Author

Year

Study type

Quality rating

Population

Outomes measured

Effect size

Confidence intervals / p values

Comments

Adults

Brambilla¹

1994

RCT

++

159 patients aged 18-67 (mean 41). FEV, 50-90% pred. And >15% reversibility to b2 agonists.
Compared inhaled salmeterol with oral SR terbutaline. Study perios 1 week run in and 2 week treatment.

No. of awakening free nights

PEF

50% salmeterol vs 27% terbutaline

Salmeterol am PEF 351+/-109 l/min. PEF variation 6+/-% (salmeterol) vs 11+/-12% (terbutaline)

Rescue decreased during daytime for salmeterol group

p=0.003


NS in evening PEF.
PEF variation reduced in salmeterol group
p=0.01

p=0.04 for daytime
NS difference in treatment groups at night

Compared to oral SR terbutaline 5mg bd, inhaled salmeterol 50 m g bd causes a minimal increase in am and pm PEF, but did cause a significant improvement in nocturnal asthma control and improved sleep.

66% of patients on salmeterol on inhaled corticosteroids and 11% oral steroil whil in the terbutaline group 67% were on ICS 13% oral steroid.

Crompton²

1999

RCT

++

118 patients aged 18-67 (mean 41).
Nocturnal fall PEF and symptoms on 400 m g-2000m g inhaled or >=20mg oral steroids.
Compared bambuterol with inhaled salmeterol. Study period of 8 weeks

Increase in am PEF from baseline.

pm PEF, % fall in PEF, No. of night time awakenings, % of nights with no awakening, No. of puffs of rescue medication, asthma symptoms

50 l/min – bambuterol
55 l/min – salmeterol

All improved by both treatments

NS differences in treatment with any outcome measures

In this short study, bambuterol 20mg po nocte and salmeterol 50 m g inh bd produced similar improvements in PEFR, nocturnal asthma symptoms and requirement for rescue medication in asthmatics using moderate doses of corticosteroids. Both treatments were well tolerated with similar incidence of tremor, but treatment with bambuterol was significantly cheaper.

Gunn³

1995

Crossover RCT

+

152 patients aged 17-78 (mean 54 years)
Nocturnal asthma symptoms 3/7 >=800 µg inhaled corticosteroid (no oral steroids)
15% reversibility to b 2 agonists .
Compared bambuterol vs CR salbutamol over 6 weeks

Severity of sleep disturbance (0-3)

Increase in PEF

Increase in FEV₁

Increase in FVC

Both treatments reduced scores to <half baseline value.

42 l/min – bambuterol

53 l/min – salbutamol CR

0.10L – bambuterol
0.14L – salbutamol CR

0.16L – salbutamol CR

p<0.001
NS between treatments


p<0.0001
NS between treatments

 p<0.01
NS between treatments

p<0.01NS between streaments

Both bambuterol and salbutamol CR improved baselind lung function and reduced the sevirity of night time symptoms in asthmatics on moderate dose inhaled corticosteroids over this short study time.

There was no significant difference in treatments except that bambuterol caused less tremor than salbutamol CR

Ringbaek⁴

1996

Crossover RCT

+

59 patients aged 19-73 (mean 47). Mean FEV, 64%pred. 26.6% reversibility to b 2 agonists.
Compared inhaled salmeterol with oral salbutamol CR. Study period 4 wkks and 2 weeks washout.

Increase in am PEF from baseline

% days asymptomatic

% days free from rescue b 2 agonist use.

35 l/min – salmeterol vs 19 l/min salbutamol

28% salmeterol vs 13% salbutamol

38% salmeterol vs 24% salbutamol

p=0.04

p=0.004

p=0.01

Salmeterol 50 mg bd was more effective than salbutamol CR 8mg po bd at reducing day and night time symptoms and rescue b 2 agonist use. It was also better tolerated.

This paper is only available in Danish, making methodological evaluation difficult.

Wallaert⁵

1999

RCT

+

117 patients aged 20-70 (mean age 45). Nocturnal fall in PEF and symptoms on 800 m g-2000m g inhaled and/or >=20mg oral steorids per day.
Compared oral bambuterol with inhaled salmeterol. Study period of 6 weeks.

Increase in am/pm PEF from baseline.

Nocturnal and daytime symptoms.

Rescue inhaled b 2 agonist use.

28 l/min / 20 l/min on bambuterol, 29 l/min, 23 l/min on salmeterol

Nocturnal awakenings reduced in both groups.

Consumption of rescue at night was lower in both groups

Bambuterol – p<0.05

Salmeterol – p<0.001/0.01

p<0.01

Bambuterol – p<0.05
Salmeterol – p<0.001

NS difference between treatments

Bambuterol 20mg po nocte and salmeterol 50 µg inh bd improved asthma control and nocturnal symptoms to a similar degree with a similar side effect profile.

Children

Akpinarli⁶

1999

Randomised, placebo-controlled trial and blind

32 Asthmatic children (6-14 y) on ICS (400-800 mcg/d) and still symoptomatic.

Formoterol 12 mcg or placebo added to ICS for 6 weeks

1] symptom scores (0-9), composite of day/night cough, wheeze and shortness of breath.

2] beta 2 agonist use per week

3] FEV1 am/pm PEFR

4] PC20

Compared to baseline Formoterol reduced score-3

Placebo reduced score 0

Formoterol reduced beta 2 agonist use by –3 and placebo by 0

FEV1 (formoterol) + 3

Am PEFR 19

Formoterol 0.05

95% ci-7 to-2
95%ci-1 to 1
P<0.05

95%ci-6 to –2
95%ci-2 to 2
P<0.05
95%ci-23 to 29)
95%ci 2 to 181 p<0.05
95%ci 0.57 to 0.74
NS

Formoterol reduced asthma symptoms and beta agonist use, increased PEFR 95% ci related to 6 weeks compared with base line.

P-values relate to comparison between formoterol and placebo

No adverse effects seen

Verberne⁷

1998

Double-blind,

randomised, placebo controlled

++

177 asthma children (6-16y), mild to moderate, currently on BDP 400 mcg /d

Study treatment was placebo or BDP 800 mcg/d or salmeterol 100mcg/d over a 12 month period

1] symptoms dyspnoea (0,1,2,3) am/pm
wheeze (0,1,2,3)am/pm
cough(0,1,2,3)am/pm

2) rescue med. Use (pred. Courses)

3) lung function PEFR
FEV1

PD20

% children no symptoms during a 2 week period:BDP400+Salm 34%, BDP800 39% and BDP400+placebo 35%





3) BDP400+salm slightly better PEFR in first months

change FEV1(BDP400+salm)=4.3%

(BDP800)=5.8%

(BDP400+placebo)=4.3%

No significant differenct between groups, all groups increased PD 20 compared to baseline

1) NS, at no time point were there sign, differences in symptom scores
2) NS Compared to baseline 95%ci (1.3, 7.2)
95%ci (2.9, 8.7)
95%ci (2.1, 1.3)
NB. Between groups NS

Found no additional benefit of adding salmeterol to BDP 400 compared with adding placebo or doubling the dose of BDP.

At end of study, after stopping Salmeterol group noted a reduction in FEV1, this did not occur in other groups.

Growth was significantly slower in BDP800 group.

Byrnes⁸

2000

Crossover RCT

++

45 asthmatic children (5-14) on >400 mcg ICS and still symptomatic.
Addition of salmeterol 50 and 100 mcg each bd were compared with salbutamol 200 mcg qds. Study period of 4 weeks.

FEV₁, PEFR am/pm

Histamine challenge, PC20

Symptom scores

Use of rescue medication

*compared salmeterol with addition of salbutamol

am PEFR increased by 9.6 l/min and 13.8 l/min for salmeterol 50 and 100 mcg

Salmeterol 50 – 1.54
Salmeterol 100 – 1.23

Median daytime score reduced from 1 to 0 for all treatments

Days without rescue medication increased for all groups compared with baseline: 65% salbutamol, 61% salme. 50 and 72% salmet.100

95% ci

95% ci 2.1 to 17
95% ci 6 to 21-5
p<0.05

ci 0.65 to 3.7
ci 0.55 to 2.78

NS between treatment groups

No difference between the two doses (50/100) of salmeterol.

No placebo, comparisons with baseline and salbutamol.

Salmeterol signigicantly improved PEFR over 4 weeks.

Heuck⁹

2000

Randomised double-blind, placebo controlled crossover trial

+
primary objective was study of bone turnover.

Secondary variables

1) symptoms day/night (0-3 scores)

2) rescue med. Use

3) FEV1/FVC

Compared to BUD 200 mcg BD at baseline

1] Day p=0.55, 95%ci-0.11,0.2

Night p=0.64,95%ci-0.1, 0.15

2] p=0.56, 95%ci-0.11, 0.2

Night p=0.64, 95%ci-0.1, 0.15

2] p=0.56, 95%ci –0.48, 0.27 puffs/d

3] PEV1 higher at week 2 (p=0.04, 95%ci –0.01, 0.17, NS at week 6 (p=0.32, 95%ci –0.02, 0.06

Symptoms and lung function secondary variables. BUD 100mcg BD + Formoterol as good as BUD 200mcg BD- no loss of asthma control

This intervention associated with better short term growth.

Russell¹⁰

1995

Randomised, placebo controlled, double blind

210

Symptomatic asthmatic children (4-16y) on ICS (> 400 mcg/d) treated with Salmeterol (50mcg Bd) or placebo for 12 weeks

1] max. proportion symptom free days (%)/nights (%)

salmeterol 60%/81%

placebo 26%/59%

2] median change in rescue med use –0.7 and –0.8 at 9-12 weeksfor salmeterol versus –0.3 for placebo

30 mean am PEFR (percentage points] was > 8 above baseline for weeks 4-12. Max. increase with placebo was 5.

Mean pm PEFR greater for salmeterol than placebo by at least 1 percentage point

1] max. proportion symptom free days (%)/nights (%)
salmeterol 60%/81%
placebo 26%/59%
2] median change in rescue med use –0.7 and –0.8 at 9-12 weeksfor salmeterol versus –0.3 for placebo
30 mean am PEFR (percentage points] was >8 above baseline for weeks 4-12. Max. increase with placebo was 5.

Mean pm PEFR greater for salmeterol than placebo by at least 1 percentage point

P>0.05 only for first 4 weeks

Improvement was better for salmeterol group at all times in 12 weeks compared with placebo

Langton Hewer¹¹

1995

RCT double-blind
Placebo controlled

+

24 children, 1217 yrs on "high doxe" ICS (not deferred) 50-1000mcg, medicine 400BD

Received Salmeterol 100mcg BD or placebo for 8 weeks

1] Day/night symptoms PEFR am/pm

2] FEV1 (clinic)

1] No stats given (wide range of values) this showed trend to improvement.

2] tend to improve

Change from baseline significantly better for salmeterol

• Change in am FEV1 +0.22 v’s-0.2 (placebo) P< 0.05, 95%ci 0.65 to 0.12
• Change in pm FEV1 + 0.2 v’s –0.16 (placebo) P< 0.05, 95%c1 0.67-0.07

Tomac¹²

1996

Cohort study

+

24 asthmatic children (7-16) on ICS and/or DSC were treated with salmeterol 50 mcg BD for 4 weeks. Comparisons made with 2 week run-in

Rescue salbutamol

Daily/nocturnal symptoms

am/pm PEFR

FEV1, FVC

 Airways resistance

Reduced on salmeterol compared with run-in period

Reduced by salmeterol

Am increased by 42 l/min, pm increased by 35 l/min

No change in FEV1, MEF but FVC increased.

sRaw decreased by 26%

P<0.02

 P<0.05

P<0.001

NS for FVC

P<0.05

Not an RCT, and includes concomitant medication – theophylines and DSC.

Difficult to interpret.