Asthma Management Handbook

General considerations when prescribing regular preventer treatment for adults

Recommendations

Consider regular preventer treatment according to pattern of symptoms and the person’s ability to use the device. Explain to the patient that preventers should be taken every day and continued long term to reduce the risk of flare-ups.

Table. Initial treatment choices (adults and adolescents not already using a preventer)

Clinical situation

Suggested starting regimen †

Alternative options and notes

Symptoms less than twice per month and no flare-up that required oral corticosteroids within previous 12 months

SABA as needed

 

Symptoms twice per month or more

Regular ICS starting at a low dose (plus SABA as needed)

Montelukast

Cromones§

Waking due to asthma symptoms at least once during the past month

Regular ICS starting at a low dose (plus SABA as needed)

If patient also has frequent daytime symptoms consider either of:

  • medium- to high-dose ICS (plus SABA as needed)
  • (private prescription) combination low-dose ICS/LABA#

Oral corticosteroids required for an asthma flare-up within the last 12 months (even if symptoms infrequent, e.g. less than twice per month on average)

Regular ICS starting at a low dose (plus SABA as needed)

 

History of artificial ventilation or admission to an intensive care unit due to acute asthma (even if symptoms infrequent, e.g. less than twice per month on average)

Regular ICS starting at a low dose (plus SABA as needed)

  • Monitor frequently

 

Patient not currently taking a preventer whose symptoms are severely uncontrolled or very troublesome

Regular ICS (plus SABA as needed)

For very uncontrolled asthma at presentation (e.g. frequent night waking, low lung function), consider (either of):

  • high-dose ICS (then down-titrate when symptoms improve)
  • a short course of oral corticosteroids in addition to ICS

Consider (private prescription) combination ICS/LABA#

† When prescribing inhaled asthma medicines, take into account the person’s preferences, ability to use the device, and cost issues.

§ Requires multiple daily doses and daily maintenance of inhaler.

‡ PBS status as at March 2019: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. Special Authority is available for Department of Veteran’s Affairs gold card holders or white card holders with approval for asthma treatments.

# PBS status as at March 2019: ICS/LABA combination therapy as first-line preventer treatment is not subsidised by the PBS, except for patients with frequent symptoms while taking oral corticosteroids.

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Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (microg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Where more than one preventer option is appropriate, explain the options and take into consideration:

  • the person’s preference
  • the person’s ability to use the device
  • cost
  • potential adverse effects.
How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

When prescribing any preventer medicine, consider each treatment adjustment as a treatment trial.

Table. Steps for conducting a treatment trial

  1. Document baseline lung function.
  2. Document baseline asthma control using a validated standardised tool such as the Asthma Score.
  3. Discuss treatment goals and potential adverse effects with the person.
  4. Run treatment trial for agreed period (e.g. 4–8 weeks, depending on the treatment and clinical circumstances, including urgency).
  5. At an agreed interval, measure asthma control and lung function again and document any adverse effects.
  6. If asthma control has not improved despite correct inhaler technique and good adherence, resume previous treatment and consider referral for specialist consultation.

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

After starting a new treatment regimen or making any adjustments to the treatment regimen, set a date to review response (e.g. 6–8 weeks) and follow up the patient, to ensure ineffective or unnecessary medication is not continued, or that the patient has not inappropriately stopped taking  the treatment.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Review asthma control periodically to step up or down as necessary to maintain good asthma control at the lowest effective dose.

Figure. Stepped approach to adjusting asthma medication in adults and adolescents Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/figure/show/31

Table. Guide to selecting and adjusting asthma medication for adults and older adolescents

Clinical situation

Action

Newly diagnosed asthma

Consider low-dose ICS (plus SABA as needed)

If symptoms severe at initial presentation, consider one of:

  • ICS plus a short course of oral corticosteroids
  • a short initial period of high-dose ICS then step down
  • (private prescription) combination ICS/LABA

See: Table. Initial treatment choices (adults and adolescents not already using a preventer) 

Good recent asthma symptom control

If maintained 2–3 months, no flare-up in previous 12 months and low risk for flare-ups, step down where possible (unless already on low-dose ICS)

Partial recent asthma symptom control

Review inhaler technique and adherence – correct if suboptimal

If no improvement, consider increasing treatment by one step and reviewing (if still no improvement, return to previous step, review diagnosis and consider referral)

Poor recent asthma symptom control

Review inhaler technique and adherence – correct if suboptimal

Confirm that symptoms are likely to be due to asthma

Consider increasing treatment until good asthma control is achieved, then step down again when possible

Difficult-to-treat
asthma ‡

Consider referral for assessment or add-on options

Patient with risk
factors §
 

Tailor treatment to reduce individual risk factors

† PBS status as at March 2019: ICS/LABA combination therapy as first-line preventer treatment is not subsidised by the PBS, except for patients with frequent symptoms while taking oral corticosteroids.

‡ Poor recent asthma symptom control despite ICS/LABA combination at high–medium dose.

§ Risk factors for asthma events or adverse treatment effects, irrespective of level of recent asthma symptom control.

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Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (microg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

For adults prescribed low-dose ICS for an indefinite period, explain that:

  • the main purpose of long-term low-dose ICS-based preventer is to reduce the risk of flare-ups, even if day-to-day symptoms are infrequent
  • even if the person has not experienced asthma symptoms for some time, they should not stop taking their preventer without discussing first.

Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (microg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

More information

Adherence to preventer treatment: adults and adolescents

Most patients do not take their preventer medication as often as prescribed, particularly when symptoms improve, or are mild or infrequent. Whenever asthma control is poor despite apparently adequate treatment, poor adherence, as well as poor inhaler technique, are probable reasons to consider.

Poor adherence may be intentional and/or unintentional. Intentional poor adherence may be due to the person’s belief that the medicine is not necessary, or to perceived or actual adverse effects. Unintentional poor adherence may be due to forgetting or cost barriers.

Common barriers to the correct use of preventers include:

  • being unable to afford the cost of medicines or consultations to adjust the regimen
  • concerns about side effects
  • interference of the regimen with the person’s lifestyle
  • forgetting to take medicines
  • lack of understanding of the reason for taking the medicines
  • inability to use the inhaler device correctly due to physical or cognitive factors
  • health beliefs that are in conflict with the belief that the prescribed medicines are effective, necessary or safe (e.g. a belief that the prescribed preventer dose is ‘too strong’ or only for flare-ups, a belief that asthma can be overcome by psychological effort, a belief that complementary and alternative therapies are more effective or appropriate than prescribed medicines, mistrust of the health professional).

Adherence to preventers is significantly improved when patients are given the opportunity to negotiate the treatment regimen based on their goals and preferences.1

Assessment of adherence requires an open, non-judgemental approach.

Accredited pharmacists who undertake Home Medicines Reviews can assess adherence while conducting a review.

Table. Suggested questions to ask adults and older adolescents when assessing adherence to treatment

  1. Many people don’t take their medication as prescribed. In the last four weeks:
    • how many days a week would you have taken your preventer medication? None at all? One? Two? (etc).
    • ​how many times a day would you take it? Morning only? Evening only? Morning and evening? (or other)
    • each time, how many puffs would you take? One? Two? (etc).
  2. Do you find it easier to remember your medication in the morning, or the evening?

Source: Foster JM, Smith L, Bosnic-Anticevich SZ et al. Identifying patient-specific beliefs and behaviours for conversations about adherence in asthma. Intern Med J 2012; 42: e136-e44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21627747

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Inhaled corticosteroids for adults: overview

Inhaled corticosteroid preventer medicines available in Australia

The following inhaled corticosteroids are registered by the TGA:

  • beclometasone dipropionate (low to high doses available)
  • budesonide (low to high doses available, including in combination with a long-acting beta2 agonist)
  • ciclesonide (low to high doses available)
  • fluticasone furoate (medium to high doses available, including in combination with a long-acting beta2 agonist)
  • fluticasone propionate (low to high doses available, including in combination with a long-acting beta2 agonist)

Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (microg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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Clinical benefits

Inhaled corticosteroids are the most effective preventer medicines for adults.2

Inhaled corticosteroids are effective in reducing asthma symptoms, improving quality of life, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation, reducing the frequency and severity of asthma flare-ups, and reducing the risk of death due to asthma.3, 45,  6, 7, 89, 101112

Most adults with asthma benefit from regular inhaled corticosteroid treatment

The current recommendation to initiate inhaled corticosteroid treatment for adults with asthma symptoms twice or more during the past month, or who experience waking due to asthma symptoms once or more during the past month, is based on consideration of clinical trial evidence that even patients with infrequent symptoms benefit from regular use of inhaled corticosteroids:

  • In patients with recent-onset (diagnosis within 2 years) mild asthma (45% with symptoms 2 days/week or less), low-dose inhaled corticosteroid (budesonide 400 microg/day) reduced the risk of severe flare-ups, increased symptom-free days and lung function, and protected against long-term decline in lung function associated with severe asthma flare-ups (evidence from a 5-year large randomised clinical trial). 6, 8, 9
  • In small clinical trials in adults with symptoms or reliever use twice per week or less, the use of regular inhaled corticosteroids (fluticasone propionate 250 microg/day) improved lung function,13 reduced airway hyperresponsiveness and inflammation,1314 and reduced the risk of mild flare-ups.13, 14

The current recommendation replaces the previous higher threshold for inhaled corticosteroid treatment (asthma symptoms three times a week or more, or waking at least one night per week with asthma symptoms), which was based on consensus.

Clinical benefits are achieved with low doses

Low doses of inhaled corticosteroids are sufficient to achieve benefits in most patients:

  • Regular use of low-dose inhaled corticosteroids reduced the risk of hospitalisation for acute asthma and death due to asthma (evidence from a large population cohort study).10 In that study, breaks in the use of inhaled corticosteroid of up to 3 months were associated with increased risk of death.11
  • In adults and adolescents with mild asthma who were not taking inhaled corticosteroids, starting low-dose inhaled corticosteroid (budesonide 200 microg/day) reduced the risk of asthma flare-ups severe enough to require oral corticosteroids, and improved symptom control (evidence from a large clinical trial).7
  • In patients with recent-onset (diagnosis within 2 years) mild asthma (45% with symptoms 2 days/week or less), low-dose inhaled corticosteroid (budesonide 400 microg/day) reduced the risk of severe flare-ups, increased symptom-free days and lung function, and protected against long-term decline in lung function associated with severe asthma flare-ups (evidence from a 5-year large randomised clinical trial). 6, 8, 9

Note: PBS status as at March 2019: Fluticasone furoate is not subsidised by the PBS, except in combination with vilanterol.

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Inhaled corticosteroid/long-acting beta-2 agonist combinations for adults: overview
  • To avoid the possibility of patients taking a long-acting beta2 agonist without an inhaled corticosteroid, long-acting beta2 agonists should (whenever possible) be prescribed as inhaled corticosteroid/long-acting beta2 agonist combination in a single inhaler, rather than in separate inhalers. If no combination product is available for the desired medications, carefully explain to the patient that it is very important that they continue taking the inhaled corticosteroid.

Meta-analysis of evidence from randomised controlled clinical trials shows that, for adult patients already taking an inhaled corticosteroid, concomitant treatment with an inhaled corticosteroid and a long-acting beta2 agonist:3

  • reduces the risk of flare-ups, compared with increasing the dose of corticosteroids
  • reduces the risk of flare-ups, compared with inhaled corticosteroids alone.

The studies included in this meta-analysis evaluated mainly budesonide/formoterol and fluticasone propionate/salmeterol.3

Each of the following inhaled corticosteroid/long-acting beta2 agonist combinations is available as a single inhaler:

  • budesonide/formoterol
  • fluticasone furoate/vilanterol
  • fluticasone propionate/salmeterol
  • fluticasone propionate/formoterol.

There are two types of dosing regimens for inhaled corticosteroid/long-acting beta2 agonist combination therapy:

  • maintenance-only regimens (applicable to all available combinations)
  • maintenance-and-reliever regimen (applicable only to the budesonide/formoterol combination).

Maintenance-only regimens

The fluticasone propionate/salmeterol combination and budesonide/formoterol combination appear to be equally effective when used for regular maintenance treatment, based on meta-analysis of evidence from clinical trials.15 Most of the evidence for inhaled corticosteroid/long-acting beta2 agonist combination therapy is from studies using these combinations.

Less evidence from double-blind randomised controlled clinical trials is available for the newer combinations: fluticasone furoate/vilanterol and fluticasone propionate/formoterol:

  • The fluticasone furoate/vilanterol combination is equivalent to a medium-to-high dose of inhaled corticosteroids.16 In adults and adolescents already taking inhaled corticosteroids, once-daily fluticasone furoate/vilanterol 100/25 microg reduced the risk of severe flare-ups (requiring oral corticosteroids or hospitalisation) and improved lung function, compared with fluticasone furoate alone.17 Efficacy data for the comparison of fluticasone furoate/vilanterol with other inhaled corticosteroid/long-acting beta2 agonist combinations is not available.
  • In adults and adolescents with persistent asthma and FEV1 50–80% at baseline, fluticasone propionate/formoterol achieved improvement in FEV1 comparable to that achieved with budesonide/formoterol in a 12-week randomised double-blind clinical trial.18 Other 12-week open-label studies have reported that fluticasone propionate/formoterol was as effective as budesonide/formoterol in improving lung function in adults and adolescents with poorly controlled asthma,19 and was as effective as fluticasone propionate/salmeterol in adults.20

Long-acting beta2 agonists should not be used without inhaled corticosteroids in the management of asthma.21222324 Long-acting beta2 agonists are well tolerated when given in combination with inhaled corticosteroids.1525

Maintenance-and-reliever regimen

The low-dose budesonide/formoterol combination can be used as both maintenance and reliever. Under this regimen, the combination is used for relief of asthma symptoms (instead of using a short-acting beta2 agonist reliever), in addition to its use as regular maintenance treatment.

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Combination budesonide/formoterol maintenance-and-reliever regimen in adults and adolescents: overview of efficacy

Low-dose budesonide/formoterol combination can be used as reliever for asthma symptoms (instead of using a short-acting beta2 agonist reliever), in addition to its use as regular long-term preventer treatment.26, 27,  28,  2930, 31 The following formulations can be used in maintenance-and-reliever regimens:

  • dry-powder inhaler (Symbicort Turbuhaler) 100/6 microg or 200/6 microg
  • pressurised metered-dose inhaler (Symbicort Rapihaler) 50/3 microg or 100/3 microg.

Neither the 400/12 microg dry-powder inhaler nor the 200/6 microg pressurised metered-dose inhaler should be used in this way.

Overall, clinical trials show that budesonide/formoterol combination as maintenance and reliever reduces the risk of flare-ups that require oral corticosteroids, compared with other current preventer regimens and compared with a fixed higher dose of inhaled corticosteroids.32

Pooled data from five randomised controlled trials assessing budesonide/formoterol maintenance-and-reliever regimens showed that similar or better levels of asthma control were achieved with budesonide/formoterol maintenance-and-reliever compared with the conventional maintenance regimen comparators:28

  • higher-dose budesonide
  • same dose budesonide/formoterol
  • higher-dose inhaled corticosteroid/long-acting beta2 agonist (budesonide/formoterol or fluticasone propionate/salmeterol).

In randomised clinical trials in patients with a history of asthma flare-up within the previous 12 months (and therefore at greater risk of flare-up in the next 12 months), the use of formoterol/budesonide as maintenance-and-reliever regimen reduced the risk of asthma flare-ups that required treatment with oral corticosteroids, compared with the use of any of the following (plus a short-acting beta2 agonist reliever as needed):283334

  • the same combination as maintenance treatment only
  • higher-dose combination as maintenance treatment only
  • higher-dose inhaled corticosteroids.

Meta-analysis of six randomised controlled trials found that maintenance-and-reliever treatment with budesonide/formoterol reduced the risk of severe asthma flare-ups (use of oral corticosteroids for 3 days or more, hospitalisation or emergency department visits), compared with higher-dose inhaled corticosteroid alone, or in combination with a long-acting beta2 agonist.35

In open-label studies in which patients were not selected for a previous history of flare-ups, there was no overall difference in time to first flare-up between budesonide/formoterol as maintenance-and-reliever regimen and conventional maintenance regimens (including inhaled corticosteroid or inhaled corticosteroid/long-acting beta2 agonist combinations, leukotriene receptor antagonists, xanthines or any other asthma medicines) with rapid-onset beta2 agonist reliever (selected according to clinician’s choice).36 However, the inhaled corticosteroid dose was higher with conventional maintenance regimens.

Note: The fluticasone propionate/formoterol combination is approved by the Therapeutic Goods Administration only for regular maintenance therapy.

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Correct use of inhaler devices

Checking and correcting inhaler technique is essential to effective asthma management.

Most patients with asthma or COPD do not use their inhalers properly,37, 38,3939, 40 and most have not had their technique checked or corrected by a health professional.

Incorrect inhaler technique when using maintenance treatments increases the risk of severe flare-ups and hospitalisation for people with asthma or COPD.37, 38, 41, 42, 43, 44

Poor asthma symptom control is often due to incorrect inhaler technique.45, 46

Incorrect inhaler technique when using inhaled corticosteroids increases the risk of local side effects like dysphonia and oral thrush.

The steps for using an inhaler device correctly differ between brands. Checklists of correct steps for each inhaler type and how-to videos are available from the National Asthma Council website.

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References

  1. Castro, M, Rubin, A S, Laviolette, M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010; 181: 116-124. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19815809
  2. Watts, K, Chavasse, R J P G. Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and children. Cochrane Database Syst Rev. 2012; Issue 5: . Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD006100.pub2/full
  3. Sin DD, Man J, Sharpe H, Gan MS. Pharmacological management to reduce exacerbations in adults with asthma: A systematic review and meta-analysis. JAMA. 2004; 292: 367-376. Available from: http://jama.jamanetwork.com/article.aspx?articleid=199101
  4. Adams NP, Bestall CJ, Jones P. Budesonide versus placebo for chronic asthma in children and adults. Cochrane Database Syst Rev. 1999; Issue 4: CD003274. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003274/full
  5. Adams NP, Bestall JC, Malouf R, et al. Beclomethasone versus placebo for chronic asthma. Cochrane Database Syst Rev. 2005; Issue 1: CD002738. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002738.pub2/full
  6. Busse WW, Pedersen S, Pauwels RA, et al. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol. 2008; 121: 1167-1174. Available from: http://www.jacionline.org/article/S0091-6749(08)00416-8/fulltext
  7. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med. 2001; 164 (8 pt 1): 1392-1397. Available from: http://ajrccm.atsjournals.org/content/164/8/1392.full
  8. O'Byrne PM, Pedersen S, Lamm CJ, et al. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med. 2009; 179: 19-24. Available from: http://ajrccm.atsjournals.org/content/179/1/19.full
  9. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003; 361: 1071-1076. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12672309
  10. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma. Thorax. 2002; 57: 880-884.
  11. Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med. 2000; 343: 332-336. Available from: http://www.nejm.org/doi/full/10.1056/NEJM200008033430504#t=article
  12. Adams NP, Bestall JC, Lasserson TJ, et al. Fluticasone versus placebo for chronic asthma in adults and children. Cochrane Database Syst Rev. 2008; Issue 4: CD003135. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003135.pub4/full
  13. Reddel HK, Belousova EG, Marks GB, Jenkins CR. Does continuous use of inhaled corticosteroids improve outcomes in mild asthma? A double-blind randomised controlled trial. Prim Care Respir J. 2008; 17: 39-45. Available from: http://www.nature.com/articles/pcrj200814
  14. Boulet LP, Turcotte H, Prince P, et al. Benefits of low-dose inhaled fluticasone on airway response and inflammation in mild asthma. Respir Med. 2009; 103: 1554-1563. Available from: http://www.resmedjournal.com/article/S0954-6111(09)00069-9/fulltext
  15. Lasserson TJ, Ferrara G, Casali L. Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children. Cochrane Database Syst Rev. 2011; 3: CD004106. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004106.pub4/full
  16. GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf
  17. Bateman ED, O'Byrne PM, Busse WW, et al. Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone. Thorax. 2014; 69: 312-319. Available from: http://thorax.bmj.com/content/69/4/312.full
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