asthma: symbicort and variants for both reliever and maintenance treatment

 A recent article confirmed the superiority of prescribing budesonide/formoterol (eg symbicort, and its ilk) as both the maintenance and the rescue inhaler, in a Korean real-world study (see asthma symbicort as maint and rescue best JAlerCLinImmunPractice2022 in dropbox, or doi.org/10.1016/j.jaip.2022.06.009

 

Brief background: there were 2 pivotal studies (SYGMA1 and SYGMA2) that set in motion a profound change in treating adult asthmatic patients, codified in the quite impressive global GINA recommendations of 2019: http://gmodestmedblogs.blogspot.com/2019/10/new-and-improved-asthma-guidelines.html . see below for more

 

Details:

-- retrospective data analysis from the medical records of the Ajou University Medical Center in Korea of adult asthmatics, from 2008 to 2021

-- patients were divided into and propensity score-matched for MART (Maintenance and Reliever Therapy, using inhaled corticosteroid with formoterol) versus non-MART (using inhaled corticosteroid with long-acting beta agonist, plus the as-needed short acting beta agonist albuterol)

    -- MART had 231 patients and non-MART had 512

-- mean age 43, 55% female, Charlson Comorbidity Index was similar (a validated assessment of comorbidities)

-- patients with COPD were excluded

-- covariates assessed in the propensity scoring included allergic conjunctivitis/dermatitis/rhinitis, bronchitis, depression, GERD, heart disease, hyperlipidemia, hypertension, kidney disease, diabetes, urticaria, malignancy, COPD

 

-- Primary endpoint: severe asthma exacerbations (SAEx) between MART and non-MART

-- secondary endpoints: asthma exacerbations (AEx), all-cause hospitalization, and pneumonia (pneumonia was included as a safety outcome)

-- corticosteroid usage was also analyzed

-- mean duration of follow-up: 120 days in the MART group and 68 days in the non-MART group

 

Results:

-- 2.9% of patients who were on MART switched to non-MART, 22.9% in the non-MART treatment switched to MART

-- primary endpoint: MART vs non-MART:

    -- incidence rates: 64.8 per 1000 person-years versus 199.6 per 1000 person-years

    -- 61% decrease, HR 0.39 (0.18-0.77)

-- MART asthma control: 94.8% did not experience SAEx; 4.8% had one or two SAEx events and 0.4% had 3 or more

-- non-MART: 11.5% had one or two SAEx events and 7.4% had 3 or more

    -- these were statistically significant at the P <0.01 level

 

-- secondary endpoints: MART vs non- MART:

    -- incident rate 152 per 1000 person-years versus 320 per 1000 person-years

    -- AEx: 39% decrease, HR 0.61 (0.37-0.99)

-- no significant difference in hospitalizations or pneumonia risk (pneumonia being chosen because of prior reports of increased risk of pneumonia in those on high dose inhaled steroids)

-- cumulative corticosteroid requirements: MART vs non-MART: median 190.0 (interquartile range 97.9-420.0) versus 411.0 (IQR 143.0- 833.0),  p<0.01

-- results were consistent when performing the as-treated versus intention to treat analysis

 

graph: cumulative incidence of severe and total asthma exacerbations by MART/non-MART groups 

Commentary:

-- asthma affects more than 350 million people worldwide, and the prevalence of asthma is increasing as is the number of patients with uncontrolled asthma

-- the combination inhaler of budesonide/formoterol is a great combination since it combines budesonide (a corticosteroid that has one of the lowest blood levels when inhaled) and formoterol (a long-acting beta-agonist that has a very rapid onset of action, so acts like a short-acting one but with prolonged effects)

-- As mentioned above, there were two important initial studies documenting benefit of budesonide/formoterol (Symbicort) for asthmatics

    -- the SYGMA1 trial found that those patients with mild asthma and taking budesonide/formoterol as needed did much better than those on terbutaline (a short-acting beta agonist similar to albuterol) also on an as-needed basis: the budesonide/formoterol group did significantly better in terms of weeks of well-controlled asthma and the annual rate of severe exacerbations. A post hoc analysis of this trial found that even a single day of budesonide/formoterol was associated with decreases in severe asthma exacerbations 21 days later (see http://gmodestmedblogs.blogspot.com/2020/11/asthma-single-day-of.html )

    -- the  SYGMA2 trial found that in patients with mild asthma, twice-daily budesonide/formoterol taken as-needed was significantly better than twice-daily budesonide maintenance therapy with terbutaline as-needed

-- though these trials used budesonide/formoterol, another long-acting beta agonist, vilanterol, is pretty similar to formoterol: formoterol has an onset of action in 2 to 3 minutes, vilanterol  reaches peak plasma concentration in 5-15 minutes

    -- some insurers prefer one inhaler over the other. it seems to me that vilanterol (another long-acting beta agonist with rapid onset of action) is clinically probably as good as formoterol (in fact, there was a large real-world study finding that asthma exacerbations were lower with vilanterol than formoterol, both with inhaled steroids: (see https://www.tandfonline.com/doi/full/10.1080/02770903.2021.1963767 ). and both are safer than salmeterol (which, i think, should not be used, and is in the common inhaler Advair)

-- there was also an article finding benefit of triple therapy for moderate to severe asthma with fluticasone as the inhaled corticosteroid, vilanterol ads the long-acting beta agonist, and umeclidinium as the long-acting muscarinic antagonist (see http://gmodestmedblogs.blogspot.com/2021/07/moderate-to-severe-asthma-triple.html ). My experience confirms the benefit of this triple-med inhaler in those not adequately controlled with just the steroid and long-acting beta agonist

-- it should be noted that the US came out with new asthma guidelines in December 2020, with no recommendation on MART similar to the GINA guidelines. The 2020 US guidelines were the first update since 2007 (see http://gmodestmedblogs.blogspot.com/2020/12/new-us-asthma-guidelines.html ). Unfortunately, these guidelines were based on 6 very specific questions and did not include any studies after October 2018: ie, they did not include the SYGMA trials or subsequent trials which confirmed the importance of SYGMA (including the PRACTICAL and Novel START trials). Several members of the guidelines' committee requested expanding the search to include these pretty paradigm-shifting SYGMA trials, but to no avail (ie, the 2020 US guidelines were less up to date than the 2019 GINA guidelines)

-- One large concern with asthma therapy is the use of systemic steroids. As we all know, systemic corticosteroids have a plethora of potentially very severe adverse effects, and they should be avoided whenever possible. This Korean real-world study found very significant decreases in corticosteroid usage in those on MART

-- unfortunately, despite the plethora of data confirming the use of budesonide/formoterol as both the maintenance and rescue inhaler, most insurers i know limit the use to a standard dose of 1-2 two puffs BID. However, the SYGMA trials allowed up to 12 inhalations a day as-needed, though the actual use of rescue inhalations was less in the budesonide/formoterol group. In general, people need so much less budesonide/formoterol that even a single canister often lasts for a month even with using it more times during an exacerbation, though would it be great (and highly clinically appropriate) if the insurance companies accepted the current and dramatically improved guidelines based on GINA...

 -- it is reassuring that there was no difference in all-cause hospitalizations, since given the low numbers of individuals with asthma, similar hospitalization rates are a surrogate marker of similarly sick patients overall

 

-- this current Korean trial is a real-world trial and not a randomized clinical trial of people who elect to be involved in a study of a medication versus placebo. both types of trials have their plusses and minuses: 

    -- RCTs are rigorously controlled studies of people who volunteer to be in the study, which is likely quite different from the demographics or implementation of an intervention in the population as a whole (eg study nurses being available to patients, reinforcing medication adherence, etc), and social demographics of those volunteering may be very different than the average person we see in the office, and many studies involve patients who are taken care of by specialists from  their hospital clinic. ie a pretty big selection bias

    -- a real-world study tends to be a retrospective data-base analysis, which probably reflects better the patients we see in clinic, but does not have the rigor of an RCT (not having granular data on some comorbidities, social issues, etc). ie may be less generalizable to other patients/situations

Limitations:

-- They included fluticasone as the inhaled corticosteroid, which does seem to have a higher blood-to-tissue level than budesonide or beclomethasone (ie: i try prescribe these latter two, though some insurers require mometasone)

-- also, they included salmeterol as one of the long-acting beta agonists in their non-MART group, which does not provide the benefits of formoterol or vilanterol (and they provide no subgroup analysis based on which steroid or long-acting beta agonist was used.)

-- they did not include some important socio-economic factors that affect asthma and asthma exacerbations (eg, stress, worker or home allergen exposures, residential crowding, exposure to air pollutants, etc.) which could make the results less generalizable

    -- in fact asthma has multiple heterogeneous phenotypes, which conceivably have different responses to different medications. The study included adults defined as having asthma without further classification

    -- though this database is huge (3 million patients inpatient and outpatient visits between1994-2018), this still were relatively small numbers of patients with asthma who met their criteria, and this decreased significantly (almost a third) through the process of propensity score matching

-- there were no data on medication adherence in either of these groups

-- the population was from one area (South Korea), so results may not be translatable to different area which may have very different baseline populations (eg exposure to air pollutants, etc)

 

So, this study provided further validation of many other studies, but in a "real-world" setting and likely to more closely reflect our clinical outpatient management; these studies in their aggregate came to similar conclusions that the most effective approach to medical treatment for asthma, even mild asthma, is based on inhalers including an inhaled corticosteroid (eg budesonide) along with a rapid-onset long-acting beta-agonist (such as formoterol, or vilanterol). Depending on the patient, this group of medicines is superior to the usual beta-agonists both as as-needed (in milder asthma)  and as maintenance therapy with use as-needed for breakthrough symptoms

geoff

 

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