Is there adequate evidence for quadrupling inhaled corticosteroid doses?

In an article in the February issue of Canadian Family Physician, Kouri et al promote an asthma action plan (“evidence-based tool”) that encourages quadrupling doses of inhaled corticosteroids for patients with worsening asthma.¹ The authors and other guideline writers have suggested the quadrupling recommendation is based on strong levels of evidence. Given that strong is a somewhat subjective term, I thought clinicians might find it of value to look in some detail at the best available evidence for this recommendation.

To date, 2 studies in adults with asthma have specifically looked at the effect of quadrupling inhaled corticosteroids as part of an asthma action plan. The details and results are outlined in Table 1.^2,3

In 2009, Oborne et al showed in a 12-month double-blind trial a 5% non–statistically significant absolute reduction in the need for oral corticosteroids.² However, in those patients who actually started the study inhaler, they did show a statistically significant reduction in the need for oral corticosteroids but also an increase in adverse events.

In 2018, these same investigators showed in a 12-month open-label study that quadrupling the inhaled corticosteroid dose reduced severe exacerbations by 7%, but again, more people experienced adverse events.³

Assuming these results represent what one would actually see in practice, it appears a quadrupling action plan (note that not all people will need to invoke the action plan) will lead to a number needed to treat (NNT) of 14 people for the end point of not having to receive a course of oral corticosteroids. However, to get this benefit for 1 person you need to expose a number of people (roughly 5 or so if the baseline rate of exacerbations was about 50%) to 1 to 2 weeks of a quadrupling of the dose (800 µg increased to 3200 µg for the beclomethasone equivalent) of their inhaled corticosteroid. The authors of these studies state “the quadrupled dose in these participants could have had the same systemic effects on adrenal suppression as a course of prednisolone that is used to treat severe asthma exacerbations.”³ While the evidence is incomplete, this amount of daily inhaled steroid is likely roughly equivalent systemically to 10 to 20 mg of daily prednisone.⁴

In addition, many guidelines recommend combination inhalers (steroid–long-acting β-agonist) as baseline asthma therapy, especially for those with poor control. Therefore, this action plan would require many patients to purchase an additional corticosteroid-alone inhaler to use if their asthma worsens. The cost would be anywhere from $50 to $150 and unfortunately these inhalers typically expire only about 1 year after purchase. Finally, for those who quadruple the dose there is a number needed to harm of roughly 20, primarily for candidiasis or dysphonia.

It is important to remember that both trials were done by the same investigators and the only study that showed a statistical benefit was an open-label trial. Of interest, a double-blind trial in which the dose of inhaled corticosteroid was quintupled showed no effect on clinical outcomes in children aged 5 to 11 years with mild to moderate asthma.⁵

Given the above, I would disagree this would be considered an adequate evidence base to justify a carte blanche recommendation of quadrupling the dose of inhaled corticosteroids. In fact, the authors of the 2 studies state that “a group of local general practitioners, asthma nurses, and asthma experts suggested that a reduction of one third in the number of people initiating a course of systemic glucocorticoids is a worthwhile treatment effect,” yet in their trial they reported only a relative reduction in exacerbations of 19%.³ They also state “guideline committees will need to consider whether the magnitude of the reduction achieved is clinically meaningful.”³

A true evidence-based tool would include the concept of shared decision making and so, at a minimum, patients should be told that adopting a quadrupling of inhaled corticosteroids action plan will lead to an NNT of 14 (about a 7% absolute difference) for not having to start oral corticosteroids. But to achieve that NNT, a number of people (depending on the baseline exacerbation rate) will have to receive doses of inhaled corticosteroids for 7 to 14 days that would be systemically about half (10 to 20 mg) of what would be used for an exacerbation (Oborne et al used 30 mg of oral prednisone for exacerbations²). In addition, for those who quadruple the dose there is a number needed to harm of about 20 (a 5% absolute increase) primarily for candidiasis and dysphonia, and there is an additional inhaler cost and inconvenience to this action plan. Given this information, some might choose this option while others might just want a discussion of what to look out for with regard to exacerbations and when to seek medical help.

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