Treatments for poorly controlled asthma
=======================================

* Orla O’Carroll
* Cormac McCarthy
* Marcus W Butler

### What you need to know

*   In a patient with worsening symptoms of asthma, confirm the diagnosis and address possible causes of worsening, including treatment adherence, comorbidities, and environmental factors

*   Combined inhaled corticosteroids with long acting β agonists (LABA) as single maintenance and reliever therapies are associated with reduced exacerbations and improved asthma related quality of life compared with traditional dual maintenance and reliever therapies

*   LABA monotherapy is not recommended owing to increased risk of exacerbations and asthma related death

*   Written asthma plans given to patients as part of a supported self-management strategy help reduce hospitalisation and emergency department attendances

*A 35 year old man with a prior diagnosis of mild asthma presents to his general practitioner with a three month history of intermittently waking at night with cough and shortness of breath. He works as a chef and has found it difficult to complete a full shift during this time. He has been prescribed beclometasone 200 μg twice a day for a long time and asks if there is a need to change his treatment in light of his new persistent symptoms.*

Poorly controlled or moderate asthma occurs when patients experience either daily symptoms of asthma, nocturnal awakenings, more than two exacerbations per year, or some limitation of their daily activities.12 With frequent alterations of guidelines, and continual development of new medications and delivery devices, choosing a suitable treatment strategy can pose a challenge in clinical practice. In this article, we present the latest guidance on drugs used in primary care for poorly controlled asthma in adults.

## What treatments are available for poorly controlled asthma?

### ICS/LABA combination

Inhaled corticosteroids (ICS, eg, beclometasone dipropionate, budesonide, fluticasone furoate, etc) and long acting β agonists (LABA, eg, formoterol, salmeterol, vilanterol, etc) are the mainstay of treatment for poorly controlled or moderate asthma (table 1). ICS suppress airway inflammation leading to reduced bronchial hyperresponsiveness. LABAs act on bronchial smooth muscle β adrenoceptors and cause bronchodilation. ICS and LABA are typically prescribed as a single fixed dose combination inhaler rather than in separate inhalers for better efficacy, safety, adherence, and convenience.1

View this table:
[Table 1](https://www.bmj.com/content/375/bmj.n2355/T1)

Table 1 
Global Initiative for Asthma treatment ladder1

National and international guidelines—Global Initiative for Asthma,1 National Institute for Health and Care Excellence (NICE),3 British Thoracic Society/Scottish Intercollegiate Guidelines Network,4 and the National Asthma Education and Prevention Program (American)5—suggest two options for commencing ICS and LABA treatments in moderate persistent asthma. The Single Maintenance and Reliever Therapy (SMART or MART) protocol recommends ICS and a fast acting LABA as both maintenance and rescue treatment for relief from symptoms (for example, low dose budesonide-formoterol or beclomethasone-formoterol).1 Alternatively, ICS plus LABA (ICS/LABA) can be combined with a short acting β agonist (SABA) as needed as reliever treatment.

### Montelukast

The guidelines recommend montelukast in patients whose symptoms are not well controlled despite adequate dosing of ICS/LABA treatments and good adherence.1235 Montelukast is a leukotriene receptor antagonist (LTRA). It blocks the production of cysteinyl leukotrienes which are potent broncho-constricting and proinflammatory mediators. This results in enhanced bronchodilation and reduced airway mucus production.6

### Newer treatments

Patients whose asthma is severe and poorly controlled with the above drugs can be considered for newer add-on treatments. These include long acting muscarinic antagonists (LAMAs), azithromycin, and biological therapies.12789 They are usually prescribed in specialist settings after careful evaluation of a patient’s symptoms, and consideration of risks and benefits.

## How well do they work?

Two Cochrane reviews published in 2013 compared budesonide and formoterol as maintenance and reliever therapy (MART) with inhaled corticosteroids alone or as combination therapy for maintenance with any reliever treatment for chronic asthma.1011 SMART was associated with reduced exacerbation rates requiring hospitalisation or emergency department visits (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57 to 0.90; I2=0%, P=0.66), oral corticosteroids (OR 0.75, 95% CI 0.65 to 0.87; I2=0%, P=0.82) and lower overall ICS total daily dose.11 The strength of evidence that SMART reduces hospitalisations or emergency department visits is weak (one fewer per 100 treated than in the control group, 95% CI, 0 to 2 fewer).1011 Two fewer people needed a course of oral steroids per 100 treated (95% CI 1 to 3 fewer) with SMART compared with alternative regimens. Two randomised controlled trials (RCTs) published in 2013 showed similar results with use of the SMART regimen.1213 Most studies are industry sponsored, and do not include children and adolescents. A post-hoc analysis of industry sponsored trials reported similar efficacy and safety for SMART regimens in adolescents (12-17 years).14 Few studies have directly compared the efficacy of various ICS preparations and have shown comparable effects.15

Very limited evidence is available for montelukast in patients with poorly controlled asthma. An open label industry sponsored trial (1681 participants) reported that addition of oral montelukast to ICS or ICS+LABA improved asthma control and asthma related quality of life over six months in adults with insufficiently controlled asthma.16 LTRAs have been shown to decrease sputum eosinophilia,17 fraction of exhaled nitric oxide,18 airway inflammation,19 and bronchial hyperresponsiveness,20 but the clinical relevance of these outcomes is not established. LTRAs may have a role in managing exercise induced asthma,2122 aspirin exacerbated respiratory disease (which includes non-steroidal anti-inflammatory drug intolerance),23 and in patients with asthma and elevated body mass index,24 but this evidence comes from small single studies.

## What are the harms?

Few studies assess the risk of systemic adverse effects associated with the use of ICS in asthma. A Cochrane review found that the rate of serious adverse events (eg, hospitalisation, intensive care admission, intubation) was 23 per 1000 patients in a pooled analysis of patients taking ICS plus salmeterol compared with 21 per 1000 patients taking ICS alone.25 ICS is generally considered safe at low to medium doses (<1000 µg beclomethasone dipropionate equivalent per day).26 Local side effects include dysphonia and oral candidiasis. These can be mitigated with careful attention to oral or throat hygiene, good inhaler technique, and the preferential use of spacer devices or valved holding chambers to reduce oropharyngeal deposition.

Higher doses of ICS are associated with systemic side effects; in particular, adrenal insufficiency. About 6.8% of patients on ICS experience adrenal insufficiency, according to a systematic review.27 These doses are not routinely used for treatment of mild to moderate asthma but some patients may be on higher cumulative doses before treatment is escalated in response to persistent symptoms. NICE recommends that patients on high dose ICS (>1000 µg/day beclomethasone dipropionate or 1600 µg/day for budesonide or equivalent) carry a steroid warning card.3

LABA monotherapy is associated with an increased risk of severe asthma attacks leading to hospitalisation and asthma related death,282930 and is discouraged by all major asthma guidelines.1345 LABAs are combined with ICS in all fixed dose combination inhalers to prevent substitution of ICS maintenance therapy with LABA monotherapy.2531

Montelukast can have neuropsychiatric adverse effects including nightmares, aggression, and depression.32 A case series reported development of eosinophilic granulomatosis with polyangiitis with use of LTRAs, sometimes linked to weaning of corticosteroids, but causation has not been established.33

## How are they given and monitored?

Confirm the diagnosis of asthma in any patient with worsening symptoms, ideally by observing for reversible airflow limitation. Table 2 lists aspects to cover on initial assessment and potential causes of reduced asthma control to address before considering a change in medication.7893435

View this table:
[Table 2](https://www.bmj.com/content/375/bmj.n2355/T2)

Table 2 
Care of a patient with worsening symptoms1

If a change in medication is indicated, prescribe ICS/LABA combinations at the lowest dose of ICS possible to achieve symptomatic control. The aims of treatment are to minimise disruptive symptoms, improve the patient’s asthma related quality of life, and prevent exacerbations and worsening. Most inhaled corticosteroids are prescribed for use twice daily. Ciclesonide is a once daily preparation associated with lower incidence of oral candidiasis compared with fluticasone at equivalent doses.36 Fluticasone furoate is a once daily preparation available in some countries, including the US and Japan, as a standalone ICS and is more widely available as a combination ICS/LABA (vilanterol) inhaler preparation. Arrange a regular review to assess symptom control.1

Choosing the appropriate inhaler device for a patient is important to optimise dosing schedule, adherence to therapy, and avoidance of critical errors in inhaler technique.37 When switching from single to combination inhalers, ensure that the equivalent ICS dosing is not lower than the patient’s current treatment.

With SMART regimens daily dosing varies in response to symptoms. Guidelines recommend a maximum safe daily dose.1 Dosing is capped at 72 μg metered dose for budesonide-formoterol and 48 μg metered dose for beclomethasone-formoterol. Provide patients with a written action plan tailored to the specific ICS prescribed, outlining how to change their dosing schedule in response to symptom triggers including exacerbation. Self-management involves patient education reinforced by an asthma action plan and supported by regular review. A meta-review (27 systematic reviews and 13 RCTs) showed that supported self-management for asthma can reduce hospitalisations, emergency department attendances, and unscheduled consultations in specialist and primary care.38

Given the uncertain benefits of montelukast and potential adverse reactions, discuss the risks and benefits with your patient before commencing this medication.

## How cost effective are they?

Few studies have compared cost effectiveness of individual ICS. A review article suggested that fluticasone propionate was associated with a marginal cost benefit over budesonide, but this effect was not seen at higher doses of ICS.39 An analysis of cost effectiveness in the UK and other European countries in 2006 found that SMART is more cost effective compared with the alternative dosing strategy of LABA/ICS plus SABA reliever.40 The current availability of generic preparations suitable for use in SMART protocols will have reduced the costs further.

The cost of inhaler devices can differ and can sometimes be a barrier to compliance. Discuss with your patient the expected costs when choosing a suitable inhaler device. Sustainability is another factor in inhaler choice. Metered dose inhalers (MDIs) contain hydrofluorocarbons, which are potent greenhouse gases that contribute significantly to the carbon footprint. A simple switch from MDI to equivalent dry powder inhaler (DPI) could reduce the yearly carbon footprint of an asthmatic patient by a similar amount as would be achieved by switching to a plant based diet (approximately 455 CO2 equivalent).

### Tips for patients

*   Always take your asthma medication as prescribed

*   Your doctor may provide written advice (asthma action plan) on how to change how often you take your inhaler if you develop symptoms or feel an asthma attack coming on. It’s important to recognise changes in your symptoms so that you can follow this asthma plan correctly

*   Peak flow meters can be useful when changing your inhaler frequency according to your asthma plan

*   Inhalers can sometimes be difficult to use. If you have any doubt about how to take your inhaler, contact your pharmacist or GP

*   Some inhalers can cause fungal infections in the mouth (white coating of your mouth or tongue) and this may require medication to treat. Report this to your doctor

*   Rinse your mouth after taking your inhaler if it contains an inhaled steroid. This can prevent fungal mouth infections from developing

### Education into practice

*   How would you assess an asthmatic patient with worsening symptoms to determine if therapy needs to be escalated?

*   How do you assess inhaler technique in your consultation with asthmatic patients?

*   How would you explain the SMART regimen to your patients?

*   How would you facilitate self-management at your practice at an institutional level for people with asthma, ideally in a way that is regularly audited to facilitate ongoing service improvement?

### How patients were involved in the creation of this article

We asked three patients who attend our asthma service to review a draft of this manuscript and to help develop the “tips for patients” box. They highlighted the importance of understanding symptom control and knowing when to seek help from their practitioner for troublesome symptoms.

## Footnotes

*   This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. To suggest a topic, please email us at practice@bmj.com

*   Advisers to this series are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Patricia McGettigan, clinical senior lecturer in clinical pharmacology, Queen Mary's University, London

*   Competing interests: Competing interests *The BMJ* has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

*   Further details of *The BMJ* policy on financial interests are here: [https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests](https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests)

*   Provenance and peer review: commissioned, based on an idea from the authors.

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