mild asthma: steroid or tiotropium not help

A recent article found the majority of patients with mild persistent asthma have a low sputum eosinophil level, with pretty much equal clinical responses to both mometasone (inhaled steroid) vs tiotropium (a long-acting muscarinic antagonist), see asthma mild no benefit steroids or tiotrop nejm2019 in  dropbox, or DOI: 10.1056/NEJMoa1814917

Details:

--295 patients with mild persistent asthma were randomized to mometasone, tiotropium, or placebo

-- the patients were categorized according to sputum eosinophil level, determined by 2 induced sputums, as being <2% vs > 2%

-- median age 31, 40% male (more so with high eos count), mean age of diagnosis of asthma 8, duration of asthma 20 years, one or more episodes requiring emergency visits 24%, one or more courses of systemic steroids in the prior year 19%, BMI 28, FEV1 90% of predicted, FEV1/FVC 0.76, percent change to bronchodilators 11% (12.7% if high eosinophil level, 9.6% low), median score on Asthma Control Test 21, eczema/atopic dermatitis 33%, positive allergen test 80% in those with low eos/97% high eos

-- primary outcome: response to mometasone as compared to placebo, and response to tiotropium vs placebo among patients with a low sputum eosinophil count, with response as determined by treatment failure, asthma control days, and FEV1

-- secondary outcome was comparison of results in people with high sputum eosinophil, vs those with low counts

Results:

-- 73% of patients had a low sputum eosinophil level

-- of those with low eosinophil levels:

    -- 59% had a differential response to meds (though neither intervention was statistically significant):

        -- 57% had a better response to mometasone vs 43% had a better response to placebo (not statistically significant)

        -- 60% had a better response to tiotropium vs 40% to placebo, p=0.029, though a priori definition of statistical significance was a two-sided p<0.025

-- of those with a high eosinophil level:

    -- 74% responsed to mometasone , significantly better than the 26% response to placebo

    -- 57% responded to tiotropium, not statistically significantly better than the 43% response to placebo

Commentary:

-- their conclusions:

    -- the percentage of people (73%) in the study with low eosinophil counts was significantly higher than the 50% found in prior studies

    -- those with low eos counts had no significant difference in the response to the steroid or the muscarinic antagonist

    -- these data suggest “equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patient with a low eosinophil level”, since their findings do conflict with guidelines that suggest that the next step after beta agonists should be an inhaled steroid

--There have been articles finding variable responses of asthmatic individuals to beta agonists, which may be related to genetic polymorphisms reducing susceptibility to beta agonists but not to ipratropium. This polymorphism is present in 1/6 of the population, more frequently in those of African descent (see asthma genotype lancet 2004 in dropbox , or Israel E. Lancet 2004; 364: 1505). other studies have suggested that there is decreased b-agonist clinical efficacy in Latinos patients as well

    --in their patient population, the mean percent change with bronchodilators in those with low eos counts was 9.6%, which is below the typical cutpoint of 12%.  Is this because of poor technique during the test? or because of the genetic variations? or because some patients defined as mild persistent asthma actually did not have asthma but some other obstructive pathology??? (eg, see http://gmodestmedblogs.blogspot.com/2017/01/asthma-misdiagnosis.html )

-- other articles have confirmed that tiotropium helps with poorly controlled asthmatics (see asthma tiotropium nejm2012 in dropbox,or DOI: 10.1056/NEJMoa1208606)

-- this study has some clear limitations.  it was not a very large study: seems like we should have bigger studies with more varied patients to draw generalizable conclusions, which, given the huge numbers of people with asthma, should not be difficult to do. It included only patients with mild persistent asthma, a huge group but results not necessarily generalizable to other asthmatics. there was the unexpected finding (i think) that such a large number of patients had low sputum eosinophil counts (73%, much higher than the 50% expected), which really changes the likelihood of the overall sample not responding so well to the mometasone (ie., those with high eos counts did respond better to mometasone, but may have been relatively underrepresented in this study/too few patients to have a robust conclusion)

    -- and one might expect that those with “allergic” asthma would have higher eos counts, though there was a very high rate of positive allergen tests in both the high and low eos groups, though the specific allergen tests were not identified. Perhaps suggesting poor specificity of the allergen testing…

-- one notable finding is the pretty dramatic response to placebo, with statistically as many in the low eos group having "a better response to placebo" as "a better response to mometasone" !!!!  this may be related to the vagaries of clinical courses of those with mild persistant asthma, but those are a lot of the patients we see clinically...

so, how should we incorporate this trial into our clinical practice?

--clearly, we are not going to check sputum eosinophil counts, especially putting the patient through 2 induced sputums as in this study, for our usual asthma patients

--there is increasingly less imperative to use inhaled steroids as the go-to med. years ago, steroids were emphasized because of the potential to decrease the adverse bronchial remodeling in asthmatics and prevent progressive lung function loss , but then a few studies found this was not the case

--so, the goal with asthmatics has reverted to controlling symptoms and preventing functionally-impairing excerbations (esp necessitating ED or urgent care visits, and worse)

--this study supports the use of muscarinic antagonists, which have relatively few systemic adverse effects (esp with studies debunking the prior reports of increased mortality associated with anti-muscarinics). And inhaled steroids do have some significant adverse effects (more local fungal infections, more systemic bone loss, and seemingly profound effects in those on strong inhibitors of the cytochrome systems, as in some HIV med cocktails (see http://gmodestmedblogs.blogspot.com/2019/05/hiv-meds-local-steroids-and-cushings.html )

--further studies are warranted prior to rewriting the asthma treatment guidelines, especially since asthma is so prevalent and the treatment approach would affect such huge numbers of people. But the following might be reasonable:

    -- since it seems that about 15% of people do not respond clinically to b-agonists, especialy African-American and Latino patients, would it make sense to try short-acting anti-muscarinics (eg ipratropium) as a single agent when there seems to be inadequate response to short-acting b-agonists?? (after checking on inhaler technique, since the vast majority of patients do not use the regular inhalers correctly)?

    --if one chooses a steroid inhaler for those with some response but still too symptomatic on prn b-agonists, and there is no clear benefit from the steroids, one might just try stopping them and trying a muscarinic antagonist (instead of adding that on). 

    --or one might just choose a long-acting muscarinic antagonist as the second line med, reserving the steroid for those with inadequate clinical response

   -- or, perhaps try a placebo inhaler, since that seems to be just as good.....

geoff

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