Journal reference: Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 650–57 ^[1]

Link: http://dx.doi.org/10.1016/S0140-6736(10)62145-9

Published: 19 February 2011

Evidence cookie says...

Children with mild persistent asthma should be treated with regular inhaled corticosteroids.  Treatment with salbutamol (Ventolin) alone significantly increases the risk of exacerbations. Inhaled beclomethasone (Qvar) used as rescue therapy with salbutamol is likely better than salbutamol alone, for children with mild persistent asthma who do not take regular inhaled corticosteroids. Note: the study is relatively underpowered.

Article details:

Study design:

prospective, double-blind, randomised controlled trial

Study aim:

to assess the effectiveness of an inhaled corticosteroid, beclomethasone dipropionate (Qvar) as rescue treatment in children with mild persistent asthma

Study conclusion:

Children with mild persistent asthma should not be treated with rescue albuterol (Australia: salbutamol, Ventolin) alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids (ICS). ICS as rescue medication with salbutamol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue salbutamol alone. Use of daily ICS treatment and related side-effects such as growth impairment can therefore be avoided. ^[1]

Critical appraisal:

Methodology (PICO):

Participants: who was studied?

• 288 children and adolescents:
  • 6 – 18 years
  • from five clinical centres in the USA
• January 2007 – May 2009
• history of mild persistent asthma during the previous 2 years, defined as:
  • on average, more than 2 days per week with symptoms (e.g., wheezing);
  • more than 2 days a week on which they had to use salbutamol to control symptoms;
  • more than two awakenings at night per month when not using controller medication; or
  • if they had to use daily controller treatment to keep their disorder well controlled
• qualified for interruption or discontinuation of controller treatment because their illness was well controlled (as defined in US National Asthma Education and Prevention Program asthma care guidelines)
• inclusion criteria:
  • naive to controller treatment;
  • history of one to two exacerbations in the previous year;
  • treated for the previous 8 weeks with a monotherapy other than inhaled corticosteroids; or
  • illness was controlled for the previous 8 weeks on low-dose corticosteroids as monotherapy (≤160 μg daily with a beclomethasone equivalent)
• exclusion criteria:
  • prebronchodilator FEV1 < 60% predicted at the first visit
  • admitted to hospital for asthma in the previous year
  • had any asthma exacerbation in the previous 3 months or more than two in the previous year
  • history of life-threatening asthma exacerbations that required intubation or mechanical ventilation, or that resulted in a hypoxic seizure
• Participants were included in the 44-week treatment phase only if their disease remained well controlled and they did not have any exacerbations during an initial 4-week run-in period

Intervention: what was the exposure?

• Combined group:
  • preventer = 1 puff (40 μg) twice daily beclomethasone
  • reliever = 2 puffs of beclomethasone (80 μg) plus salbutamol (180 μg) as needed
• Rescue ICS group:
  • preventer = twice daily placebo inhaler
  • reliever = 2 puffs of beclomethasone (80 μg) plus salbutamol (180 μg) as needed
• Daily ICS group:
  • preventer = 1 puff (40 μg) twice daily beclomethasone
  • reliever = 2 puffs of placebo plus salbutamol (180 μg) as neded

Comparator: what was the control/alternative?

• Placebo group:
  • preventer = twice daily placebo inhaler
  • reliever = 2 puffs of placebo plus salbutamol (180 μg) as needed

Outcomes: what was measured?

Primary outcome:

• the time to first exacerbation that required treatment with prednisone

Secondary outcomes:

• spirometry FEV1
• fractional exhaled nitric oxide (FENO)
• symptom diaries and control and quality of life questionnaires
• linear growth

Are the trial results valid?

Internal validity: Wikipedia

Were there sufficient participants in the trial?

Unclear.

• The target sample size was 280 randomised participants (70 per treatment group)
  • 90% statistical power for a two-sided, 0.05 significance level test, allowing for 10% withdrawals
  • to detect a hazard ratio of 0.5 in the time to first exacerbation for each main effect in the two by two factorial design
• The trial had a drop-out rate higher than the 10% (54 out of 288 patients, or 18.75%, dropped out)
• The detected magnitude of treatment effects were smaller than the HR of 0.5.

Was the assignment of patients to treatment randomised?

Yes.

• The randomisation sequence was stratified according to clinical centre and age group (6–11 years and 12-18 years), in blocks of four.

Were the groups similar at the start of the trial?

Yes.

• There were only minor differences between participant groups at baseline (see Table 1 ^[1])

Aside from the allocated treatment, were groups treated equally?

Yes.

Were all patients who entered the trial accounted for?

Yes.

• intention to treat analysis

Were measures objective or were the patients and clinicians kept blind to which treatment was received?

Yes.

• Both clinicians and participants were blinded.

What were the results?

Primary outcome

• Compared with the placebo group, the hazard ratios for asthma exacerbations were significantly lower in the daily ICS group,  and the combined group, but the difference was not significant in the rescue ICS group:
• Combined group vs placebo group:
  • HR = 0.56 (95% CI 0.32-0.96), P = 0.033
  • Interpretation:
    • use of corticosteroids both regularly and in rescue treatment was significantly associated with fewer exacerbations
    • note: there are wide-confidence intervals, the actual magnitude of the effect is unclear
• Daily ICS group vs placebo group:
  • HR = 0.49 (95% CI 0.28-0.85), P = 0.011
• Rescue ICS group vs placebo:
  • HR = 0.62 (95% CI 0.37-1.05), P = 0.073
  • Interpretation:
    • use of corticosteroids in rescue treatment only was associated with fewer exacerbations
    • however, this was not a statistically significant effect

Other outcomes:

Linear growth:

• Combined and daily ICS groups vs placebo group:
  • -1.1 cm (SD 0.3), P < 0.0001
  • Interpretation: children on daily inhaled beclomethasone on average grew 1.1 cm less than children in the placebo group
• Rescue ICS group vs placebo group:
  • -0.3 cm (SD 0.2), P = 0.26
  • Interpretation: children on the rescue ICS group grew 0.3 cm less but this result was not statistically significant

Will the results help me care for my patient?

External validity: Wikipedia

Are the participants different to my patient?

• study included only children with well controlled, mild persistent asthma
• they were mainly older children (mean age ~ 11 years)
• care needs to be taken in translating these results to intermittent asthma or asthma of greater severity

Is the treatment feasible?

Yes.

• The treatments studied were combinations of standard asthma treatments currently in use.

Were all the clinically important outcomes considered?

• the study focused on time to first exacerbation, and not necessarily long-term improvement in asthma severity

Are the treatment benefits worth the potential harms/costs?

Probably.

• rescue beclomethasone (compared to salbutamol alone) was associated with reduced exacerbations in children with mild persistent asthma
• rescue beclomethasone (without daily ICS use) was not associated with reduced linear growth, unlike daily corticosteroid use
• the results are arguably clinically significant despite the low statistical power and the lack of a statistically significant result for rescue beclomethasone for the primary outcome

Study weaknesses (summary)

The power of the study was reduced due to a number of factors:

• unanticipated subadditive interaction between treatments required a major deviation from the planned analysis
• instead of a two by two factorial analysis, the authors compared the effects recorded in the individual active treatment groups with the effects recorded in the placebo group.
• because the study was powered on the basis of a factorial design, such change in analysis decreased the study’s power substantially
• the recorded effects of the two groups in which rescue beclomethasone was used were less than those assumed when the study was planned

Study strengths (summary)

• first study to examine the use of ICS as rescue with salbutamol in school children, an age at which exacerbations play a major part in asthma morbidity
• otherwise well designed randomised controlled trial

Biases and conflicts of interests

• various authors have received consulting fees, research grants and honoria from major pharmaceutical companies that produce ICS
• the results of this study potentially support use of ICS in an expanded setting

Clinical relevance to primary health care

This study supports the use of regular inhaled corticosteroids (ICS) for children with mild persistent asthma.

Even though this study was relatively underpowered, it clearly demonstrates the superiority of daily inhaled beclomethasone (Qvar) for the primary outcome (time to first exacerbation that required treatment with prednisone).  Regular inhaled corticosteroids should still be considered the mainstay of therapy.

However, many children and their parents will resist long-term ICS therapy for mild persistent asthma.  In this setting, it might be reasonable to suggest ICS with salbutamol (Ventolin) for rescue therapy.  It appears to be associated with fewer exacerbations (when compared to salbutamol rescue/reliever therapy alone).  With regards to use of this strategy as  step-down management, the data from this study is suggestive but hardly definitive.

This study does not support the use of ICS in addition to salbutamol as a reliever where a regular ICS is already used.

References

1. Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 650–57

Editor: Michael Tam