Is there adequate evidence for quadrupling inhaled corticosteroid doses?

We would like to thank Dr. McCormack for his letter regarding our Practice article in the February issue of Canadian Family Physician.[1,2] He raises some important points that merit further discussion and clarification.

Dr. McCormack’s letter raises thoughtful concerns about the relative paucity of literature supporting quadrupling the inhaled corticosteroid (ICS) dose in the face of asthma worsening as part of an asthma action plan. Although we did recommend this approach in the “yellow” (acute loss of control) zone of the asthma action plan, at no point did we claim that this approach is supported by a strong level of evidence. The crucial distinction here, and the main purpose of our Practice article was to support clinicians in providing their patients with asthma action plans – a practice which, when combined with education and regular clinical review, is unquestionably supported by strong evidence.

Use of asthma action plans improves quality of life, reduces symptoms, and reduces hospitalizations, emergency room visits and unscheduled healthcare use in adults with asthma. This is a recommendation that has been found across international asthma guidelines for almost 30 years[3] and is supported by multiple systematic reviews of well-conducted randomized controlled trials (RCTs), including a more recent meta-review of 27 systematic reviews (244 RCTs) by Pinnock and colleagues.[4–6] Despite this, our own audit of three large family practices in Ontario found that not a single one of 884 adults with asthma followed for one year received an asthma action plan,[3] which was similar to findings of previous Canadian and US chart audits.[7,8] This is a major evidence-to-practice gap, and represents a lamentable lost opportunity to improve our asthma patients’ health and lives.[9] Studies that have sought to identify reasons for this gap suggest that primary care physicians lack the training and experience required to produce an asthma action plan for their patients, and particularly, to provide “yellow zone” recommendations.[10] This is what motivated us to develop a practical bedside tool for this purpose, which is the subject of our Practice article.

Here, as strong as the evidence is for provision of asthma action plans, we recognize Dr. McCormack’s point that the evidence for how inhaled medications should actually be augmented in the yellow zone of an asthma action plan is not nearly as strong. In our original publication describing the development of our evidence-based asthma action plan tool, we outlined the various levels of evidence for different yellow zone escalation strategies (including quadrupling ICS), as assigned in major international asthma guidelines, and found them to range from strong to consensus-based.[11] We also reviewed primary evidence for adjusting ICS dose in the asthma action plan yellow zone, and noted 3 negative trials of doubling the ICS dose and 2 positive trials of quadrupling.[12–17] The latter include the RCT by Oborne, et al. mentioned by Dr. McCormack, and another RCT by Foresi, et al. (which he did not mention), which showed statistically significant reductions in asthma exacerbations and days receiving oral corticosteroids in the quadrupling group vs. standard therapy, with similar rates of adverse events.[16] Since our publication, a third positive trial, the largest to date, was published by McKeever, et al.[18] These authors found a number needed to treat (NNT) of 14 people with quadrupling ICS dose to avoid a course of oral corticosteroids and an NNT of 17 to avoid unscheduled healthcare use (including a reduction in hospitalizations). In contrast with Dr. McCormack, we contend that each of these represents a clinically significant reduction in an important healthcare event. For comparison, the widely accepted standard of care to provide patients experiencing acute exacerbations of COPD with oral corticosteroids has an NNT of 10 to avoid treatment failure (hospital readmission or return to the emergency room), and a number needed to harm of 7.[19] Although we agree with his argument that the systemic effects of high ICS doses are not negligible, and that local side effects such as oral candidiasis and dysphonia can occur, we believe these compare favorably to the demonstrated morbidity and mortality associated with severe asthma exacerbations, including the costs of urgent healthcare use and the known risks of systemic glucocorticoids.[20] Unlike high-dose ICSs, even short courses of systemic glucocorticoids carry a risk of avascular necrosis, viral infections, ocular hypertension and open-angle glaucoma in susceptible patients, severe mood changes and psychotic reactions, GI upset, insomnia, weight gain, increased blood pressure, and perturbations in blood sugar in diabetic patients.[21–23] It is also of note that the higher-than-expected exacerbation rate in McKeever, et al.’s trial may have been a function of late activation of the asthma action plan – an issue which may also have affected the magnitude of the benefit, and reinforces the importance of providing education alongside the asthma action plan.[24]

This is not the first, nor will it be the last scientific forum in which the significance of the observed magnitude of benefit of quadrupling ICS in the yellow zone of the asthma action plan will be debated. Accordingly, we strongly agree with Dr. McCormack that the best approach is to present patients with the benefits and harms and to reach a conclusion based on shared decision-making. However, we also strongly disagree with his conclusion that a reasonable alternative to an asthma action plan with quadrupling would be to just have “a discussion of what to look out for with regard to exacerbations and when to seek medical help” (suggesting that a written action plan in not needed). With this statement, Dr. McCormack appears to conflate the debate around dosing in the asthma action plan yellow zone with the benefits of asthma action plans themselves. It is critical to note that patients in the control arms of all the mentioned studies of yellow zone ICS dosing received an asthma action plan.[12,18] Accordingly, their results do not offer any insight into the benefits of asthma action plans themselves, and should not be misappropriated to challenge the well-established literature supporting use of asthma action plans. Aside from the dose intensification recommendation in the yellow zone, action plans likely affect outcomes through multiple other mechanisms, including by reinforcing adherence to “green zone” (daily preventative) medications; by providing warning signs meriting urgent attention (averting deterioration into life-threatening asthma); and through general educational information (e.g. trigger avoidance).[25]

In conclusion, although we agree with Dr. McCormack that more research is required, to date, we believe that the balance of the evidence favours a recommendation to quadruple the ICS dose as part of the asthma action plan. Most importantly, asthma action plans remain a cornerstone of asthma management, and our focus must be to redouble efforts to help primary care physicians to deliver this complex intervention.

References:

1. Kouri A, Kaplan A, Boulet L-P, Gupta S. New evidence-based tool to guide the creation of asthma action plans for adults. Can Fam Physician. 2019 Feb 1;65(2):103–6.

2. McCormack J. Is there adequate evidence for quadrupling inhaled corticosteroid doses? Can Fam Physician. 2019 May 1;65(5):313–4.

3. Price C, Agarwal G, Chan D, Goel S, Kaplan AG, Boulet L-P, et al. Large care gaps in primary care management of asthma: a longitudinal practice audit. BMJ Open. 2019 Jan 1;9(1):e022506.

4. Gibson PG, Powell H, Coughlan J, Wilson AJ, Abramson M, Haywood P, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev. 2003;(1):CD001117.

5. Peytremann‐Bridevaux I, Arditi C, Gex G, Bridevaux P-O, Burnand B. Chronic disease management programmes for adults with asthma. Cochrane Database Syst Rev [Internet]. 2015 [cited 2019 May 29];(5). Available from: http://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007988.pub2/a...

6. Pinnock H, Parke HL, Panagioti M, Daines L, Pearce G, Epiphaniou E, et al. Systematic meta-review of supported self-management for asthma: a healthcare perspective. BMC Med. 2017 Dec;15(1):64.

7. Tsuyuki RT, Sin DD, Sharpe HM, Cowie RL, Nilsson C, Man SFP, et al. Management of asthma among community-based primary care physicians. J Asthma Off J Assoc Care Asthma. 2005 Apr;42(3):163–7.

8. Cicutto L, Dingae MB, Langmack EL. Improving asthma care in rural primary care practices: a performance improvement project. J Contin Educ Health Prof. 2014;34(4):205–14.

9. Gupta S, Kaplan A. Solving the mystery of the yellow zone of the asthma action plan. Npj Prim Care Respir Med. 2018 Jan 11;28(1):1.

10. Ring N, Jepson R, Hoskins G, Wilson C, Pinnock H, Sheikh A, et al. Understanding what helps or hinders asthma action plan use: a systematic review and synthesis of the qualitative literature. Patient Educ Couns. 2011 Nov;85(2):e131-143.

11. Kouri A, Boulet L-P, Kaplan A, Gupta S. An evidence-based, point-of-care tool to guide completion of asthma action plans in practice. Eur Respir J. 2017 May 1;49(5):1602238.

12. Quon BS, FitzGerald JM, Lemière C, Shahidi N, Ducharme FM. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev [Internet]. 2010 [cited 2019 May 29];(12). Available from: http://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007524.pub3/full

13. Rice-McDonald G, Bowler S, Staines G, Mitchell C. Doubling daily inhaled corticosteroid dose is ineffective in mild to moderately severe attacks of asthma in adults. Intern Med J. 2005 Dec;35(12):693–8.

14. Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet Lond Engl. 2004 Jan 24;363(9405):271–5.

15. FitzGerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax. 2004 Jul 1;59(7):550–6.

16. Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Chest. 2000 Feb;117(2):440–6.

17. Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Am J Respir Crit Care Med. 2009 Oct 1;180(7):598–602.

18. McKeever T, Mortimer K, Wilson A, Walker S, Brightling C, Skeggs A, et al. Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations. N Engl J Med. 2018 08;378(10):902–10.

19. Wood-Baker RR, Gibson PG, Hannay M, Walters EH, Walters J a. E. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001288.

20. Boulet L-P, Gupta S, FitzGerald M. Inhaled Glucocorticoids in Asthma - Response to McKeever et al. 2018. 2018.

21. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma [Internet]. 2018. Available from: www.ginaasthma.org

22. Richards RN. Side Effects of Short-Term Oral Corticosteroids. J Cutan Med Surg. 2008 Mar 1;12(2):77–81.

23. Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018 Aug 29;11:193–204.

24. Partridge MR, Molen T van der, Myrseth S-E, Busse WW. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med. 2006 Dec;6(1):13.

25. Gupta S, Wan FT, Hall SE, Straus SE. An asthma action plan created by physician, educator and patient online collaboration with usability and visual design optimization. Respir Int Rev Thorac Dis. 2012;84(5):406–15.