asthma reliever therapy

 a recent systematic review and meta-analysis compared short-acting β agonists (SABA) alone with SABA combined with inhaled corticosteroids (ICS), and with the fast-onset, long-acting β agonist (LABA) formoterol combined with ICS for asthma, finding that a SABA alone was the least effective (see asthma best reliever rx JAMA2024 in dropbox, or doi:10.1001/jama.2024.22700)

Details:

-- 27 randomized clinical trials with 50,496 adult and pediatric patients treated in outpatient settings were included in this network meta-analysis, with 2 studies done just in pediatric patients aged <19yo 

-- here are the comparisons in this network meta-analysis; the size of the lines and circles represent the numbers of RCTs and patients in the comparisons (82% of these comparisons were considered to have a low overall risk of bias):

-- mean age 41.0 years; 20,288 male (40%)

-- formoterol was the long-acting β agonist (LABA, alone or combined with an ICS, inhaled corticosteroid) as a reliever therapy

-- use of oral steroids in the studies for severe asthma exacerbations was per the physician discretion

 

-- main outcomes: asthma symptom control (5-item Asthma Control Questionnaire; range, 0-6, lower scores indicate better asthma control; minimum important difference [MID], 0.5 points), asthma-related quality of life (Asthma Quality of Life Questionnaire; range, 1-7, higher scores indicate better quality of life; MID, 0.5 points), risk of severe exacerbations, and risk of serious adverse events

 

--median duration of studies 26 weeks with range from 3-65 weeks 

 

Results:

--Compared with SABA alone, both ICS-containing relievers were associated with fewer severe asthma exacerbations:

    --ICS-formoterol:

        -- risk ratio [RR] 0.65 [0.60-0.72]; risk difference [RD], −10.3% [−11.8% to −8.3%], with high certainty evidence

    -- ICS-SABA:

        -- RR 0.84 [0.73-0.95]; RD, −4.7% [−8.0% to −1.5%], with high certainty evidence

    -- ICS-formoteral vs ICS-SABA (indirect comparison): 

        -- RR 0.78 [0.66-0.92]; RD, −5.5% [−8.4% to −2.0%], with moderate certainty 

            -- ie, ICS-formoterol bettered ICS-SABA, but limited data to be more conclusive

    -- similar associations for asthma-related hospitalizations

    -- the risk differences were smaller in those in the lower risk GINA step (less severe asthma)

 

-- Compared with SABA alone, both ICS-containing relievers were associated with improved asthma symptom control:

    -- ICS-formoterol:

        -- RR improvement in total score, 1.07 [1.04-1.10]; RD, 4.1% [2.3%-5.9%], with high certainty

    -- ICS-SABA:

        -- RR 1.09 [1.03-1.15]; RD, 5.4% [1.8%-8.5%], with high certainty

 

-- Improvement in asthma symptom quality by ACQ-5 (scores range from 0-6, the lower the better):

    --ICS-formoterol vs SABA:

        -- mean difference, −0.09 [−0.13 to −0.05]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.07 [1.04-1.10]; RD, 4.1%[2.3%-5.9%], high-certainty evidence 

     -- ICS-SABA vs SABA:

        -- mean difference, −0.12 [−0.19 to −0.04]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.09 [1.03-1.15]; RD, 5.4% [1.8%-8.5%], high-certainty evidence 

    -- these effects favoring both combo meds over SABA alone were statistically significant but represented small and perhaps not clinically relevant changes

    -- and the difference between ICS-SABA and ICS-formoterol was very small and of low-certainty evidence

 

-- improvement in asthma-related quality of life, per the AQLQ (scores range from 1-7, the higher the better):

    --ICS-formoterol vs SABA:

        --mean difference, 0.04 [−0.04 to 0.13]; RR corresponding to ≥0.5-point improvement [MID] in total score,1.03 [0.97-1.10]; RD, 1.6% [−1.6%to 5.2%], moderate-certainty evidence favoring ICS-formoterol    

    --ICS-SABA vs SABA:

        --mean difference, 0.07 [−0.06 to 0.19]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.05 [0.95-1.15]; RD, 2.8% [−2.4%to7.6%), moderate-certainty evidence favoring ICS-SABA

   -- and as above, not clearly a clinically important difference and little to no difference between ICS-SABA and ICS-formoterol

 

--safety outcomes: 

   -- the 2 most commonly reported were cardiovascular events and pneumonia, all moderate certainty of evidence:

    -- cardiovascular events, all moderate certainty of evidence::

       -- ICS-formoterol vs SABA alone: RD, −0.2% [−0.5% to 0.1%]

       -- ICS-SABA vs SABA alone: RD, −0.2% [−0.7% to 0.4%]

    -- pneumonia, all moderate certainty of evidence:

        -- ICS-formoterol vs SABA alone: RD, 0.1% [−0.1% to 0.2%]

        -- ICS-SABA vs SABA alone: RD, 0.2% [−0.5% to 0.8%]

    -- inhaler discontinuations due to an adverse event:

        -- ICS-formoterol vs SABA alone: RD,−0.7% [−1.2% to−0.3%],high certainty

        -- ICS-SABA vs SABA alone: RD, 0.3% [−0.8% to 1.4%], moderate certainty

    -- mortality:

        -- ICS-formoterol vs SABA alone: RD, 0% [−0.1% to 0.1%], high certainty

        -- ICS-SABA vs SABA alone: RD, 0.1% [−0.3% to 0.4%], high certainty

 

-- Consistent associations were found between adult and pediatric studies for all outcomes

-- Compared with SABA alone, ICS-formoterol (RD, −0.6% [−1.3% to 0%] was not associated with increased risk of serious adverse events (high certainty) and ICS-SABA (RD, 0% [−1.1% to 1.2%] was not associated with increased risk of serious adverse events (moderate certainty)

Commentary:

-- as we know, asthma is remarkably common, with a prevalence of 262 million people globally

-- the GINA guidelines of 2019 (Global Initiative for Asthma), largely citing the SYGMA 1 and 2 studies from 2018 of people with mild asthma, elevated budesonide-formoterol to the primary med for both intermittent (as a reliever med) and persistent asthma (as a daily med) asthma symptomatology (https://gmodestmedblogs.blogspot.com/2019/10/new-and-improved-asthma-guidelines.html, a conclusion subsequently supported by other studies (eg, the PRACTICAL trial of patients with intermittent to moderate persistent asthma; the Novel START trial of patients with intermittent to mild persistent asthma)

    --the updated US guidelines in 2020 (from the prior 2007 guidelines) did not include the SYGMA studies from 2018 regarding reliever therapy in mild asthma (that clearly showed superiority of ICS/formoterol therapy). Instead, step 1 (intermittent asthma) had the recommendation of as-needed SABA, step 2 recommended low-dose ICS and as-needed SABA, and then (finally) ICS-formoterol starting at the step 3 (moderate persistent asthma ) stage, in striking contrast to the 2019 GINA recommendations from the year before

 

-- the US Food and Drug Administration (FDA) recently approved ICS-SABA as a reliever inhaler, based on a 24-week drug company-performed study comparing Airsupra (albuterol and budesonide) inhaler with albuterol alone but at the same concentration as in Airsupra (160mcg) as needed for asthma symptoms in patients with moderate to severe asthma and finding a 28% reduction in the risk of a severe asthma attack as assessed by assessing the time to first severe asthma attack: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-combination-treatment-adults-asthma

-- the incentive for the current study was that there was no full assessment of the relative effectiveness of a SABA vs ICS-SABA vs ICS-formoterol. 

 

-- one tangential but quite important concern about asthma inhalers is the environmental toxicity of HFA inhalers, which have hydrofluorocarbon as the propellant; each inhalation releases hydrofluorocarbon gas that is 1430 to 3000 times as powerful as carbon dioxide as a greenhouse gas: https://gmodestmedblogs.blogspot.com/2024/06/asthma-hfa-inhalers-are-really.html . My quick and dirty internet search found that the following inhalers do not use propellants and are environmentally safer because they are dry powder inhalers: Symbicort, trelegy ellipta, QVAR redihaler, Pulmicort flexhaler, albuterol/ipratropium, anoro ellipta, some albuterol brands and Flovent diskus (these do not have the boot-shaped appearance).

-- this current analysis found that ICS-formoterol and ICS-SABA were both better than SABA alone as relievers; these former two are associated with impressively decreased severe asthma exacerbations, with a suggestion that ICS-formoterol may well be the best. And these 2 inhalers were associated with modest improvement in asthma symptom control, and with no statistically significant difference in adverse event risk, though the combination ICS-formoterol vs SABA alone just reached a statistically significant lower likelihood of a serious adverse event (defined, per the FDA as death, life-threatening states, hospitalization, disability or permanent damage, congenital anomalies or birth defects or requiring an intervention to prevent permanent impairment or damage)

Limitations:

-- a network meta-analysis is a statistical methodology to compare different meds from different studies (eg, comparing drug A vs placebo finding a 10% benefit for drug A, and drug B to placebo finding a 20% benefit for drug B, then suggesting that drug B is better, but perhaps the patients in the drug B trial had fewer comorbidites and less severe asthma and looked nothing like those in the drug A trial??). so, overall, this type of meta-analysis is probably the least reliable

    -- there are no direct comparisons of ICS-formoterol and ICS-SABA, hence it is problematic determining which is better (though ICS-formoterol seemed a bit better, perhaps since the LABA component of that combination provided longer β-agonist action than a SABA would)

    -- since there were so many studies involved and their many potential biases, one can only derive associations and not clear causality (it would, of course, be much more statistically rigorous to have direct comparisons of all three potential pairings). For one thing, they included results from a study of only 3 months duration with those lasting up to 65 months) and with patients from GINA step 1 to step 4 (form mild to moderate-to-severe asthma)

-- too few RCTS (2 of them) in kids to come to a conclusion (by the way, the GINA guidelines still endorsed SABAs alone for kids)

-- there are impressive data showing that adding a long-acting anti-muscarinic agent to the ICS/LABA mix helps a lot in patients who do not respond well to ICS-LABA (https://gmodestmedblogs.blogspot.com/2021/07/moderate-to-severe-asthma-triple.html ). that would be important to explore as compared to ICS-SABA

so, pretty suggestive evidence that either the ICS-formoterol or ICS-SABA are much better than using a SABA alone (eg albuterol or terbutaline) as the rescue inhaler for asthma symptoms (as found in the SYGMA and other studies with more advanced asthma noted above):

-- in particular, there was a large benefit in decreasing servere asthma exacerbations (which was especially evident for ICS-formoterol)

    -- there were modest improvements in symptom control

    -- all with a trend to somewhat fewer adverse events

-- which all means that we really should abandon SABAs as the appropriate treatment for asthma exacerbations in those needing a rescue inhaler for asthma symptoms, as clearly promulgated in the GINA recommendations

    -- though there was also clear benefit for the ICS-SABA, which is now an option, post-dating the GINA recommendations

    -- adoption of this approach does raise a couple of issues:

        -- probably the best inhaler is the combination of the ICS budesonide (which has the lowest overall plasma level of the steroids: https://pmc.ncbi.nlm.nih.gov/articles/PMC1885155/ ) plus formoterol (which has rapid onset but lasts a long time, ie a LABA that begins to work about as quickly as a SABA)

            -- but these inhalers can be remarkably expensive and not covered by several insurers

            -- however, you should not begin to think that the ICS-SABA combination of the decades-old albuterol with budesonide in Airspura would be much cheaper than the combination of formoterol with budesonide: though the prices of these meds will vary by insurance and coverage, GoodRx lists the monthly cost of generic Symbicort (budesonide/formoterol) as about $100 (the brand name was between $400-$500 in the past), whereas Airsupra is $500. Just goes to show you, there seems to be rather frequent divergence from what makes sense logically and the reality......

                -- that being said, there are other LABAs that are pretty much the same as formoterol, including vilanterol, which seems to work at least as well: https://pmc.ncbi.nlm.nih.gov/articles/PMC11293254/ and https://gmodestmedblogs.blogspot.com/2022/11/asthma-symbicort-and-variants-for-both.html

                -- it should be noted that the prices of the meds do vary a lot over time. This last blog on vilanterol was at a time when only non-generic Symbicort was around and that was the most expensive. Now that is generic and much cheaper than brand-name symbicort, and the vilanterol containing ones are more expensive: eg Breo-Elipta, which is the ICS fluticasone with vilanterol), has a generic now logging in at $230

                -- so it is useful to find the cost of these inhalers, since they may be unaffordable for many patients (especially since asthma is more common in poorer communities)

            -- by the way, i do have a few patients who have rare asthma symptoms and have not had a severe asthma exacerbation for many years who do continue with SABAs with adequate symptom control, which does spare them of the potential adverse effects of the steroid

geoff

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