Dr Mark L Levy argues that current UK treatment regimens for asthma are not as safe or effective as the ones recommended in the updated GINA asthma strategy

Levy mark

Dr Mark L Levy

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Read this article to learn more about:

  • GINA’s recommendation that all patients with asthma should be treated with regular or intermittent inhaled corticosteroids (ICS)
  • use of regular or intermittent ICS plus formoterol (ICS-FORM) in people aged over 12 years
  • reasons for early referral of people with difficult-to-treat asthma.

For nearly 50 years, guidelines and guidance on asthma management have favoured prescription of a short-acting beta2-agonist bronchodilator (SABA) as first-line treatment. Despite evidence that this practice is unsafe,1–8 it is still recommended as first-line treatment in the UK by NICE9 and in the British guideline on the management of asthma.10 Furthermore, there is strong evidence of a reduction of symptoms, exacerbations, and asthma deaths with inhaled corticosteroid (ICS) treatment,11,12 even in people with very infrequent symptoms.13

Members of the Global Initiative for Asthma (GINA) science committee designed and published two landmark studies,14,15 followed by another international study, with patients aged 12 years or older with mild asthma.16 These studies compared as-needed SABA plus regular ICS with SABA when needed; and with ICS plus formoterol (ICS-FORM) used as needed for respiratory symptoms.

Formoterol is a rapid-acting, long-acting beta2-agonist bronchodilator (LABA). The research demonstrated a large reduction in severe exacerbations with ICS-FORM compared with SABA as needed;14 non-inferiority for severe exacerbations for ICS-FORM compared with daily low-dose ICS plus SABA as needed;14,15 and, notably, fewer severe exacerbations in ICS-FORM as needed compared with regular ICS plus SABA as needed.16

With this compelling evidence relating to patient safety, the 2019 GINA strategy document17 now recommends that all patients with asthma, irrespective of severity, should be treated with regular or intermittent ICS. Short-acting beta2-agonists should not be prescribed as initial or for regular treatment of asthma.17

In practice, a number of patients state that they are not willing to use regular medication, especially if they have intermittent symptoms, with the result that they simply use intermittent reliever medication in the form of salbutamol or terbutaline (SABAs) for their symptoms. However, the UK National Review of Asthma Deaths7 (NRAD) and subsequent preventable child asthma death inquests8 demonstrated very clearly that excess prescribing and use of salbutamol can result in tragedy.

Many people experience symptom benefit from short-acting reliever treatment and therefore don’t understand why they should continue to take ICS when their symptoms have improved. Asthma is defined as a disease that is usually characterised by chronic (i.e. ongoing) airway inflammation, and given that even people with very infrequent symptoms are at risk of asthma attacks, it is usually advisable to continue treatment with ICS.

So, for reasons of safety, the new GINA 2019 recommendations are that patients over 12 years old should be prescribed either regular or intermittent ICS-FORM. The GINA 2019 strategy also recommends that patients aged over 12 years are advised to use ICS-FORM as the preferred reliever medication rather than SABA alone. The recommendation for intermittent treatment alone is made as an off-licence recommendation on the basis of patient safety.17

Currently, there are six licensed preparations in the UK, depending on brand, for maintenance and reliever therapy (MART) (or SMART, which refers specifically to MART with Symbicort®):

  • Fobumix® 160/4.518
  • Fostair® 100/619
  • Fostair NEXThaler® 100/620
  • DuoResp Spiromax® 160/4.521
  • Symbicort® 100/622
  • Symbicort® 200/6.23

The GINA strategy recommends that anyone diagnosed with asthma should be prescribed ICS, and for those who are prescribed ICS-FORM combination inhalers that are licensed for regular and intermittent use, they should use their ICS-FORM for relief rather than a SABA.17 So, according to the UK licensed indication, patients can be prescribed MART (or SMART), without a SABA, with advice to use the medication as per the licence regularly, plus as needed for symptom relief (prescribers should of course be familiar with the licensed indications). In this way, people who do not adhere to prescribing advice to use their medication regularly (as many with intermittent symptoms don’t) will at least get the protection from poor outcomes from the intermittent, albeit infrequent, use of the ICS component of this medication. Ideally, intermittent use of ICS-FORM is preferable to SABA in those people with mild asthma (i.e. those who have symptoms less than twice a month) for the prevention of asthma exacerbations.16 Solely intermittent use of ICS-FORM is currently only licensed in Brazil; in the UK, intermittent use of ICS-FORM is only licensed as part of a MART (or SMART) regimen.

Practically, in my personal view, for those patients who are adamant that they wish to continue using their SABA, these SABAs should not be prescribed as authorised repeat items and the patient should:

  • be advised of the risks of poor outcome (even death) due to excess use of SABA without ICS
  • be advised to use the MART (or SMART) treatment regimen (and this should be clearly detailed on the Asthma UK personal asthma self-management plan, available at: www.asthma.org.uk)
  • be advised to attend for review when they request a SABA prescription, and
  • if they insist on a SABA, be prescribed both a SABA and an ICS-FORM; they should be advised to first try the ICS-FORM for relief, and if no success then use the SABA, in the hope that the patient will be weaned off their SABA as they realise that they get rapid, similar bronchodilator relief from the ICS-FORM (a colleague recommends this as the ‘two-pocket’ regimen—SABA in one pocket and ICS-FORM in another).

GINA 2019 has clearly indicated that the advice to use ICS-FORM (in accordance with local regulations) for relief as first-line treatment only applies to patients aged 12 years and over who are prescribed ICS-FORM combination inhalers licensed for MART or SMART,17 because there is no safety evidence for combining other LABAs with formoterol. So those patients prescribed other combinations of ICS-LABA should be advised to continue to use SABA for relief medication.17

Apart from one study, there is little evidence to support the new recommendations for children under 12 years of age with diagnosed asthma; therefore GINA 2019 recommends (off-label recommendation on the basis of safety) that patients in this group are advised to use a low-dose ICS whenever they use their SABA for relief.17 

Readers should note that the current GINA 2019 recommendations are based on ensuring safety for people with asthma,1–8, 11–13 justified by good quality evidence from studies utilising budesonide-formoterol combination inhalers by one manufacturer.14–16 Many patients do not use their preventer medication regularly, and although intermittent use of ICS-FORM is currently (September 2019) an ‘off-licence’ recommendation, patients who don’t adhere to maintenance advice may benefit from being prescribed a MART or SMART inhaler and therefore intermittent use of ICS-FORM rather than a SABA. Prescribers should follow relevant professional guidance, taking full responsibility for all clinical decisions. Informed consent should be obtained and documented. See the General Medical Council’s guidance on Good practice in prescribing and managing medicines and devices for further information.24

GINA 201917 has also recommended earlier referral of patients for specialist assessment. Because there are new biological treatments available for people with severe asthma (see the GINA 2019 strategy document,17 under ‘difficult to treat and severe asthma’, p.84), those whose asthma remains uncontrolled on medium doses of ICS-LABA should be referred to a specialist. This is in keeping with the 2014 NRAD recommendation for referral to a specialist of any patient who has experienced two or more asthma attacks or exacerbations in 12 months.7 Sadly, despite continued preventable deaths,8 as yet there has been no national UK action in this regard. Meanwhile, among comparable countries in Europe, the UK continues to have the worst record for asthma deaths in young people;25 and among comparable countries in the world, it has the fifth worst record for asthma deaths in people aged 5–34 years.26

In summary, the new GINA 2019 recommendations may be a potential saviour for people in the UK with asthma; the guidance is very clear. On the basis of safety, every patient with asthma should be prescribed ICS and those prescribed combinations with formoterol should be advised to use this treatment as their reliever of choice.

Dr Mark L Levy

Locum GP, London

Clinical Lead, National Review of Asthma Deaths (2011–2014)

Member of GINA Board of Directors

Declaration of interests

Dr Levy reports personal fees from Clement Clarke International, personal fees from Teva, personal fees from AstraZeneca, non-financial support and other from GINA, personal fees from Chiesi, grants from Conzorcio Futuro In Ricerca, personal fees from Soar Beyond, personal fees from Orion Pharmaceuticals, other from Napp Pharmaceuticals, personal fees from National Services for Health Improvement, a company providing services for practices (Nurse asthma Reviews), personal fees from Novartis Pharmaceuticals, personal fees from Glaxo Smith Klein, non-financial support from Asthma and COPD (Joint) Lead for Whole Systems Integrated Care (WSIC) North West London, personal fees from Trudel Pharmaceuticals, outside the submitted work.

References

  1. Dusser D, Montani D, Chanez P et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy 2007; 62 (6): 591–604.
  2. Suissa S, Blais L, Ernst P. Patterns of increasing beta-2-agonist use and the risk of fatal or near-fatal asthma. Eur Respir J 1994; 7 (9): 1602–1609.
  3. Reddel H, Ampon R, Sawyer S, Peters M. Risks associated with managing asthma without a preventer: urgent healthcare, poor asthma control and over-the-counter reliever use in a cross-sectional population survey. BMJ Open 2017; 7: e016688. doi:10.1136/bmjopen-2017-016688
  4. Hancox R, Cowan J, Flannery E et al. Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled short acting beta-agonist treatment. Respir Med 2000; 94 (8): 767–771.
  5. Stanford R, Shah M, D’Souza A et al. Short-acting beta-agonist use and its ability to predict future asthma-related outcomes. Ann Allergy Asthma Immunol 2012; 109 (6): 403–407.
  6. Hull S, McKibben S, Homer K et al. Asthma prescribing, ethnicity and risk of hospital admission: an analysis of 35,864 linked primary and secondary care records in East London. NPJ Prim Care Respir Med 2016; 26: 16049.
  7. Royal College of Physicians. Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report. London: RCP, 2014. Available at: www.rcplondon.ac.uk/sites/default/files/why-asthma-still-kills-full-report.pdf
  8. Levy M, Fleming L, Warner J, Bush A. Paediatric asthma care in the UK: fragmented and fatally fallible. Br J Gen Pract 2019; 69: 405–406.
  9. NICE. Asthma: diagnosis, monitoring and chronic asthma management. NICE Guideline 80. NICE, 2017. Available at: www.nice.org.uk/ng80
  10. Scottish Intercollegiate Guidelines Network (SIGN), the British Thoracic Society (BTS). British guideline on the management of asthma 2019. Available at: www.sign.ac.uk/sign-158-british-guideline-on-the-management-of-asthma.html
  11. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343 (5): 332–336.
  12. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma. Thorax 2002; 57 (10): 880–884.
  13. Reddel H, Busse W, Pedersen S et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet 2017; 389 (10065): 157–166.
  14. O’Byrne P, FitzGerald J, Bateman E et al. Inhaled combined budesonide–formoterol as needed in mild asthma. New Engl J Med 2018; 378 (20): 1865–1876.
  15. Bateman E, Reddel H, O’Byrne P et al. As-needed budesonide–formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018; 378 (20): 1877–1887.
  16. Beasley R, Holliday M, Reddel H et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med 2019; 380 (21): 2020–2030.
  17. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, 2019. GINA, 2019. Available at: www.ginasthma.org
  18. Orion Pharma (UK) Limited. Fobumix Easyhaler 160 micrograms/4.5 micrograms, inhalation powder. Summary of product characteristics. www.medicines.org.uk/emc/product/8706/smpc
  19. Chiesi Limited. Fostair 100/6 micrograms per actuation pressurised inhalation solution. Summary of product characteristics. www.medicines.org.uk/emc/product/6318
  20. Chiesi Limited. Fostair NEXThaler 100 micrograms/6 micrograms per actuation inhalation powder. Summary of product characteristics. www.medicines.org.uk/emc/product/3317
  21. Teva Pharma B.V. DuoResp Spiromax 160 micrograms/4.5 micrograms inhalation powder. Summary of product characteristics. www.medicines.org.uk/emc/product/3323/smpc
  22. AstraZeneca UK Limited. Symbicort® Turbohaler® 100 micrograms/6 micrograms/inhalation, inhalation powder. Summary of product characteristics. www.medicines.org.uk/emc/product/1326
  23. AstraZeneca UK Limited. Symbicort® Turbohaler® 200 micrograms/6 micrograms/inhalation, inhalation powder. Summary of product characteristics. www.medicines.org.uk/emc/product/1327/smpc
  24. General Medical Council. Good practice in prescribing and managing medicines and devices. GMC, 2013. Available at: www.gmc-uk.org/Prescribing_guidance.pdf_59055247.pdf
  25. Shah R, Hagell A, Cheung R. International comparisons of health and wellbeing in adolescence and early adulthood. Nuffield Trust; 2019. Available at: www.nuffieldtrust.org.uk/files/2019-02/1550657729_nt-ayph-adolescent-health-report-web.pdf
  26. Global Asthma Network. The Global Asthma Report 2018. Auckland, New Zealand: Global Asthma Network, 2018. Available from: www.globalasthmareport.org