exacerbations. 

Tolerance

In this setting, the term tolerance refers to an impaired response to beta2-agonists in patients who have been using regular beta2-agonist treatment previously (Haney 2006). Tolerance is likely to result from a combination of reduced receptor numbers secondary to receptor internalisation and reduced production and also uncoupling of receptors to downstream signalling pathways following repeated activation (Barnes 1995). This phenomenon is likely to explain the beneficial reduction in systemic side effects seen with regular use of beta2-agonists including salbutamol after 1 to 2 weeks (Lipworth 1989). However, the same effect on beta2-adrenoceptors in the lung might be expected to produce a diminished response to the bronchodilating activity of beta2-agonists following regular use. In patients with stable asthma, whilst there is some evidence of tolerance to both salbutamol (Nelson 1977) and terbutaline (Weber 1982) other studies have been less conclusive (Harvey 1982; Lipworth 1989).  However, evidence of tolerance to short and long-acting beta2-agonists in both protecting against and reducing bronchoconstriction is much stronger in the setting of an acute bronchoconstrictor challenge with chemical, allergen and 'natural' stimuli (Haney 2006; Lipworth 1997). 

Studies comparing salmeterol and formoterol have shown that both cause tolerance compared to placebo, but there was no significant difference between the drugs (van der Woude 2001).  There also appears to be little difference in the tolerance induced by regular formoterol and regular salbutamol treatment (Hancox 1999; Jones 2001).  To the authors' knowledge no studies have looked specifically at the degree of tolerance caused by isoprenaline and fenoterol in the setting of acute bronchoconstriction. Tolerance to bronchodilation has been shown to clearly occur with addition of inhaled corticosteroids to salmeterol and formoterol (Lee 2003) and terbutaline (Yates 1996).  There is conflicting evidence as to whether high dose steroids can reverse tolerance in the acute setting (Lipworth 2000; Jones 2001).

At first glance the toxicity and tolerance hypotheses might appear incompatible, as systemic and cardiovascular tolerance ought to protect against toxicity in the acute setting and there is good evidence that such tolerance occurs in stable asthmatic patients (Lipworth 1989).  However, whilst this study showed that changes in heart rate and potassium levels were blunted by previous beta2-agonist use, they were not abolished; furthermore, at the doses studied these side-effects appear to follow an exponential pattern (Lipworth 1989).  In contrast, in the presence of bronchoconstrictor stimuli the bronchodilator response to beta2-agonists follows a flatter curve (Wong 1990; Hancox 1999) and as previously discussed this curve is shifted downwards by previous beta2-agonist exposure (Hancox 1999).  Thus, it is theoretically possible that in the setting of an acute asthmatic attack and strong bronchoconstricting stimuli, bronchodilator tolerance could lead to repetitive beta2-agonist use and ultimately more systemic side-effects than would otherwise have occurred.  Of course, other sequelae of inadequate bronchodilation including airway obstruction will be detrimental in this setting.

Whilst the tolerance hypothesis is often cited as contributing towards the asthma mortality epidemics, it is difficult to argue that reduced efficacy of a drug can cause increased mortality relative to a time when that drug was not used at all.  However, tolerance to the bronchodilating effect of endogenous circulating adrenaline is theoretically possible, and there is also evidence of rebound bronchoconstriction when stopping fenoterol (Sears 1990), which may be detrimental.  Furthermore, it appears that regular salbutamol treatment can actually increase airway responsiveness to allergen (Cockcroft 1993); a potentially important effect that could form a variant of the toxicity hypothesis.  Differences between beta2-agonists in this regard are unclear, but the combination of rebound hyperresponsiveness and tolerance of the bronchodilator effect with regular beta2-agonist exposure has been recently advocated as a possible mechanism to explain the association between beta2-agonists and asthma mortality (Hancox 2006).

Other explanations

Confounding by severity

Historically, this hypothesis has been used extensively to try to explain the association between mortality and the use of fenoterol during the 1970s New Zealand epidemic (see Pearce 2007) and is still quoted today.  The hypothesis essentially relies on the supposition that patients with more severe asthma are more likely to take either higher doses of beta2-agonists or a particular beta2-agonist (such as fenoterol) thereby explaining the association.  This hypothesis was carefully ruled out in the three case-control studies by comparing the association between fenoterol and mortality in patients with varying severity of disease (Crane 1989; Pearce 1990; Grainger 1991).  Furthermore, the hypothesis cannot explain the overall increase in mortality in the 1960s and 1970s, nor can it explain any significant increase in mortality (whether taking inhaled steroids or not) from randomised controlled trial data.

The delay hypothesis

This hypothesis accepts that beta2-agonists or a particular beta2-agonist cause an increased risk of mortality but indirectly by causing patients to delay before getting medical help and further treatments including high dose steroids and oxygen.  There is evidence that both salmeterol and formoterol can reduce awareness of worsening underlying inflammation (Bijl-Hofland 2001; McIvor 1998).  It is difficult to rule out the delay hypothesis in either explaining or contributing towards both the asthma mortality epidemics and an association with regular use of LABAs.  There is evidence that beta2-agonists with higher intrinsic efficacy are more effective at relieving bronchoconstriction in the acute setting (Hanania 2007) and could paradoxically cause patients to delay longer in seeking medical help. For the delay hypothesis to explain the increase in mortality during the 1960s and 1970s, one has to imply that hospital treatment of asthma when mortality rates were low during the earlier years of the 20th century was effective.  It is difficult to say exactly how effective such treatment is likely to have been.   

Reduced corticosteroid treatment

A slight but significant variation of the delay hypothesis suggests that patients who have separate beta2-agonists and corticosteroid inhalers may choose to take less corticosteroid because of better symptom control from the inhaled beta2-agonists, and it is reduced corticosteroid treatment that contributes to a rise in mortality.  It is rather difficult to see how this hypothesis explains the epidemics of asthma deaths in the 1960s and 1970s relative to the 1920s and 1930s, given that corticosteroids were not used for the treatment of asthma in the earlier decades.  If this hypothesis were to explain increased mortality from more recent randomised controlled trial data, one would not expect to see an increase in mortality in those taking LABAs alone. 

Appendix 3. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

DatabaseFrequency of search
CENTRAL (The Cochrane Library)Monthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly
CINAHL (EBSCO)Monthly
AMED (EBSCO)Monthly

 

Handsearches: core respiratory conference abstracts

ConferenceYears searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

What's new

Last assessed as up-to-date: 1 August 2012.

DateEventDescription
1 August 2012New search has been performedNew literature search run
1 August 2012New citation required but conclusions have not changed

The 2012 update identified five additional studies including 2574 adults and adolescents (Bailey 2008; Godard 2008; Katial 2011; Kerwin 2011; Renzi 2010) and two additional studies including 689 children (Li 2010; NCT01192178). Two large ongoing studies were also identified, which aim to recruit 6000 children and 11,000 adults. They are expected to report in 2017 (NCT01462344; NCT01475721).

There is currently insufficient evidence to conclude that regular salmeterol in combination with fluticasone is safe in adults or children.

Contributions of authors

CJC: Conception of the idea and co-writing of protocol (Cates 2009) with Matthew J Cates.

Toby Lasserson: Co-writing of the protocol (Cates 2009), trial selection, data extraction and co-writing the original review (Cates 2009b).

RJ: Trial selection, data extraction and co-writing the original review (Cates 2009b).

MF & SS: Data extraction and co-writing the 2012 update.

Declarations of interest

More than five years ago, Dr Jaeschke received honoraria for lectures from Boehringer Ingelheim (2006; USD 4000) and GlaxoSmithKline (2007; EUR 2000) and travel support from Boehringer Ingelheim and GlaxoSmithKline (2006 and 2007; up to USD 1000).

Sources of support

Internal sources

  • NHS R&D, UK.

External sources

  • NIHR, UK.

    Programme Grant (10/4001/01)

  • European Union (FP7), Not specified.

    ASTROLAB project (EC HEALTH-F5-2011-282593)

Differences between protocol and review

Although the protocol (Cates 2009) originally included studies comparing salmeterol and ICS with higher doses of , we restricted this review and update to studies randomising patients to the same dose of ICS with and without salmeterol. Due to problems with fixed continuity corrections for zero cells we used the Peto OR as the primary metric for analysis of relative measures, and the risk difference for absolute measures. Subgroup analysis was not attempted on the basis of asthma severity or dose of ICS.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aubier 1999

MethodsA randomised, double-blind, double-dummy, multicentre, parallel-group study over 28 weeks from May 1996 to November 1997 at 55 centres in 3 countries (Germany, France and the Netherlands). Run-in 2 weeks and follow-up 2 weeks.
Participants

Population: 503 adolescents and adults (12 to 79) years with asthma. 

Baseline Characteristics: Mean age 48 years. FEV1 73% predicted.

Concomitant ICS used by 100% of participants.

Inclusion Criteria: At least 12 years old with a documented clinical history of reversible airways disease, and received treatment with any inhaled corticosteroid continuously for 12 weeks prior to run-in. FEV1 % predicted between 50% to 100%, At the end of the 2-week run-in period were symptomatic (symptom score 2 or more on at least 4 of the last 7 consecutive days), had a mean morning PEF that was > 50% and < 85% of the maximum PEF 15 min after administration of inhaled salbutamol 400 mcg. 

Exclusion Criteria: taking long-acting beta2-agonists.

Interventions
  1. Fluticasone propionate/salmeterol 500/50 mcg BD

  2. Fluticasone propionate 500 mcg + salmeterol 50 mcg BD

  3. Fluticasone propionate 500 mcg BD

Delivery was Diskus device.

Outcomes

Primary outcome: Mean morning PEF during weeks 1 to 12.

The paper reports "The incidence of drug-related adverse events was similar for the three treatments".

Full SAE data from web report. One death from bronchial carcinoma on salmeterol and fluticasone (separate inhalers). This death was not included in Jaeschke 2008b as the patient stopped taking study medication to allow for elective surgery and died of surgical complications, but was still in the trial and had intended to restart treatment post-operatively.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk403/503 (80%) completed the study
Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Bailey 2008

MethodsA randomised, double-blind, multicenter, parallel-group study over 52 weeks from November 2004 to April 2007 at 59 centers in the USA.  Run-in: 2 weeks on usual ICS and then 4 weeks on fluticasone 250 mcg twice daily.
Participants

Population: 475 adolescents and adults (12 to 65) years of African descent with persistent asthma, and symptomatic while taking low dose ICS.

Baseline Characteristics: Mean age 32 years. FEV1 85% predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria:12 years or older with a documented clinical history of persistent asthma for at least six months and had been symptomatic using ICS (FP 200 mcg daily or equivalent) for at least 4 weeks before entering the run-in period. FEV1 % predicted between 60% and 90%, with at least 12% reversibility following 2 to 4 puffs of albuterol. 

Exclusion Criteria:  Participants were only included in the 52-week study period if on the 2 week run-in taking low dose ICS twice daily, they showed FEV1 at least 60% predicted and in the last 7 days of run-in they had at least 4 days with albuterol use or were symptomatic. They were excluded if they had an exacerbation in the 4 weeks on fluticasone 250 mcg twice daily.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg Diskus BID

  2. Fluticasone propionate 100 mcg Diskus BID alone.

OutcomesPrimary outcome was rate of asthma exacerbations.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind treatment period"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk70/239 lost to follow-up on combined treatment and 85/236 on fluticasone alone
Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website (SFA103153SFA103153)

Bateman 2001

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study over 12 weeks from March 1998 to June 1999  at 69 centers in 10 countries.  Run-in 2 weeks and 2 weeks follow-up.
Participants

Population: 497 adolescents and adults (12 to 79) years with documented clinical history of reversible airways obstruction.

Baseline Characteristics: Mean age 40 years. FEV1 76% predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria:12 years or older with a documented clinical history of reversible airway obstruction, a smoking history of less than 10 pack-years and been using ICS (beclomethasone dipropionate, budesonide or flunisolide 400-500 mcg day or FP 200-250 mcg day) for at least 4 weeks before entering the run-in period. FEV1 % predicted at least 50%.  

Mean PEF over the last 7 days of the run-in period of between 50% and 85% measured after inhalation of salbutamol (400 mg). Had to be symptomatic, i.e. have a cumulative total symptom score (daytime plus night-time) greater than 8 for the last 7 days of the run-in period, and be taking salbutamol up to 800 mcg day.  

Exclusion Criteria:  Received a long-acting beta2-agonist or oral beta2-agonist within 2 weeks of the run-in period, changed asthma medication, had a lower respiratory tract infection within 4 weeks of the run-in period or had an acute asthma exacerbation requiring hospitalisation within 12 weeks of study entry. Other exclusion criteria included prior treatment with oral, depot or parenteral corticosteroids or combination therapy (containing a beta2-agonist and/or ICS).

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg HFA MDI

  2. Fluticasone propionate/salmeterol  100/50 mcg Diskus

  3. Fluticasone propionate 100 mcg CFC MDI

Outcomes

Primary efficacy variable was the mean morning PEF over the 12-week treatment period.

A serious adverse event was described as any event which was fatal, life-threatening, disabling or incapacitating, or which required or prolonged hospitalisation.

Paper reports: "During treatment, serious adverse events were reported by three patients (2%) in each group. These included asthma exacerbations (n.5), breast neoplasia (n.1) and events associated with the gastrointestinal system (n.2) and ear, nose and throat (n.1). The only serious adverse events considered by the investigator to be drug-related were asthma exacerbations in two patients (one each in the fluticasone propionate/salmeterol MDI and Diskus groups)."

SFCB3022 reports 5 patients with asthma SAE in fluticasone propionate/salmeterol groups (333 pts) and none on fluticasone propionate alone (165 pts).

NotesBateman reports 4 asthma hospitalisations in fluticasone propionate/salmeterol groups
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk430/497 (87%) completed the study
Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

GOAL 2004

MethodsA randomised, double-blind, multicentre, stratified, parallel-group study over 12 months from December 2000 to December 2002 in 326 centres in Europe, North America, Latin America and Asia Pacific. Run-in 4 weeks.
Participants

Population: 3416 adolescents and adults (9 to 83) with uncontrolled asthma.  

Baseline Characteristics: Mean age 40 years. FEV1 77% predicted. Concomitant ICS not previously used in stratum 1, low dose in stratum 2 and medium to high dose in stratum 3 at baseline. 

Inclusion Criteria:12 years old or more and less than 80 years old with at least a 6-month history of asthma, bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline (and 200 mL) based on FEV1 measured pre- and post-inhalation of any short-acting beta2-agonist within the last six months or to demonstrate reversibility at Visit 1, Visit 2, or between Visit 1 and Visit 2 using 200-400 mcg of salbutamol/albuterol. 

Eligible for Stratum 1 of the study if had not received ICS for at least 6 months prior to Visit 1. For Stratum 2, if receiving ≤500 mcg BDP or equivalent daily, Stratum 3, receiving > 500 and ≤ 1000 mcg BDP or equivalent daily.

During 2 or more of the 4 weeks prior to Visit 2, subjects should have failed to achieve the criteria for 'Well-Controlled' asthma. 

Exclusion Criteria:  assessed as having Well-Controlled asthma on more than 3 of the 4 weeks during run-in, change in regular asthma medication; emergency visits due to asthma; treatment with systemic corticosteroids; respiratory tract infection; more than 3 days of morning PEF less than 50% predicted; non-compliance with the diary record card.

Interventions
  1. Fluticasone propionate/salmeterol 100/50, 250/50 or 500/50 mcg BD (by strata)

  2. Fluticasone propionate 100, 250 or 500 mcg BD (by strata)

Delivery was Diskus device

Outcomes

The primary efficacy variable was the proportion of subjects who achieved 'Well-Controlled' asthma with the fluticasone propionate/salmeterol combination compared with fluticasone propionate alone during Phase I of the study.

Paper states that "Serious adverse events were observed during the double-blind period in 4% and 3% of patients in the salmeterol/fluticasone and fluticasone arms, respectively". Web report gives the number of patients (67 and 53 respectively).

Website reports 2 deaths on fluticasone propionate (both myocardial infarction) and 3 deaths on fluticasone propionate/salmeterol (2 myocardial infarction and 1 pneumonia). No asthma-related deaths are reported.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was done telephonically from a computer-generated allocation schedule balanced per stratum and per country
Allocation concealment (selection bias)Unclear riskNot reported  
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk2890/3416 (85%) completed the study
Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Godard 2008

MethodsA randomised double-blind 24 week multicenter study at 124 centers in France. 8 week open run-in on SFC (50/250 mcg twice daily).
Participants

Population: 308 adults (18+) years with asthma controlled on ICS (1000 mcg CFC beclomethasone equivalent daily) and LABA. 

Baseline Characteristics: Mean age 44 years. FEV1 90% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Currently receiving ICS at a dose of 1000 mcg daily of inhaled beclomethasone dipropionate (BDP) or equivalent and LABA.  Asthma controlled on a stable dose for at least 4 weeks were entered into run-in, and then entered into full study if asthma was well-controlled (as defined in GOAL) in last two weeks of 8-week run-in on fluticasone propionate/salmeterol.

Exclusion Criteria: Patients were excluded from entry into the run-in period if they had a smoking history of 10 pack-years or more, a respiratory tract infection during the last 4 weeks prior to the initial clinic visit (V1), acute asthma exacerbation requiring emergency room treatment or hospitalisation within 4 weeks prior to V1, and/or use of oral/parenteral corticosteroids during the last 4 weeks prior to V1 (12 weeks for depot corticosteroids), or any change in their asthma maintenance treatment in the previous 4 weeks.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone 250 mcg  BD

  3. Fluticasone propionate/salmeterol 100/50 mcg BD (not analysed in this review)

Delivery device Diskus

OutcomesThe primary efficacy endpoint was the variation in mean morning PEF over the first 12 weeks of the treatment period compared to the last 2 weeks of the run-in period (baseline).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind randomised 24-week study"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
High riskUneven withdrawals (18/159 on fluticasone propionate/salmeterol and 30/159 on fluticasone)
Selective reporting (reporting bias)Low riskFull SAE data reported in paper

Ind 2003

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study over 28 weeks from January 1995 to December 1996 at 99 centers in Canada, Denmark, Iceland, Ireland, Italy and the United Kingdom. Run-in 4 weeks
Participants

Population: 502 adolescents and adults (16 to 75) years with asthma poorly controlled on current ICS.  

Baseline Characteristics: Mean age 45 years. FEV1 2.3L. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Currently receiving ICS at a dose of 1000 to 1600 mcg daily of inhaled beclomethasone dipropionate (BDP) or equivalent.  Asthma poorly controlled (demonstrated by a PEF of < 85% of maximal achievable PEF after inhaling 400 mcg salbutamol) and had experienced at least 2 exacerbations of asthma in the last year that required a change in asthma therapy. Therefore, over the last 10 days of the baseline period had to demonstrate an average morning PEF which was < 90% of their maximal achievable PEF measured at screening and a diurnal variation in PEF of at least 15%. They also had to have asthma symptoms on at least 4 of the last 7 days or nights of the baseline period.

Exclusion Criteria: Receiving continuous oral corticosteroids, any serious uncontrolled systemic disease or participation was deemed unsuitable

by the physician, had to demonstrate a period variation in PEF of at least 15% (highest evening value-lowest morning value as a percentage of highest

PEF) over the last 10 days and/or nights of the run-in period and to have sub-optimal PEF, with average PEF over the last 10 days of the run-in not exceeding 90% of post-bronchodilator PEF (measured at visit 1).

Interventions
  1. Fluticasone propionate 250 mcg + salmeterol 50 mcg BD

  2. Fluticasone propionate 250 mcg BD

  3. Fluticasone propionate 500 mcg BD

Delivery was MDI (fluticasone propionate 500 arm not used in this review).

Outcomes

The primary efficacy variables were: mean morning PEF; incidence and severity of asthma exacerbations.

No SAE information found in paper publication. Full SAE data on web report. One fatal pneumothorax on salmeterol and fluticasone (separate inhalers).

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk432/502 (86% completed study)
Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Katial 2011

MethodsA 52-week, randomised, double-blind, parallel-group study of fluticasone propionate/salmeterol combination product 250/50 mcg BID and fluticasone propionate (FP) Diskus 250 BID in treatment of subjects with asthma. 61 centers in North and South America, Canada and the Philippines from May 2007 to May 2009.
Participants

Population: 621 adults and adolescents (12+) years with asthma that was not controlled on ICS at low dose (with or without LABA), or at medium dose without LABA. Clinical diagnosis of asthma, defined by the ATS, for ≥ 6 months before screening.

Baseline Characteristics: Mean age 38 years. FEV1 74% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Subjects were required to have treatment with a low-to-medium dose of ICS or combination inhaled corticosteroid/long-acting beta2 –agonist (ICS/LABA) controller medications if the ICS was a low dose for ≥ 4 weeks before screening.

Subjects must have reported being symptomatic while taking their controller medication in the 4 weeks before screening.

Exclusion Criteria: Life-threatening asthma in the 12 months before screening, seasonal or exercise induced asthma without other manifestations of persistent asthma, or concurrent respiratory disease or any other significant concurrent condition/disease.

Subjects were excluded if they had worsening asthma in the 4 weeks before screening including an emergency room visit, hospitalisation, or use of oral/ parenteral corticosteroid. Concurrent use of medications that could have affected the course of asthma or interacted with study medication was prohibited.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone 250 mcg  BD

Delivery device Diskus

OutcomesPrimary outcome was FEV1 over a 52 treatment week period. SAE data fully reported in the published paper and GlaxoSmithKline web report (ADA109055).
NotesClinicalTrials.gov identifier NCT00452699 (Identical design to Kerwin 2011)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
High risk81/306 withdrew on fluticasone propionate/salmeterol and 73/315 on fluticasone propionate. Of these 14 and 4 respectively withdrew due to adverse events or lack of efficacy.
Selective reporting (reporting bias)Low riskSAE data fully reported

Kavuru 2000

MethodsRandomized, double-blind, double-dummy, parallel-group placebo-controlled study over 12 weeks at 42 centers in the USA. Run-in 2 weeks single blind placebo.
Participants

Population: 356 adolescents and adults (12 to 70) years with asthma.

Baseline Characteristics: Mean age 37 years. FEV1 64% predicted.

Concomitant ICS used by 100% of participants in group 1 and 0% of participants in group 2. 

Inclusion Criteria:  At least 12 years old and a medical history of asthma (as defined by the ATS) of at least 6 months duration. FEV1 % predicted between 40% to 85%,bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline 30 minutes after two puffs (180 mcg)  of inhaled albuterol.

Stratified into 2 groups according to type of asthma therapy used at enrolment. 

Exclusion Criteria: History of life-threatening asthma; hypersensitivity reaction to sympathomimetic drugs or corticosteroids; smoking within the previous year or a history of > 10 pack-years; use of oral, inhaled or injectable corticosteroid therapy within the previous month; use of intranasal corticosteroid therapy except for Flonase (GlaxoWellcome Inc.); use of daily oral corticosteroid treatment within the previous 6 months; use of any other prescription or over-the-counter medication that could have affected the course of asthma or interacted with sympathomimetic amines; abnormal chest x-ray films; clinically significant abnormal 12-lead electrocardiograms (ECGs); or a history of significant concurrent disease (e.g., glaucoma, diabetes, hypertension).

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone 100 mcg  BD

Delivery was Diskus inhaler

Outcomes

Mean morning pre-dose FEV1 at endpoint; area under the 12-hour serial FEV1 curve relative to baseline [AUC(bl)] after I week of treatment (mean FEV1 AUC); and probability of remaining in the study over time without withdrawal due to lack of efficacy.

Paper reports no serious drug-related adverse events, and reports two serious adverse events that led to withdrawal. Website records 2 events on Fluticasone propionate/salmeterol and 1 event on fluticasone propionate. (Unclear whether the 2 fluticasone propionate/salmeterol events were in separate patients, so treated as one patient).

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk142/182 (78%) completed the study
Selective reporting (reporting bias)Low riskData on GlaxoSmithKline website

Kerwin 2011

MethodsA 52-week, randomised, double-blind, parallel-group study of fluticasone propionate/salmeterol combination product (fluticasone propionate/salmeterol) 250/50 mcg BID and fluticasone propionate (FP) Diskus 250 BID in treatment of subjects with asthma. 76 centers in North and South America, Canada and the Philippines from May 2007 to April 2009.
Participants

Population: 628 adults and adolescents (12+) years with asthma that was not controlled on ICS at low dose (with or without LABA), or at medium dose without LABA. Clinical diagnosis of asthma, defined by the ATS, for ≥ 6 months before screening.

Baseline Characteristics: Mean age 40 years. FEV1 74% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Subjects were required to have treatment with a low-to-medium dose of ICS or combination inhaled corticosteroid/long-acting beta2 –agonist (ICS/LABA) controller medications if the ICS was a low dose for ≥ 4 weeks before screening.

Subjects must have reported being symptomatic while taking fluticasone propionate/salmeterol Diskus 100 mcg twice daily in the 4 weeks before screening.

Exclusion Criteria: Life-threatening asthma in the 12 months before screening, seasonal or exercise induced asthma without other manifestations of persistent asthma, or concurrent respiratory disease or any other significant concurrent condition/disease.

Subjects were excluded if they had worsening asthma in the 4 weeks before screening including an emergency room visit, hospitalisation, or use of oral/ parenteral corticosteroid. Concurrent use of medications that could have affected the course of asthma or interacted with study medication was prohibited.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone 250 mcg  BD

Delivery device Diskus

OutcomesPrimary Outcome was FEV1 over a 52 treatment week period. SAE data fully reported in the published paper and GlaxoSmithKline web report (ADA109057).
NotesClinicalTrials.gov identifier NCT00452348 (Identical in design to Katial 2011).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind therapy"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk79/310 withdrew on fluticasone propionate/salmeterol and 84/318 withdrew on fluticasone, but balanced withdrawals for adverse events of lack of efficacy.
Selective reporting (reporting bias)Low riskFull SAE data reported in paper and GlaxoSmithKline web report

Koenig 2008

MethodsA randomised, double-blind, multicenter, parallel-group study over 40 weeks from February 2003 to October 2004 at 55 sites (50 in the USA, 3 in Latin America, 2 in Latvia). Run-in 2 weeks.
Participants

Population: 466 adolescents and adults(12 to 81) with asthma.  

Baseline Characteristics: Mean age 34 years. FEV1 78% predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 12 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 3 months prior to visit 1, must have been treated with a short-acting beta2-agonist, an anticholinergic, or an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks prior to the screening visit. FEV1 % predicted between 60% to 95%, bronchodilator reversibility by an increase of at least 12%  in FEV1 over baseline within 30 minutes of inhalation 2 puffs of inhaled albuterol (180 mcg).

Exclusion Criteria: Pregnancy, life-threatening asthma, hospitalisation attributable to asthma within the last 6 months, current smoker or a more than10 pack-year history of smoking, a recent (within 2 weeks) upper or lower respiratory tract infection, or significant concurrent diseases. Medications that could confound the evaluation of the study treatments or treatment strategies were prohibited before and throughout the study, including inhaled (up to 250 mcg fluticasone propionate allowed prior to randomisation), oral, or parenteral corticosteroids (with the exception of protocol defined use of oral corticosteroids following second consecutive assignment to the highest dose of fluticasone propionate/salmeterol), theophylline or other bronchodilators, leukotriene modifiers, anticholinergics, cromolyn, and nedocromil.

Interventions
  1. Fluticasone propionate/salmeterol 100/50, 250/50 or 500/50 mcg BD (BHR strategy)

  2. Fluticasone propionate 100, 250 or 500 mcg (BHR strategy)

  3. Fluticasone propionate 100, 250 or 500 mcg (Reference strategy) - data were not used from this arm

Delivery was Diskus device

Outcomes

Primary efficacy variable was the average inhaled corticosteroid treatment dose over the treatment period.

Paper reports "There were no non-fatal serious adverse events in any treatment group that were considered to be drug related. One patient in the fluticasone propionateBHR treatment group died due to convulsions and cardiac arrest following deep vein thrombosis."

Web report indicates one patient with SAE related to asthma on fluticasone propionate/salmeterolBHR and one patient with ear infection and sinusitis on fluticasone propionateBHR.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk321/466 (69%) completed the study
Selective reporting (reporting bias)Low riskFull data on GlaxoSmithKline website

Koopmans 2006

Methods

A randomised, double-blind, single-centre, parallel-group study over 12 months from September 2000 to December 2003 in the Netherlands. Run-in 4 weeks.

A study to compare the long-term effects on airway inflammation of Seretide versus Flixotide in adult subjects with asthma

Participants

Population: 54 adults (19 to 59) with mild to moderate persistent allergic asthma. 

Baseline Characteristics: Mean age 32 years. FEV1 89% predicted. Concomitant ICS used by 100% of participants (Median dose 600 mcg/day).  

Inclusion Criteria: Aged between 18 and 50 years with reversible airways obstruction, informed consent, allergic to house dust mite, PC20 histamine < 8 mg/mL, FEV1 greater than 70% predicted.  

Exclusion Criteria: serious concurrent disease likely to interfere with the study, lower respiratory tract infection, or use of antibiotics in the previous 4 weeks.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone propionate 250 mcg BD

Delivery was Diskus device

OutcomesThe primary efficacy variables were the percentage of eosinophils and eosinophil cationic protein (ECP) in induced sputum (baseline and after allergen challenge) at randomisation and 1, 3 6, 9 and 11 months later.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk50/54 (93%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

Li 2010

Methods

A randomised, double-blind, double-dummy, 12 week parallel-group study evaluating the safety of fluticasone propionate/salmeterol 100/50 mcg HFA (2 inhalations of 50/25 mcg) twice daily compared with fluticasone propionate 100 mcg HFA (2 inhalations of 50 mcg) twice daily in subjects 4-11 years of age with persistent asthma. Ran from February 2007 to February 2008.

25 centers in North America, 13 centers in Latin America , and 18 centers in Europe.

Participants

Population: 350 children (age 4 to 11 years) with persistent asthma who were symptomatic on an ICS.

Baseline characteristics: 22% were aged 4 to 5 years and 78% 6 to 11 years. Spacers were used by 78% of children at baseline.

Inclusion criteria: Male and female subjects 4 to 11 years of age diagnosed with asthma requiring ICS for control of asthma symptoms for at least 1 month prior to screening. Subjects 6 to 11 years of age were required to have an FEV1 ≥ 60% of predicted value and subjects 4 and 5 years of age were required to have a clinic AM PEF ≥ 60% of predicted value at the screening visit. Subjects also had to demonstrate reversibility ≥ 12% over baseline to albuterol or have historical documentation of ≥ 12% reversibility within 24 months prior to the screening visit.

Exclusion criteria: life-threatening asthma or hospitalised for asthma ≥ twice in the past year.

Interventions

1. Fluticasone propionate/salmeterol 100/50 mcg HFA (administered as 2 inhalations of 50/25 mcg ex-valve strength via HFA MDI), twice daily

2. Fluticasone propionate 100 mcg HFA ex-valve strength, HFA (administered as 2 inhalations ex-valve strength of 50 mcg via HFA MDI), twice daily

Delivery was via MDI (with spacer if inhalation technique was not well coordinated).

OutcomesAdverse events and serious adverse events on treatment. There were no fatal events, and 1 patient on fluticasone propionate/salmeterol had a head injury occurring after a fall (reported on the GSK website 25 Sept 2008, study ID SFA106484, but not found in the paper publication).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind, double dummy"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk93% completed
Selective reporting (reporting bias)Low riskData on GSK website

Lundback 2006

Methods

A randomised, double-blind, parallel-group study over 12 months from August 1997 to December 2002 in Sweden. Run-in 2 months.

An interventional 3 year study for asthma control - In what way and in what kind of population is it possible to get asthmatic patients free from symptoms, keep the patients in work, restore a normal lung function, diminish hyperreactivity and normalise quality of life?

Participants

Population: 282 adults (18 to 70) with mild to moderate persistent asthma. 

Baseline Characteristics: Mean age 40 years. FEV1 93% predicted. Concomitant ICS used by 68% of participants. 

Inclusion Criteria: Clinically representative mild to moderate asthma, symptoms, or use of rescue medication at least twice a week, required to have airway hyperreactivity (AHR) demonstrated by methacholine challenge with a PC20 (the concentration required to provoke a 20% reduction in FEV1) < 8 mg/mL. If AHR was not demonstrated via methacholine challenge then one of the following: diurnal variability in PEF of at least 20% on > 3 days during the last 14 days of the run-in; at least 30% difference between the highest and lowest PEF reading during any 7 days in the run-in period; or an increase of at least 15% in FEV1 or PEF after salbutamol inhalation (0.8 mg). 

Exclusion Criteria: taking daily doses of ICS greater than 1200 mcg, had experienced one or more life-threatening exacerbation requiring hospitalisation during the previous 12 months, were hypersensitive to beta-agonists or ICS, were pregnant or lactating or had a respiratory tract infection during the 4 weeks prior to run-in.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone propionate 250 mcg BD

  3. Salmeterol 50 mcg BD

Delivery was Diskus device (arm three was not used in this review).

OutcomesThe primary efficacy variable was the requirement for an increased dose of study medication.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk263/282 (93%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

Malone 2005

MethodsA randomised, double-blind, active-controlled, multicenter, parallel-group study over 12 weeks from April 2002 to January 2003 at 79 centres (66 in the USA and 13 in Canada). Run-in 2 weeks. 
Participants

Population: 203 children (4 to 11) years with persistent asthma.

Baseline Characteristics: Mean age 8 years. FEV1 mean 80% predicted. (6-11 years) PEF mean 87% predicted. (4-5 years).

Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 4-11 years of age diagnosed with asthma (ATS definition), who required physician-prescribed treatment for at least 2 months and taking an inhaled corticosteroid for asthma for at least one month prior to visit 1.

FEV1 % predicted between 50% to 95% (6-11 years), am PEF % predicted between 50% to 95% (4-5 years). Bronchodilator reversibility by an increase of at least 12%  in FEV1 (6-11 years) or am PEF (4-5 years) over baseline within 30 minutes of 2-4 actuations of albuterol (180-360 mcg) or to have historical documentation of 12% or greater reversibility within the previous year. 

Exclusion Criteria: History of life-threatening asthma,  hospitalisation due to asthma twice or more in the previous year, significant concurrent disease (e.g. cystic fibrosis, malignancy or immunologic compromise), recent upper or lower respiratory tract infection, current chickenpox or recent exposure to chickenpox in a nonimmune patient, severe milk protein allergy, hypersensitivity to beta2-agonist, sympathomimetic or corticosteroid therapy, clinically significant abnormal laboratory test results.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

Delivery was Diskus device.

Outcomes

This was a safety study and no primary efficacy endpoint was identified.

No SAE occurred in this study.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk168/203 (83%) completed the study
Selective reporting (reporting bias)Low riskFull data on GSK website

Murray 2004

MethodsA randomised, double-blind, active-controlled, multicenter, parallel-group study over 12 weeks from November 1999 to September 2000 at 33 centres in the USA. Run-in 2 weeks, single blind placebo.
Participants

Population: 267 adolescents and adults (12 to 73) years with persistent asthma. 

Baseline Characteristics: Mean age 34 years. FEV1 66% predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: 12 years or older with a 6 month history of asthma and must have been treated with as-needed, short-acting, inhaled beta2-agonists alone during the previous month with no oral or inhaled corticosteroid use within 1 month or long-acting beta-agonist within 72 hours of study entry.

FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 30 minutes of inhalation of 2 puffs (180 mcg) of albuterol. 

Exclusion Criteria: Pregnancy and/or lactation, life-threatening asthma, hospitalisation attributable to asthma twice or more in the last year, current smoker or a more than 10 pack-year history of smoking, significant concurrent diseases including a recent upper or lower respiratory tract infection. Medications prohibited before and throughout the study included inhaled, oral or parenteral corticosteroids, theophylline or other bronchodilators, anticholinergics, leukotriene modifiers, cromolyn and nedocromil.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

Delivery Diskus

OutcomesTwo primary efficacy variables were defined: (1) mean change from baseline in AM predose FEV1 at endpoint for fluticasone propionate/salmeterol 100/50 compared to salmeterol 50, (2) area under the serial FEV1curve at treatment week 12 relative to treatment day 1 baseline for fluticasone propionate/salmeterol 100/50 compared to fluticasone propionate 100.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTreatment assignments were generated in blocks of 6 by a computer-based random codes system
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk228/267 (85%) completed the study
Selective reporting (reporting bias)Low riskFull data on GSK website

Nathan 2006

MethodsParallel group multicentre study over 12 weeks.
Participants365 adults and adolescents randomised. Age range: 12 to 82 years, mean FEV1 68% predicted. Inclusion criteria: Fluticasone propionate 440-660 mcg/d for at least 3 months prior to study entry; FEV1 40-85%; reversibility >=15%
InterventionsCombination HFA fluticasone propionate/salmeterol 110/42 BID (220/84) versus CFC salmeterol 42 BID (84) versus CFC fluticasone 110 BID (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.
OutcomesThe paper publication mentions one drug-related SAE (an upper gastrointestinal bleed from the placebo group).
Website: SAS30004. No fatal SAE. No SAE on fluticasone propionate/salmeterol or fluticasone propionate.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk243/365 (67%) completed the study, no SAE events occurred
Selective reporting (reporting bias)Low riskFull data on GSK website

NCT01192178

MethodsRandomized, double-blind, 16 week parallel-group study in paediatric subjects from 02 August 2010-16 December 2010 at 39 centers in the USA.
Participants

Population: 339 children (age 4 to 11 years) with persistent asthma who were symptomatic on an inhaled corticosteroid (ICS).

Baseline characteristics: 22% were aged 4 to 5 years and 78% 6 to 11 years. Spacers were used by 78% of children at baseline.

Inclusion criteria: Male and female subjects 4 to 11 years of age diagnosed with asthma requiring an ICS for control of asthma. Subjects were required to have an AM PEF ≥ 70% of predicted value at the screening visit. Subjects also had to have a history of at least 1 exacerbation of asthma during the previous respiratory viral season, that required the use of out-patient systemic corticosteroids or an urgent-care visit, emergency room visit, or hospitalisation.

Exclusion criteria: life-threatening asthma, unstable asthma, evidence of concurrent respiratory disease, history of any upper or lower respiratory tract infection within 4 weeks of randomisation that required the use of an antibiotic or accompanied by worsening asthma, or other clinically significant medical conditions.

Interventions

1, Fluticasone propionate/salmeterol Diskus 100/50 mcg, one inhalation twice daily

2. Fluticasone propionate Diskus 100 mcg, one inhalation twice daily, for 16 weeks.

OutcomesPrimary outcome: number of exacerbations of asthma during the double blind period. There were no deaths and two children suffered SAEs on fluticasone propionate/salmeterol (one was status asthmaticus) and on child suffered an SAE (syncope) on fluticasone propionate.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk86% completed treatment in both groups
Selective reporting (reporting bias)Low riskFull data on GSK website

Nelson 2003

MethodsRandomized, double-blind, active-controlled, parallel-group study over 12 weeks at 33 centres in the USA. Run-in 2 weeks, (run-in was single blind placebo).
Participants

Population: 283 adolescents and adults  (12 to 77) years with asthma.  

Baseline Characteristics: Mean age 32 years. FEV1 66% predicted.

Concomitant ICS used by 0% of participants. 

Inclusion Criteria: At least 12 years old and a medical history of asthma (as defined by the ATS) requiring asthma pharmacotherapy for at least 6 months, FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline within 30 minutes after 2 inhalations of inhaled albuterol (180 mcg)  

Exclusion Criteria: History of life-threatening asthma; hypersensitivity reaction to sympathomimetic drugs or corticosteroids; smoking within the previous year or a history of > 10 pack-years; use of oral, inhaled or injectable corticosteroid therapy within the previous month; use of intranasal corticosteroid therapy except for Flonase (GlaxoWellcome Inc.); use of daily oral corticosteroid treatment within the previous 6 months; use of any other prescription or over-the-counter medication that could have affected the course of asthma or interacted with sympathomimetic amines; abnormal chest x-ray films; clinically significant abnormal 12-lead electrocardiograms (ECGs); or a history of significant concurrent disease (e.g., glaucoma, diabetes, hypertension).

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg HFA BD

  2. Fluticasone propionate 100 mcg CFC BD

  3. Salmeterol 502 mcg CFC BD (not considered in this review)

Delivery was MDI.

Outcomes

Primary efficacy measures were area under the serial FEV1 curve for 12 hours following administration of study medication and change from baseline at endpoint in morning pre-dose  FEV1.

The paper reports "no serious drug related adverse events".

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk257/283 (91%) completed the study
Selective reporting (reporting bias)Low riskFull data on GSK website

Pearlman 2004

MethodsRandomized, double-blind, active-controlled, parallel-group study over 12 weeks at 36 centers in the US and 1 center in Puerto Rico.
Participants

N = 360. Fluticasone propionate/salmeterol arm N = 92, fluticasone propionate arm N = 89.
Population: Males and females 12 years of age or older, with a diagnosis of asthma using the ATS definition were screened. All subjects were required to have a FEV1 of 40% to 85% predicted normal and > 15% reversibility following 2 puffs of ventolin at screening. The study population was stratified according to whether or not subjects were treated with ICS or inhaled beta2-agonists at screening (salmeterol or short-acting beta2-agonists only). Subjects treated with ICS must have been treated for at least 3 months prior to Visit 1 and receiving a daily dose of: 252-336 mcg beclomethasone dipropionate, 600-800 mcg triamcinolone acetonide, 1000 mcg flunisolide, 400-600 mcg budesonide, 176 mcg fluticasone propionate inhalation aerosol or 200 mcg fluticasone propionate inhalation powder for at least one month prior to Visit 1 with no change in regimen. Eligible subjects using only, as-needed, short-acting beta-agonist therapy were required to have received treatment for at least 1 week prior to Visit 1 and have a 7 day total symptom score >7 for the 7 days prior to Visit 2. Eligible subjects using salmeterol at baseline were required to have received salmeterol and as-needed, short-acting beta2-agonists only for at least one week prior to Visit 1.

No details on distribution between the groups provided. Participants described as symptomatic. Baseline medication: prn SABA alone: 142; salmeterol: 84; ICS: 134 (37%).

Interventions

1. Fluticasone propionate/salmeterol 100/50 mcg BD

2. Fluticasone 100 mcg BD

The other arms were not used for this review.

OutcomesPaper reports no serious drug-related adverse events.
Website: SAS3003. No fatal SAE in the fluticasone propionate/salmeterol or fluticasone propionate group. One tachyarrhythmia on fluticasone propionate.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk279/360 (77%) completed study
Selective reporting (reporting bias)Low riskData on GSK website

Renzi 2010

MethodsA 24 week, multicentre, randomised, double-blind, parallel group trial to compare the efficacy and tolerability of salmeterol/fluticasone propionate (ADVAIR®) Diskus inhalation device 50/100 mcg bid with fluticasone propionate Diskus inhalation device 100 mcg bid as initial maintenance treatment in adult and adolescent subjects with symptomatic, persistent asthma not controlled on short-acting bronchodilators alone.
Participants

Population: 532 adults and adolescents (12+) years with a documented history of asthma treated with SABA only.

Inclusion Criteria: Male and female patients aged > 12 years with a documented history of asthma treated with SABA only and with FEV1 > 80% predicted were eligible for recruitment to the 2-week run-in period. They were recruited to the trial if they were symptomatic for the last 7 days of run-in on SABA alone.

Exclusion Criteria: Key exclusion criteria were the use of asthma controller

medications in the previous month or systemic corticosteroids in the previous 12 weeks; exacerbation requiring either emergency room treatment in the previous 6 weeks or hospitalisation in the previous 12 weeks; and smoking history of > 10 pack years.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone 100 mcg  BD

Delivery device Diskus

OutcomesChange in morning PEF over 24 weeks. SAE fully reported in paper and GSK web report (SAS40068).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double blind"
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk53/262 lost to follow-up on fluticasone propionate/salmeterol and 46/270 on fluticasone propionate (Withdrawn due to adverse events 6 and 11 respectively)
Selective reporting (reporting bias)Low riskSAE fully reported in paper and GSK web report (SAS40068)

Rojas 2007

MethodsA randomised, double-blind, multicenter, parallel-group study over 12 weeks from February 2003 to September 2003 at 48 centres worldwide (Argentina (4), Czech Republic (8), France(9), Israel (4), Italy (9), Poland(4), Slovakia (6), Turkey (4)). Run-in 2 weeks.
Participants

Population: 362 adolescents and adults (12to 78) years with moderate persistent asthma.

Baseline Characteristics: Mean age 41 years. FEV1 72% predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria:12 to 80 years with a documented clinical history of persistent asthma for at least 6 months and currently receiving inhaled short-acting beta2-agonists alone. FEV1 % predicted between 60% and 80%, bronchodilator reversibility by an increase of at least 15%  in FEV1 over baseline after 400 mcg salbutamol, or a mean morning PEF during the last 7 days of the run-in of less than 85% of the post-bronchodilator value, and a daytime symptom score of at least 2 on at least 4 of the last 7 days of the run-in.

Exclusion Criteria: Taken corticosteroids within 12 weeks, leukotriene receptor antagonists within 4 weeks or long acting inhaled or oral beta2-agonists, sodium cromoglycate, nedocromil sodium, ketotifen, methylxanthines, or inhaled anticholinergics within 2 weeks of entering the study, or had an acute asthma exacerbation requiring hospital treatment within 6 weeks, or had a respiratory tract infection within 4 weeks of entering the study, or a smoking history of more than10 pack-years.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone propionate 250 mcg BD

Delivery was Diskus inhaler

Outcomes

Primary efficacy variable was mean morning PEF.

Paper reports: "Only three serious adverse events occurred and none were considered related to study treatment."

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk350/362 (97%) completed the study
Selective reporting (reporting bias)Low riskFull data on GSK website

SAM30007

Methods

A randomised, double-blind, multi centre, parallel-group study over 30 weeks from September 2000 to May 2002 at 5 centres in Denmark. Run-in 2 weeks.

A comparative investigation of the corticosteroid-saving potential of the combination therapy fluticasone propionate and salmeterol (SERETIDE) compared with fluticasone propionate alone, given to adult asthmatic subjects, when reducing the inhaled corticosteroid dose from an initially high level of 500 mcg bd.

Participants

Population: 61 adults (18 + ) with stable asthma.  

Baseline Characteristics: Mean age 37 years. FEV1 not reported % predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: At least18 years old with a clinical diagnosis of stable asthma, treated with 1500-2000 mcg of budesonide, beclomethasone dipropionate or flunisolide, or 750 to 1000 mcg of fluticasone propionate for at least 10 weeks prior to the study. FEV1 % predicted at least 60%, need to  be able to use the data capture method (electronic diary, AM-2) correctly. 

Exclusion Criteria: not reported

Interventions
  1. Fluticasone propionate/salmeterol 500/50, 250/50 or 100/50 mcg BD

  2. Fluticasone propionate 500, 250 or 100 mcg BD

OutcomesThe primary efficacy endpoint was the minimum dose at which the subject’s asthma remained controlled ? the minimum acceptable dose (MAD).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk55/61 (90%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAM40004

MethodsA multicentre, randomised, double-blind, placebo-controlled parallel group study to compare the effect on airway inflammation and remodelling of treatment with salmeterol/fluticasone propionate combination product (50/100 mcg strength) bd via the Accuhaler inhaler, or fluticasone propionate 100 mcg bd via the Accuhaler inhaler or placebo via the Accuhaler inhaler for 16 weeks, followed by double-blind treatment for 52 weeks with the salmeterol/fluticasone propionate combination product (50/100 mcg strength) bd via the Accuhaler inhaler or fluticasone propionate 100 mcg bd via the Accuhaler inhaler, in adults with reversible airways obstruction (SIRIAS - Seretide in Inflammation and Remodelling In Asthma Study).
Participants

Population: 63 adults (18 to 50) with mild asthma. 

Baseline Characteristics: Mean age 32 years. FEV1 unknown % predicted. Concomitant ICS used by unknown % of participants, but all withdrawn during the run-in period.  

Inclusion Criteria: Aged 18 to 50 years with a history of reversible airways obstruction, to have received short-acting beta2- agonist alone or Beclometasone dipropionate or budesonide at a constant daily dose of up to 400 mcg per day (excluding any CFC-free formulation) or fluticasone propionate at a constant daily dose of up to 200 mcg per day via any device for at least 4 weeks prior to the first visit. In addition subjects were to have had a fall in FEV1 of at least 20% with a histamine challenge test at the first visit and have a post-bronchodilator FEV1 of > 60% of predicted normal. To be randomised subjects had to have a fall in FEV1 of at least 20% with a standardised histamine challenge test, AND at least one of the following criteria: have recorded symptoms on at least 4 of the last 7 days of the preventer-free run-in period; have recorded using their inhaled short-acting beta2 -agonist on at least 2 occasions on at least 4 of the last 7 days of the preventer-free run-in period; have a period variation of at least 10% over the last 7 days of the preventer-free run-in period. 

Exclusion Criteria: not reported.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD throughout

  2. Placebo initially and then fluticasone propionate/salmeterol 100/50 mcg BD

  3. Fluticasone propionate 100 mcg BD throughout

Delivery as DPI.

Outcomes

Outcome: The primary efficacy endpoint was the  level of airway hyper-reactivity (as measured by histamine PC20) and response of the induced airway spasm to bronchodilator (post-bronchodilator FEV1)

SAE data were used for the 52 week extension period as reported. There were no SAEs reported in the 16 week initial period.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
High risk37/63 (59%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAM40008

Methods

A multicentre, randomised, double-blind, parallel group comparison of the efficacy of SERETIDE* bd and fluticasone propionate bd (Both Via Diskus*/ACCUHALER*, Inhaler) when tapering the inhaled corticosteroid dose in asthmatic adults.

Carried out over 26 weeks from May 2000 to July 2001 at 34 centres in 10 countries (Australia, Estonia, Finland, France, Germany, Israel, Latvia, New Zealand, Spain, the United Kingdom)

Participants

Population: 186 adults (18+) with persistent asthma. 

Baseline Characteristics: Mean age 50 years.  FEV1 unknown % predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: 18 years or older with documented evidence of asthma within the previous 2 years and who were receiving 1500 to 2000 mcg/day of BUD or equivalent ICS, excluding fluticasone propionate, for at least 3 months prior to the start of baseline. 

Exclusion Criteria: not reported

Interventions
  1. Fluticasone propionate/salmeterol 500/50 mcg BD

  2. Fluticasone propionate 500 mcg BD

Delivery as DPI.

OutcomesThe primary efficacy endpoint was the minimum acceptable daily dose of ICS.
NotesHigh drop-out rate. Only 8% completed the study.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
High riskonly 14/186 (8%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAM40012

Methods

A  randomised, double-blind, double-dummy, multi centre, parallel-group study over 24 weeks from June 2000 to June 2001 at 38 centres in 7 countries (Bulgaria, Hungary, Israel, Poland, Russia, Spain, the United Kingdom). Run-in 2 weeks.

A comparison of three treatments : 1) salmeterol/fluticasone propionate (SFC) (50/100 mcg strength) bd via Diskus/ACCUHALER inhaler, 2) fluticasone propionate 200 mcg bd via Diskus/ACCUHALER inhaler, 3) fluticasone propionate 100 mcg bd via Diskus/ACCUHALER inhaler in children aged 4-11 years with asthma.

Participants

Population: 548 children (4 to 11) with asthma.

Baseline Characteristics: Mean age 8 years.  FEV1 not reported % predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: Aged 4-11 years, inclusive, with documented evidence of asthma and receiving BDP, BUD or equivalent at a dose of 400-500 mcg/day or fluticasone propionate at a dose of 200-250 mcg/day for at least 4 weeks before Visit 1. Recorded a symptom score (i.e. total score of daytime and night-time scores) on the electronic daily record card of at least 2 on at least 3 of the last 7 consecutive days of the run-in period and had a mean morning PEF (calculated from the last 7 days of the run-in period) of between 50% and 85% of the PEF measured 15 minutes after administration of 400 mcg of salbutamol at the randomisation visit. In addition, subjects had to have recorded at least 70% of data into their electronic daily record cards. 

Exclusion Criteria: not reported.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

  3. Fluticasone propionate 200 mcg BD

Delivery was Diskus device (third arm not used in this review)

OutcomesThe primary efficacy endpoint was the percentage of combined symptom-free days and nights during weeks 1-24.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk513/548 (94%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAM40031

Methods

A one year, randomised, double-blind, parallel-group comparison of the efficacy of Seretide (fluticasone propionate/salmeterol combination Accuhaler) and Flixotide(fluticasone propionate Accuhaler) when down-titrating the inhaled corticosteroid dose in asthmatic adults who have previously received Seretide 500/50 mcg twice daily for at least 4 weeks

A study over 52 weeks from March 2002 to February 2006 at 3 centres in Australia.

Participants

Population: 82 adolescents and adults (18 to 80) with asthma. 

Baseline Characteristics: Mean age 47 years. FEV1 unknown % predicted. Concomitant ICS used by 100% of participants. 

Inclusion Criteria: Aged between 18 and 80 years with a clinical diagnosis of asthma according to ATS criteria for at least 6 months prior to enrolment, currently receiving fluticasone propionate/salmeterol, either via dry powder inhaler or metered dose inhaler (with or without spacer) at a dose of 500/50 mcg bd or 250/25mc 2 inhalations bd for a minimum of 4 weeks prior to enrolment. 

Exclusion Criteria: not reported

Interventions
  1. Fluticasone propionate/salmeterol 500/50, 250/50 or 100/50 mcg BD (Reduced incrementally)

  2. Fluticasone propionate 500, 250 or 100 mcg BD (Reduced incrementally)

Delivery was DPI.

OutcomesThe primary efficacy endpoint was the average daily fluticasone propionate dose (mcg/day) from week 0 to completion/withdrawal, including study medication and exacerbation medication.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk60/82 (73%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAM40065

Methods

A randomised, double-blind, double-dummy, multicentre, parallel-group study for 40 weeks from January 2003 to October 2004 at 44 centres (United States (39), Brazil (3), Bulgaria (2)). Run-in 2 weeks.

A comparison of asthma control using bronchial hyper responsiveness as an additional guide to long-term treatment in adolescents and adults receiving either fluticasone propionate/salmeterol Diskus BID or fluticasone propionate Diskus BID (or placebo BID if asymptomatic).

Participants

Population: 449 adults (12 + years) with asthma. 

Baseline Characteristics: Mean age 34 years. FEV1 not reported % predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 12 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 3 months prior to visit 1 and must have been treated with a short-acting beta2-agonist, an anticholinergic, or an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks prior to the screening visit. FEV1 % predicted between 60% to 95%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline within 30 minutes following 2 puffs of albuterol inhalation aerosol at the screening visit.  Documentation of historical reversibility within 24 months was allowed. 

Exclusion Criteria: History of life-threatening asthma, current unstable asthma, current respiratory tract infection or clinically significant concurrent disease that would put the subject at risk during the study if the condition exacerbated.

Interventions
  1. Fluticasone propionate/salmeterol 100/50, 250/50 or 500/50 mcg BD

  2. Fluticasone propionate 100, 250 or 500 mcg BD (BHR strategy)

  3. Fluticasone propionate 100, 250 or 500 mcg  BD (Reference strategy)

Delivery was Diskus device (third arm not used in this review)

OutcomesThe primary efficacy endpoint was the average ICS treatment dose over the treatment period.
NotesSAE data included run-in.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk322/449 (72%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAS30021

Methods

A stratified, randomised, double-blind, placebo-controlled, parallel-group study for 12 weeks from November 2001 to February 2004 at 164 centres (United States (153), Latin America(11))

A Stratified, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 12-Week Trial Evaluating the Safety and Efficacy of the Fluticasone Propionate/salmeterol Diskus Combination Product 100/50 mcg Once Daily Versus Fluticasone Propionate Diskus 100 mcg Once Daily and Placebo in Symptomatic Pediatric Subjects (4-11 Years) With Asthma

Participants

Population: 908 children(4 to 11) with asthma. 

Baseline Characteristics: Mean age 8 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: 4-11yrs of age with a diagnosis of asthma for at least 6 months and treated with short-acting beta2-agonists only or non-ICS controller medications for at least one month prior to screening. FEV1 % predicted between 50% to 85%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 30 minutes following 2 puffs of albuterol at screening. At the randomisation visit, subjects were required to demonstrate AM PEF reproducibility of +15% of the screening visit pre-albuterol PEF, demonstrate a PM PEF 50 to 90% of predicted normal, and have either an asthma symptom score of at least 2 on 4 or more days in the week prior to randomisation, or have used albuterol on at least 4 days in the week prior to randomisation.

Exclusion Criteria: Not reported

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg QD

  2. Fluticasone propionate 100 mcg QD

Delivery was Diskus device

OutcomesThe primary efficacy endpoint was the change from Baseline in % predicted PM Peak Expiratory Flow (PEF) over Weeks 1-12
NotesOnce daily dose
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk715/908 (79%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAS30022

Methods

A randomised, double-blind, placebo-controlled, parallel-group study for 12 weeks from November 2001 to June 2003 at 121 centres. (US (103), Canada (18)).

A trial evaluating the efficacy and safety of the fluticasone propionate/salmeterol Diskus combination product 250/50 mcg once daily versus fluticasone propionate/salmeterol Diskus combination product 100/50 mcg twice daily versus fluticasone propionate Diskus 250 mcg once daily versus placebo in symptomatic adolescent and adult subjects with asthma that is not controlled on short acting beta2-agonists alone

Participants

Population: 844 adolescents and adults (12 + years ) with asthma that was not controlled on short-acting beta2-agonists alone. 

Baseline Characteristics: Mean age 33 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants.

Inclusion Criteria: 12 years of age or older with a diagnosis of asthma for at least 3 months and treated with short-acting beta2-agonists only for at least 1 month prior to screening. FEV1 % predicted between 50% to 85%, bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline within 30 minutes following 2 puffs of albuterol at screening.

At the randomisation visit, subjects were required to demonstrate FEV1 reproducibility of ±15% of the screening visit pre-ventolin FEV1, demonstrate a PM PEF 50 to 90% of predicted normal, and have either an asthma symptom score of at least 2 on 4 or more days in the week prior to randomisation, or have used ventolin on at least 4 days in the week prior to randomisation. 

Exclusion Criteria: not reported

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg QD

  2. Fluticasone propionate/salmeterol 100/50 mcg BD

  3. Fluticasone propionate 250 mcg QD

(Second arm not used in this review)

OutcomesPrimary outcome/efficacy variable was the change from baseline in % predicted PM PEF over weeks 1 to 12.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk698/844 (83%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAS30023

Methods

A randomised, double-blind, multicentre, placebo-controlled, parallel-group study over 12 weeks from April 2002 to April 2003 at 69 centres in 9 countries (Australia, France, UK, Hungary, Ukraine, Italy, Philippines, Thailand, Russia).

A study to compare the efficacy and tolerability of fluticasone propionate/salmeterol combination (SERETIDE/VIANI/ADVAIR) 88/42 mcg once daily in the morning with fluticasone propionate 88 mcg once daily in the morning and placebo (short-acting beta2-agonist as required only) once daily in the morning, all via the HFA MDI as initial maintenance therapy in mild asthmatic subjects.

Participants

Population: 464 adolescents and adults (12 to 80) with mild asthma. 

Baseline Characteristics: Mean age 34 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants. 

Inclusion Criteria: a documented clinical history of asthma for at least 6 months who were currently receiving short-acting beta2-agonists alone.

Exclusion Criteria: Not reported.

Interventions
  1. Fluticasone propionate/salmeterol 50/25 mcg two puffs once daily

  2. Fluticasone propionate 50 mcg two puffs once daily

Delivery was MDI device with HFA propellant.

OutcomesThe primary efficacy endpoint was the morning PEF.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk433/464 (93%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAS40036

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study for 16 weeks from October 2001 to May 2003 at 85 centres in the United States. Run-in 2 weeks.
Participants

Population: 331 adolescents and adults(15+ years old) with persistent asthma.

Baseline Characteristics: Mean age 41 years. FEV1 not reported (% predicted). Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 15 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 6 months prior to visit 1 and must have been treated with an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least four weeks prior to the screening visit. FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline within 30 minutes following 2 to 4 puffs of albuterol inhalation aerosol at the screening visit. Documentation of historical reversibility within 24 months was allowed. 

Exclusion Criteria: Not reported 

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

Delivery was Diskus device (other arms of trial not considered for this review)

OutcomesThe primary efficacy endpoint was the mean change from baseline at endpoint in morning PEF
NotesNo SAEs at all reported in double blind phase of the study.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk243/331 (73%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAS40037

MethodsA randomised, double-blind, double-dummy, multicenter, parallel-group study for 16 weeks from October 2001 to May 2003 at 87 centres in the United States. Run-in 2 weeks.
Participants

Population: 331 adolescents and adults (15+ years old) with persistent asthma.

Baseline Characteristics: Mean age 41 years. FEV1 not reported (% predicted). Concomitant ICS used by 100% of participants.  

Inclusion Criteria: 15 years of age or older, with a diagnosis of asthma, as defined by the ATS, for at least 6 months prior to visit 1 and must have been treated with an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks prior to the screening visit. FEV1 % predicted between 40% to 85%, bronchodilator reversibility by an increase of at least 12% in FEV1 over baseline within 30 minutes following 2 to 4 puffs of albuterol inhalation aerosol at the screening visit. Documentation of historical reversibility within 24 months was allowed. 

Exclusion Criteria: Diagnosed with life-threatening asthma, hospitalised for asthma within the previous 6 months, had a concurrent respiratory disease, or had intermittent or seasonal asthma alone, had a respiratory tract infection or used antibiotics for the treatment of a suspected or diagnosed respiratory tract infection within 14 days of visit 1.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

Delivery was Diskus device (other arms of trial not considered for this review)

OutcomesThe primary efficacy endpoint was the mean change from baseline at endpoint in morning PEF.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk230/322 (71%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SAS40068

Methods

A randomised, double-blind, multicenter, parallel-group study for 24 weeks from October 2002 to February 2004 at 58 centres in Canada.

A trial to compare the efficacy and tolerability of salmeterol/fluticasone propionate (ADVAIR) Diskus inhalation device 50/100 mcg bid with fluticasone propionate Diskus inhalation device 100 mcg bid as initial maintenance treatment in adult and adolescent subjects with symptomatic, persistent asthma not controlled on short-acting bronchodilators alone.

Participants

Population: 532 adolescents and adults(12+ years ) with symptomatic, persistent asthma. 

Baseline Characteristics: Mean age 35 years. FEV1 not reported % predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: 12 years of age or older with symptomatic, persistent mild asthma (defined as FEV1 at least 80% predicted and over the last 7 consecutive days of run-in, had an asthma symptom score of 2, or more on at least 3 days or disruptions of normal sleep patterns on 2 or more occasions, or had used rescue bronchodilator medication on 4 or more days), and treated with inhaled short-acting bronchodilators alone 

Exclusion Criteria: Taken any other asthma therapy (e.g. ICS, leukotriene modifiers, inhaled long-acting beta2-agonists) within 1 month prior to screening, had a smoking history of 10 pack-years or more, or had an acute asthma exacerbation requiring emergency room treatment within the last 6 weeks or hospitalisation within the last 12 weeks prior to screening.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate100 mcg BD

Delivery was Diskus device

Outcomes

The primary efficacy endpoint was the change from baseline in daily record card (DRC) mean morning PEF over 24 weeks.

One death due to aorta hypoplasia and ventricular hypertrophy on fluticasone.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk433/532 (81%) completed the study
Selective reporting (reporting bias)Low riskData in GSK website

SFA103153

MethodsA randomised, double-blind,multicenter, parallel-group study for 52 weeks from November 2004 to April 2007 at 59 centres in the United States. Run-in 4 weeks.
Participants

Population: 475 adolescents and adults(12 to 65) of African descent with persistent asthma. 

Baseline Characteristics: Mean age 32 years. FEV1 78% predicted. Concomitant ICS used by 100% of participants.  

Inclusion Criteria: Subjects were of African descent, 12 to 65 years of age with persistent asthma, and were symptomatic while taking an ICS.

Exclusion Criteria: Not reported. 

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

Delivery was Diskus device

OutcomesThe primary efficacy endpoint was asthma exacerbation rate per subject per year.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk320/475 (67%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

SFCF4026

Methods

A randomised, double-blind, multicenter, parallel-group study for 24 weeks from May 2002 to November 2003 at 124 centres in France. Run-in 8 weeks.

Maintenance of asthma control in adults: comparison of three therapeutic strategies in patients whose asthma is controlled by a medium dose of inhaled corticosteroid and a long-acting inhaled beta2-agonist.

Participants

Population: 476 adolescents and adults(18+ years) with asthma.

Baseline Characteristics: Mean age 45 years. FEV1 not reported % predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria: 18 years of age or older with a documented history of asthma (for at least 6 months) and whose asthma was controlled with the current treatment (inhaled corticosteroid at a dose of 1000 mcg of CFC beclomethasone dipropionate or equivalent and a long-acting beta2-agonist at recommended dose) at stable dose for at least 4 weeks prior to the run-in period. Randomized if fulfilled the following criteria: at least 2 of the following: diurnal symptoms at least 2 days per week, use of rescue short-acting bronchodilator no more than 2 days per week and no more than 4 occasions per week, PEF at least 80 % predicted every day. Plus all the following criteria: no night-time awakenings due to asthma, no exacerbations, no emergency visits, no treatment-related adverse events enforcing a change in asthma therapy. 

Exclusion Criteria: For entry in the run in period:smoking history of ten pack-years or more, respiratory tract infection during the last 4 weeks prior to visit 1 (the last 2 weeks after amendment number 1), acute asthma exacerbation requiring emergency room treatment or hospitalisation within 4 weeks prior to visit 1, use of oral/parenteral corticosteroids during the last 4 weeks prior to visit 1 or any change in maintenance treatment, use of depot corticosteroid within 12 weeks of visit 1. For entry into the treatment period: changes in asthma medication (excluding study rescue medication), use of oral/parenteral or depot corticosteroids, respiratory tract infection, insufficient asthma control, according to daily record card, asthma control questionnaire and investigator’s judgement to allow a reduction in maintenance treatment.

Interventions
  1. Fluticasone propionate/salmeterol 250/50 mcg BD

  2. Fluticasone propionate/salmeterol 100/50 mcg BD

  3. Fluticasone propionate 250 mcg BD

Delivery was Diskus device (arm two not used in this review)

OutcomesThe primary efficacy endpoint was the morning PEF over the first 12 weeks of the treatment period.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk413/476 (87%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

Shapiro 2000

MethodsMulticentre study, USA
Participants

349 adults and adolescents randomised (4 treatment arm study; fluticasone propionate/salmeterol: 84; fluticasone propionate: 84. Data from 13 participants excluded from the analysis due to poor procedure at one site).

Inclusion criteria: ≥ 12 years; ATS defined asthma of ≥ 6 months duration requiring pharmacotherapy for at least 6 months; FEV1 between 40 and 85% predicted; ≥ 15% increase in FEV1 30 mins 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 chest x-ray; clinically significant abnormal 12-lead electrocardiogram or history of concurrent disease.

Interventions

1. Fluticasone propionate/salmeterol 250/50 bd

2. Fluticasone 250 bd

Third arm not used in this review

Outcomes83% completed study in fluticasone propionate/salmeterol arm and 73% in fluticasone propionate 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 fluticasone propionate/salmeterol arm; one in fluticasone propionate arm (Asthma exacerbation).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk131/168 (78%) completed the study
Selective reporting (reporting bias)Low riskFull data on GSK website

SLGF75

Methods

A randomised, double-blind, multicenter, parallel-group study for 12 weeks from January 1998 to December 1998 at 7 centres in Italy. Run-in 4 weeks, follow-up 2 weeks.

Salmeterol plus low-dose fluticasone propionate versus high-dose fluticasone propionate in naive patients with mild to moderate asthma: effects on pulmonary function, and inflammatory markers of induced sputum

Participants

Population: 46 adolescents and adults(16 to 65 ) with mild to moderate asthma.

Baseline Characteristics: Mean age 39 years. FEV1 unreported % predicted. Concomitant ICS used by 0% of participants.  

Inclusion Criteria: performed on three study visits.

Pre-study visit: all subjects with asthma disease for at least 6 months, 

Visit 2: 16 to 65 years old with asthma at moderate level (score of severity at least 6), did not use anti-inflammatory drugs for last month before visit 1, FEV1 % predicted at least 60%, eosinophils at least 5% in induced sputum. 

Visit 4: bronchial asthma assessed up to 6 (severity classes value) and with persistence of eosinophils at least 5% (or at least 3% in sites where an amendment was applicable) in induced sputum.

Exclusion Criteria: Inhaled steroids or cromones in last 3 months, more than 1 short course of oral steroids in last 3 months or 1 short course of oral steroids in last month before pre-study visit; respiratory tract infection in the last 1 month pre-study visit, with lung or other important disease, or on beta-blocker therapy; hypersensitivity to beta2-agonist and suspected to abuse drug or alcohol.

Interventions
  1. Fluticasone propionate 100 + salmeterol 50 mcg BD

  2. Fluticasone propionate 100 mcg BD

  3. Fluticasone propionate 250 mcg BD

Delivery was Diskus (third arm not used in this review)

OutcomesThe primary efficacy endpoint was the daily morning PEF.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk42/46 (91%) completed the study
Selective reporting (reporting bias)Low riskData on GSK website

Strand 2004

MethodsA randomised, double-blind, comparative, multicenter, parallel-group study over 12 weeks from May 2001 to September 2002  at 45 centres in Denmark. Run-in 2 weeks.
Participants

Population: 150 adults with persistent asthma 

Baseline Characteristics: Mean age 39 years. PEF 80% predicted. Concomitant ICS used by 0% of participants. 

Inclusion Criteria: At least 18 years old and an asthma medical history of at least 3 months, either diurnal PEF variation ?20% on at least 2 days or one of the following must have been determined within 3 years prior to baseline: FEV1 reversibility ?15% in response to bronchodilator, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) less than 4 mg/mL, diurnal PEF variation at least 20%; mean relief medication (albuterol) use at least 1 episode/week; and day or night symptom score 1 or more at least once/week. 

Exclusion Criteria: Upper or lower respiratory tract infection or middle ear infection within 1 month prior to visit 1; other lung diseases than asthma; known or suspected other diseases or situations likely to affect the outcome of the study results;  known serious cardiovascular disease, diabetes mellitus, untreated hypokalaemia, or thyrotoxicosis; use of long-acting bronchodilators, ICS, or other long-acting asthma medication within 2 months prior to visit 1; use of daily oral corticosteroid treatment within 2 months of visit 1 or oral corticosteroid therapy within 1 month prior to visit.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 mcg BD

  2. Fluticasone propionate 100 mcg BD

Outcomes

The primary efficacy variable was symptom-free days and nights.

"1 patient in the fluticasone propionate/salmeterol group and 2 patients in the fluticasone propionate group had a serious adverse event. None of these serious adverse events was considered related to the study drug."

One death reported on the website in the fluticasone propionate/

arm but no cause given.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk126/150 completed study
Selective reporting (reporting bias)Low riskFull data from GSK website

van Noord 2001

MethodsA randomised, double-blind, double-dummy, multicenter, placebo-controlled, parallel-group study over 3 months from December 1997 to March 1999 at 61 centres in 13 countries. Run in 2 weeks.
Participants

Population: 509 adolescents and adults (12 to 82) years with moderate to severe asthma.

Baseline Characteristics: Mean age 47 years. FEV1 72% predicted. Concomitant ICS used by 100% of participants.

Inclusion Criteria:12 years old or more with a documented clinical history of reversible airways obstruction and symptomatic on ICS therapy (beclomethasone dipropionate, budesonide or flunisolide at a dose of 1500 to 2000 mcg/day or fluticasone propionate 750 to 1000 mcg day) for at least 4 weeks before the start of the study. FEV1 % predicted between 50% to 100%.

During the last 7 days of the run-in period, required to have had a mean morning PEF of > 50% and < 85% of PEF measured 15 minutes after administration of 400 mcg of salbutamol at the randomisation visit, and a cumulative total symptom score (daytime plus night-time) in the daily record card of at least 8.  

Exclusion Criteria: Received a long-acting beta2-agonist or oral beta2-agonist with 2 weeks of the run-in period, changed asthma medication, had a lower respiratory tract infection in the 4 weeks preceding the run-in period or had an acute asthma exacerbation requiring hospitalisation in the 12 weeks preceding study entry. 

Interventions
  1. Fluticasone propionate/salmeterol 500/50 mcg HFA BD via MDI

  2. Fluticasone propionate/salmeterol 500/50 mcg HFA BD via Diskus

  3. Fluticasone propionate 500 mcg  CFC BD via MDI

Outcomes

Primary efficacy variable was the mean morning PEF over the 12-week treatment period.

Paper reports eight patients with SAE in fluticasone propionate/salmeterol groups and 2 on fluticasone propionate. These included 3 asthma exacerbations. Web report indicates that 2 of these were on fluticasone propionate/salmeterol and one on fluticasone propionate.

One death report on fluticasone propionate/salmeterol via MDI due to leukaemia

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk447/509 (88%) completed the study
Selective reporting (reporting bias)Low riskFull data on GSK website

Wallin 2003

  1. a

    ATS: American Thoracic Society; BD/BID: twice a day; CFC: chlorofluorocarbon; BDP: beclomethasone dipropionate; FEV1: Forced Expiratory Volume in one second; GSK: GlaxoSmithKline; HFA: hydrofluoroalkane; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; MDI: metered-dose inhaler; PEF: peak expiratory flow; QD: once daily; SAE: serious adverse event.

MethodsA randomised, double-blind, parallel-group study over 12 weeks. Run-in 2 to 4 weeks.
Participants

Population: 56 asthmatics, previously not well-controlled on ICS 

Baseline Characteristics: Mean age 42 years. FEV1 88% predicted.

Concomitant ICS used by 100% of participants. 

Inclusion Criteria: Asthma symptoms on 6 or more days or 4 or more nights; need for rescue salbutamol on 6 or more days or 4 or more nights; greater than 20% variation between AM and PM PEF on 4 or more days; pulmonary function, one or more of: at least 15% increase in FEV1 15 mins after inhalation of 400 to 800 mcg salbutamol, at least 15% increase in PEF 15 mins after inhalation of 400 to 800 mcg salbutamol compared to the mean AM PEF values in the preceding week, more than 20% variation between AM and PM PEF on at least 4 consecutive days, PC20 methacholine < 4 mg/mL.

Exclusion Criteria: Not reported as such

Interventions
  1. Fluticasone propionate 200 + salmeterol 50 mcg BD

  2. Fluticasone propionate 200 mcg BD

  3. Fluticasone propionate 500 mcg BD (not used in this review)

Delivery was Diskus device

Outcomes

Primary end points were submucosal eosinophil and mast cell counts.

No information in paper but no SAEs reported on GSK website

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Independent Assessment of causation (detection bias)
Asthma-related events
High riskCausation of SAEs not independently assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk46/56 (82%) completed the study
Selective reporting (reporting bias)Low riskSAE data on GSK website

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    BDP: beclomethasone dipropionate; COPD: chronic obstructive pulmonary disease; FP: fluticasone propionate;FSC: fluticasone propionate/salmeterol; ICS: inhaled corticosteroid; LTRA: leukotriene receptor antagonist;

Adinoff 1998Not randomised to ICS
Adolfsson 2005Dose response study
Bateman 1998Device comparison
Bateman 2006Higher dose ICS in control arm
Baumgarten 20024 week study
Bergmann 2004Higher dose ICS in control arm
Bjermer 2000Salmeterol versus LTRA
Bjermer 2003Salmeterol versus LTRA
Bleecker 2006Salmeterol versus salmeterol/fluticasone
Bleecker 2007Review
Bleecker 2008Salmeterol versus LTRA
Bracamonte 2005Device comparison
Busse 2006Cross-over study
Calhoun 2001Salmeterol versus LTRA
Chapman 1999Device comparison
Condemi 1999Higher dose ICS in control arm
Cook 1998Higher dose ICS in control arm
D'Urzo 20016 week duration
Del 2001Salmeterol versus LTRA
Deykin 2007Comparison between different combined inhalers
Didier 1997No ICS control arm
Dorinsky 2004Comparison between different combined inhalers
Faurschou 19943 week cross-over study
Fish 2001Salmeterol versus LTRA
Fujimoto 2006Salmeterol versus tolobuterol
GlaxoSmithKline 2004Higher dose ICS in control arm
GlaxoSmithKline 2005aSalmeterol versus LTRA
GlaxoSmithKline 2005bHigher dose ICS in control arm
GlaxoSmithKline 2005cDevice comparison
GlaxoSmithKline 2005dHigher dose ICS in control arm
GlaxoSmithKline 2005eCross-over study
Greening 1994Higher dose ICS in control arm
Grutters 19998 week duration
House 20042 week duration
Ilowite 2004Salmeterol versus LTRA
Isabelle 2001Device comparison
Jarjour 2006FSC compared to higher dose FP
Johansson 2001Different ICS in control arm
Juniper 2002Different ICS in control arm
Kelsen 1999Higher dose ICS in control arm
Koopmans 2005Single dose study
Lazarus 2001Not randomised to ICS
Lemanske 2001Not randomised to ICS
Lotvall 2006Single dose study
Lundback 2000Different ICS in control arm
Martinat 2003Device comparison
Murray 1999Higher dose ICS in control arm
Nan 2004Different ICS in control arm
Nathan 2001Review of SAS30003 and SAS30004
Nelson 2000Salmeterol versus LTRA
Nelson 2001Salmeterol versus LTRA
O'Byrne 2005Different ICS in control arm
O'Connor 2004Salmeterol versus LTRA
Pauwels 1998Different ICS in control arm and salmeterol given in both groups
Pearlman 19994 week study
Peters 2007Higher dose ICS in control arm
Reddel 2010Down-titration study designed to allow uneven fluticasone dose between the two arms of the trial
Ringdal 2003Salmeterol versus LTRA
Rosenthal 1999No randomisation to ICS
Russell 1995No randomisation to ICS
SAM30002FSC compared to Budesonide at higher dose
SAM30013FSC compared with higher dose fluticasone
SAM40116Patients with asthma and COPD compared to higher dose fluticasone
SAS30015FSC compared to BDP
Schermer 2007Higher dose ICS in control arm
Schlosser 1998Device comparison
Scott 2005Device comparison
SLGA5021FSC comparison with higher dose fluticasone
Tonnel 2004Device comparison in acute asthma
Van den 2000Device comparison
Van Noord 1999Higher dose ICS in control arm
Vermetten 1999Higher dose ICS in control arm
Woolcock 1996Higher dose ICS in control arm
You-Ning 2005Device comparison
Zhong 2002Device comparison
Zhong 2005Comparison to different ICS in control arm

Characteristics of ongoing studies [ordered by study ID]

NCT01462344

Trial name or titleA 6-month Safety and Benefit Study of Inhaled Fluticasone Propionate/ Salmeterol Combination Versus Inhaled Fluticasone Propionate in the Treatment of 6,200 Pediatric Subjects 4-11 Years Old With Persistent Asthma
Methods

The purpose of this study is to assess whether the risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) in children 4-11 years old taking inhaled fluticasone propionate/salmeterol combination is the same as those taking inhaled fluticasone propionate alone.

The target enrolment is 6200 subjects. The expected completion date for accrual and the study remains unchanged from August 2016 and February 2017 respectively.

Participants

Inclusion Criteria:

  1. Consent to participate in the study

  2. Age 4-11 years old

  3. Male or eligible female - Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation

  4. Asthma diagnosis for at least 6 months

  5. Ability to answer questions regarding asthma control and use a metered dose inhaler and Diskus

  6. A history of clinical varicella infection or recipient of a varicella vaccine in countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids.

  7. History of at least once occurrence of asthma exacerbation within the prior 12 months

  8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks (Eligible subjects include: subjects with use of short-acting beta-agonist, leukotriene receptor antagonist, theophylline, or cromolyn whose asthma is not well-controlled; subjects on low-dose ICS monotherapy whose asthma is not well-controlled; subjects on low-dose ICS and one or more adjunctive therapy whose asthma is either controlled or not well-controlled asthma; subjects on medium-dose ICS monotherapy whose asthma is either controlled or not well-controlled; and subjects on medium-dose ICS and one or more adjunctive therapy whose asthma is well-controlled)

Exclusion Criteria:

  1. History of life-threatening asthma

  2. Unstable asthma

  3. Current use of high-dose ICS or ICS/LABA therapy to treat asthma symptoms

  4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma.

  5. Respiratory infection

  6. Subjects with only exercise-induced asthma

  7. An asthma exacerbation within the last 4 weeks or more than 4 separate exacerbations in the last 12 months

  8. Hospitalization for asthma within 4 weeks or more than 2 hospitalizations within the last 12 months

  9. Other current evidence of clinically significant uncontrolled disease/conditions of any body or organ system

  10. Neurological or psychiatric disease or history of drug or alcohol abuse of a subject or his/her guardian which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements

  11. Participation in an interventional study or used any investigational drug for any disease state within the last 30 days

  12. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medication

  13. Severe hypersensitivity to cow's milk proteins

  14. Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, beta-adrenergic blockers; phenothiazines, monoamine oxidase inhibitors, or diuretics

  15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole)

  16. Affiliation with investigator's site, including a immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.

  17. A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 twice daily

  2. Fluticasone propionate/salmeterol 250/50 twice daily

  3. Fluticasone propionate 100 twice daily

  4. Fluticasone propionate 250 twice daily

Delivery Device Diskus

Outcomes

Primary Outcomes

  • Time to first event in the composite endpoint of serious asthma-related outcomes (asthma-related hospitalizations, endotracheal intubations, or deaths) over the 6-month study treatment period

  • Time to first asthma exacerbation

Starting dateNovember 2011
Contact informationGSKClinicalSupportHD@gsk.com
NotesAs of April 24, 2012, 313 subjects have been randomised. The target enrolment is 6200 subjects. The expected completion date for accrual and the study remains unchanged from August 2016 and February 2017 respectively.

NCT01475721

Trial name or titleSAS115359, a Safety and Efficacy Study of Inhaled Fluticasone Propionate/Salmeterol Combination Versus Inhaled Fluticasone Propionate in the Treatment of Adolescent and Adult Subjects With Asthma
MethodsThe purpose of this study is to assess whether the risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) in adolescents and adults (12 years of age and older) taking inhaled fluticasone propionate/salmeterol combination is the same as those taking inhaled fluticasone propionate alone.
Participants

Inclusion Criteria:

  • Provided consent to participate in the study

  • Male or female, 12 years of age and older

  • Clinical diagnosis of asthma for at least 1 year prior to the randomisation

  • Clinic PEF of greater than or equal to 50% of predicted normal value

  • Subject must be appropriately using one of the treatments for asthma listed in the protocol

  • Subject must be able to complete the asthma control questionnaire, daily questions about asthma, and use a Diskus inhaler

  • Subject must have history of at least 1 asthma exacerbation including one of the following in the year prior to randomisation:

  • requiring treatment with systemic corticosteroids

  • an asthma-related hospitalisation

Exclusion Criteria:

  • History of life threatening asthma defined for this protocol as asthma episode that required intubation and/or was associated with hypercapnea requiring non-invasive ventilatory support

  • Concurrent respiratory disease other than asthma

  • Current evidence of, or ever been told by a physician that they have chronic bronchitis, emphysema, or chronic obstructive pulmonary disease.

  • Exercise induced asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine

  • Presence of a bacterial or viral respiratory infection that is not resolved at randomisation

  • An asthma exacerbation requiring systemic corticosteroids within 4 weeks of randomisation or more than 4 separate exacerbations in the 12 months preceding randomisation

  • More than 2 hospitalizations for treatment of asthma in the 12 months preceding randomisation

  • Subject must not meet unstable asthma severity criteria as listed in the protocol

  • Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole)

  • Pregnancy, breast-feeding or planned pregnancy during the study

  • A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.

Interventions
  1. Fluticasone propionate/salmeterol 100/50 twice daily

  2. Fluticasone propionate/salmeterol 250/50 twice daily

  3. Fluticasone propionate/salmeterol 500/50 twice daily

  4. Fluticasone propionate 100 twice daily

  5. Fluticasone propionate 250 twice daily

  6. Fluticasone propionate 500 twice daily

Delivery Device Diskus

Outcomes

Primary Outcome Measures:

  • Time to first event in the composite endpoint of serious asthma related events (i.e. asthma-related hospitalisation, asthma-related endotracheal intubation, or asthma-related death) over the 6-month treatment period

  • Time to first severe asthma exacerbation

Starting dateNovember 2011
Contact informationGSKClinicalSupportHD@gsk.com
NotesAs of April 24, 2012, 552 subjects have been randomised. The target enrolment is 11,664 subjects. The expected completion date for accrual and the study remains unchanged from August 2016 and February 2017 respectively.

Ancillary