Triple therapy in asthma - why and when you should use it

Most general practice nurses will be familiar with the use of triple therapy in patients with COPD, but less so in patients with asthma. However, this approach has its merits, not least as an alternative to increasing the dose of inhaled corticosteroids

With the new Global Initiative for Obstructive Lung Disease (GOLD) guidelines for chronic obstructive lung disease (COPD) released in November 2018,¹ and the new National Institute for Health and Care Excellence COPD update also due out imminently, triple therapy is in the news at present. However, it is important to remember that triple therapy (usually an inhaled corticosteroid with a long acting beta 2 agonist plus either a long acting muscarinic antagonist or a leukotriene receptor antagonist) is recommended in the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidelines for asthma too.² In this article, we will discuss the evidence base for using triple therapy in asthma and work through some case studies which show where and how different drugs might be initiated. For all the drugs mentioned below, please consult the summary of product characteristics for the individual medication, at https://www.medicines.org.uk/emc/ for further details.

By the end of this article you should:

• Be familiar with the BTS/SIGN and NICE guidelines stepwise approach to asthma management
• Be aware of the options when stepping up to triple therapy in asthma
• Recognise how to tailor triple therapy to the individual according to their needs and preferences
• Know when to refer people with asthma who do not respond to treatment

THE BTS/SIGN APPROACH

The British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidelines on asthma were last updated in 2016.² They are currently being updated again and due to be published around the middle of 2019. This article will refer to the place for triple therapy in adult asthma, based on the 2016 guidance, but also contains additional recommendations that reflect new inhaler licences that have come into force since those guidelines were published.

In the current guidelines, the approach to pharmacological management of asthma is relatively straightforward in both adults and children. The advice is that once the diagnosis is confirmed, using a combination of history taking, lung function tests and response to treatment (bronchodilator reversibility testing and/or improvements in symptoms score and/or lung function post corticosteroid therapy) treatment with an inhaled corticosteroid (ICS) should be the mainstay of treatment. This should be at a low dose for adults (400mcg total daily dose of a standard ICS) or at a very low dose for the under 12s (200mcg total daily dose of a standard ICS).

If the patient responds to this treatment but is still getting some breakthrough symptoms, consideration should be given to stepping up the treatment. However, this should only be done after adherence to treatment (dose, frequency, technique) has been fully assessed. If these are good, the addition of a long-acting beta2 agonist (LABA) to the ICS in a combination therapy is the next step, maintaining the low (or very low, in the case of the under 12s) dose of ICS as it is.

Examples of low dose combination inhalers include:

• Duoresp 160/4.5mcg 1 puff bd (licensed from age 18)
• Flutiform 50/5mcg 2 puffs bd (licensed from age 12)
• Fobumix 80/4.5mcg or 160/4.5mcg 1 puff bd (licensed from age 18)
• Fostair 100/6mcg 1 puff bd (licensed from age 18)
• Relvar 92/22mcg 1 puff od (low-medium dose) (licensed from age 12)
• Symbicort 100 or 200/6mcg 1 puff bd (licensed from age 6)

If the use of a low dose ICS/LABA combination inhaler is still not fully controlling symptoms, the next step would be to increase the ICS component up to a medium dose. Examples of medium dose combinations include:

• Duoresp 160/4.5mcg 2 puffs bd
• Flutiform 100/5mcg 2 puffs bd
• Fobumix 160/5mcg 2 puffs bd
• Fostair 100/6mcg 2 puffs bd
• Relvar 92/22mcg 1 puff od

(low-medium dose)

• Symbicort 200/6mcg 2 puffs bd

If the patient is still getting asthma symptoms on a medium dose ICS/LABA and technique and adherence remain good, then the next step is to consider the addition of a different therapy, usually a leukotriene receptor antagonist (LTRA) e.g. montelukast, or a LAMA i.e. Spiriva Respimat, although BTS/SIGN does endorse the use of theophyllines too. Theophyllines have a range of potential side effects and interactions, however, so are not often used for asthma in primary care.

It is useful to note that these third line options may be introduced sooner if the patient presentation and history suggests that this would be appropriate.

THE NICE APPROACH

NICE published its guidelines on asthma management in 2017.³ NICE took a different approach from BTS/SIGN by recommending LTRA therapy as the second line option after an ICS. Montelukast is licensed to prescribe at 4mg daily from age 6 months to age 5 years, 5mg from 6-14 years and 10mg from age 15 and beyond.

In children age 5-16 years who do not respond to montelukast, NICE recommends that it should be stopped and that an ICS/LABA should then be tried, first as a fixed dose and then as maintenance and reliever therapy (MART). However, it is important to remember that at the present time, only Symbicort Turbohaler is licensed to use as MART in children and then only in those aged 12 and above. If a low dose comination does not work, either as a fixed or MART regimen, then NICE advises moving to a medium dose ICS/LABA either as a fixed dose or as a MART regime. NICE then advises that if the symptoms are still not controlled, the clinician should consider increasing the dose of ICS to a high maintenance dose or should try a different drug, i.e. a LAMA or a theophylline. The same general approach is recommended for those age 17 and above. Interestingly, NICE states that in the case of a patient who is not responding fully to a moderate dose of ICS/LABA with or without an LTRA, consideration should be given to ‘seeking advice from a healthcare professional with expertise in asthma’. One might argue that asthma care should only ever be delivered by such a healthcare professional and in fact, the National Review of Asthma Deaths linked a lack of expertise on the part of the clinician to an increased risk of asthma deaths.⁴

So what are the licensed indications for an LTRA and a LAMA in asthma?

Montelukast

The summary of product characteristics states that montelukast is indicated in the treatment of asthma in children and adults from age 6 months as an add-on therapy to inhaled corticosteroids in patients who have mild to moderate persistent asthma, where the ICS along with ‘as required’ short-acting beta2 agonists provide inadequate symptom control. It goes on to say that in patients who have asthma and hay fever, montelukast can also provide symptomatic relief of the hay fever symptoms. Furthermore, montelukast can also help patients who have asthma with exercise-induced bronchoconstriction.

BTS/SIGN includes an additional recommendation for motelukast 4mg, saying that it may also be used as an alternative treatment option to a very low-dose ICS for the under 5s, based on evidence from a study by Knorr et al.⁵ The licence for montelukast 4mg says that it may be used in this way for children with mild persistent asthma or asthma with exercise induced bronchoconstriction who do not have a recent history of serious asthma attacks that required oral corticosteroid use, and who have demonstrated that they are not capable of using inhaled corticosteroids.

The evidence base for LTRAs

Adding an LTRA to an ICS has shown a tendency to improvements in lung function and symptoms along with fewer asthma attacks in all age groups.⁶ However, there is some extrapolation of this evidence when BTS/SIGN recommends their use after an ICS/LABA. Nonetheless, a systematic review of studies comparing the addition of an LTRA to an ICS with using a LABA with the ICS showed that the latter was slightly more effective at reducing asthma attacks and reducing the need for rescue therapy.⁷ NICE notes this in its own guidelines but states that this small difference in effectiveness led the guidelines group to decide that the cost benefit of trialling an LTRA first outweighed the pragmatism (and potential safety) of using a combination ICS/LABA inhaler when stepping up.³

Spiriva Respimat

There is only one LAMA which is licensed for asthma and that is tiotropium as Spiriva, delivered through the Respimat device. No other LAMAs are licensed for asthma although others are, of course, licensed for COPD. Spiriva via the Handihaler is also only licensed for COPD. The summary of product characteristics for Spiriva Respimat in asthma states that it is indicated as add-on maintenance bronchodilator treatment in patients aged 6 years and older with severe asthma who experienced one or more severe asthma exacerbations in the preceding year. This licence changed in 2017 when the inhaler went from being licensed in adults over 18 only, to being licensed in children age 6 and above. It is worth noting that there is some discrepancy between the licence for Spiriva in asthma (severe asthma and after at least one severe exacerbation) and where the BTS/SIGN guidelines recommend using it (after a moderate ICS/LABA has not achieved complete asthma control).

The evidence base for Spiriva in asthma

Randomised control trials in adults taking tiotropium in addition to an ICS/LABA indicated that they reported fewer exacerbations and better lung function than those just on an ICS/LABA, and fewer adverse events were reported in those taking tiotropium.⁸ In adolescents and also children age 6-11, tiotropium via the Respimat improved lung function and, in children with severe symptomatic asthma, it was well tolerated as an add-on therapy to ICS.^9,10

Theophyllines

As mentioned previously, theophyllines are included as a possible third or fourth option and they have been shown to improve lung function and symptoms, but side effects occur more commonly so these are not often initiated for asthma in primary care.¹¹

THE FUTURE

At the moment triple therapy for asthma will mean, by and large, an ICS/LABA plus an LTRA or an ICS/LABA plus Spiriva Respimat. However, in the future there may be the possibility of at least one of the triple therapies in one device, i.e. those used for COPD gaining a license for use in asthma. This will simplify asthma care for those in whom triple therapy with an ICS/LABA/ LAMA has been shown to be effective.

CASE STUDY 1

Candy is 23 years old and has had asthma for 10 years. Initially she was well controlled on a low dose ICS/LABA but when she moved from the city to a rural area she found aeroallergens were causing her to have more asthma symptoms, along with a marked increase in her hay fever symptoms. She tried a moderate dose of ICS/LABA and moved to a MART regime but she still found that her hay fever symptoms were impacting on her asthma. She did not get on with a nasal spray and antihistamines did not work for her. She found it embarrassing when she had to keep using her reliever inhaler in public and was using 1 x 200-dose inhaler every 2-3 months in summer.

In this situation, an LTRA – montelukast 10mg – would be a good choice for Candy. This is licensed for asthma which is not controlled with an ICS alone and it will also help resolve her seasonal allergic rhinitis symptoms. Following initiation of the LTRA, Candy was seen in practice and reported that her symptoms had improved from the second day of treatment and she had not used her reliever for the past 2 weeks.

CASE STUDY 2

Aaron is 13 years old and was recently diagnosed with asthma following an acute asthma attack which occurred out of the blue at a music festival. Careful history taking revealed that he had been having asthma symptoms for some time but that he had ignored them. Aaron’s sister and father have asthma and he did not want to get into the same situation he had seen them in – lots of asthma symptoms, annual trips to the emergency department and not being able to do sport or travel abroad for fear of causing a flare up of symptoms. Aaron was particularly concerned because he is a committed sportsman, hoping to represent his country at rowing in the future.

Sensitive discussions with Aaron about his diagnosis and about how it could be managed effectively so that it did not impact on his day to day life resulted in Aaron being prescribed a low dose ICS (fluticasone 50mcg 2 puffs bd) and then a low dose ICS/LABA (Flutiform 50/5mg 2 puffs bd). However, he had noticed that he still suffered from a tight chest and wheeze when he was training. Stepping up the dose of Flutiform to 125/5mcg 2 puffs bd made no difference but the addition of montelukast 5mg to his Flutiform 50/5 mcg 2 puffs bd resulted in control of his exercise-induced symptoms and ensured that he was soon able to get back to training at full capacity.

CASE STUDY 3

Stefan, age 21, is a university student. He had asthma as a child, which recently recurred and he has been prescribed an ICS/LABA with reasonable results. He still gets symptoms, however, not helped by the fact that he smokes 15 cigarettes a day. He prefers to use a MART regimen for taking his ICS/LABA as he can’t always be relied upon to keep his reliever inhaler with him. In spite of this, he was recently admitted to hospital following an acute severe exacerbation of asthma.

Stefan was discharged home with his Fostair NextHaler 100/6mcg 1 puff bd plus extra puffs as required up to a maximum of 8 a day, along with Spiriva Respimat 2.5mcg 2 puffs daily.

CASE STUDY 4

Imogen, age 7, was diagnosed with asthma when she was just 4 years old. She is a confident, articulate youngster who us already taking an interest in her asthma management. Imogen’s asthma is at the more severe end of the spectrum and she is already taking Symbicort 200/6mcg bd and montelukast 5mg.

After a severe exacerbation linked to a viral infection last winter, Imogen has been prescribed Spiriva Respimat. She is adept at putting it together and has demonstrated excellent inhaler technique with the device. Her asthma has been well controlled since.

WHEN TO REFER

In line with BTS/SIGN, anyone who is not controlled on a moderate dose of ICS/LABA and a LAMA with or without an LTRA should be referred to secondary care as they may have severe or difficult asthma. These patients may benefit from further assessment, which might indicate if they could benefit from a biologic therapy for their asthma.

STEPPING DOWN

As asthma is a variable condition, the treatment should also vary. In general, treatments should be reduced or removed in the order they were added in – moving down the escalator illustrated in the BTS/SIGN guidelines treatment algorithm.²

However, in some cases, the additional benefit of a particular therapy may mean that the first step down will be in the dose of the ICS, because the other treatment, e.g. the LTRA, has been shown to have particular benefit for exercise induced symptoms or allergy, for example. Each case will be different and the pros and cons of any step down approach should be weighed up and discussed with the patient and/or their parent (or carer).

IN SUMMARY

Asthma is a variable condition, underpinned by inflammation which requires the use of an ICS to control symptoms. When the need to step up treatment becomes clear, the addition of a LABA is the safest and most practical step. If further treatment is needed, consideration should be given as to the merits and disadvantages of increasing the dose of ICS in the combination inhaler, adding an LTRA or introducing a LAMA (Spiriva Respimat). Patients should be at the centre of all decision making and clinicians should ensure that they practise effectively, preserving safety and promoting professionalism and trust.

RESOURCES

Asthma UK – national asthma charity www.asthma.org.uk

Education for Health Education for courses and resources for asthma and other long term conditions www.educationforhealth.org

Respiratory Futures website https://www.respiratoryfutures.org.uk/

REFERENCES

1. Global Initiative for Chronic Obstructive Lung Disease. 2019 Global Strategy for Prevention, Diagnosis and Management of COPD, 2018. https://goldcopd.org/gold-reports/

2. British Thoracic Society/Scottish Intercollegiate Guidelines Network (2016) British guideline on the management of asthma https://www.brit-thoracic.org.uk/standards-of-care/guidelines/btssign-british-guideline-on-the-management-of-asthma/

3. NICE NG80. Asthma: diagnosis, monitoring and chronic asthma management, 2017 https://www.nice.org.uk/guidance/ng80

4. Royal College of Physicians. Why Asthma Still Kills: The National Review of Asthma Deaths (NRAD), 2014 https://www.asthma.org.uk/globalassets/campaigns/nrad-full-report.pdf

5.Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108(3):E48.

6. Joos S, Miksch A, Szecsenyi J, et al. Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review. Thorax 2008;63(5):453-62.

7. Cao Y, Wang J, Bunjhoo H, et al. Comparison of leukotriene receptor antagonists in addition to inhaled corticosteroid and inhaled corticosteroid alone in the treatment of adolescents and adults with bronchial asthma: a meta-analysis. Asian Pac J Allergy Immunol 2012; 30(2):130-8.

8. Kew KM, Dahri K. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database Syst Rev 2016; Jan 21;(1):CD011721 https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011721.pub2/full

9. Hamelmann E, Vogelberg C, Szefler SJ. Tiotropium for the treatment of asthma in adolescents. Exp Opin Pharmacother 2017;18(3):305-312

10. Szefler SJ, Murphy K, Harper T, et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol 2017;140(5):1277-1287. doi: 10.1016/j.jaci.2017.01.014

11. Barnes PJ. Theophylline. Pharmaceuticals (Basel), 2010;3(3):725-747. doi:10.3390/ph3030725