moderate to severe asthma: triple therapy is better

 A new systematic review/meta-analysis found that triple inhaler therapy significantly decreased severe asthma exacerbations in those with moderate to severe asthma (see asthma triple vs dual therapy jama2021 in dropbox, or doi:10.1001/jama.2021.7872) 

  

Details: 

 -- systematic review/meta-analysis of 20 RCTs in children and adults with persistent uncontrolled asthma, comparing triple therapy of inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), and long-acting muscarinic antagonist (LAMA) versus ICS/LABA as dual therapy. Databases used from November 2017 to December 2020, without language restriction 

 -- 11,864 children (including 1870 children aged 6 to 18 in three trials) and adults were included: mean age 52, 58% female

--variability between studies:

    -- two studies had patients with asthma/COPD overlap syndrome

    -- seven had a crossover study design

    -- six required patients to have had an asthma exacerbation in the previous 12 months

    -- 3 LAMA types were used: tiotropium, umeclidinium, glycopyrronium/glycopyrrolate 

    -- all included medium to high ICS dose/LABA with short acting beta-agonist as rescue 

    -- two trials included patients who were active smokers 

    -- 18 trials were deemed to have a low risk of bias, two were at high risk of bias 

-- median trough pre-bronchodilator FEV was 1.85 L or 62.2% 

 

-- main outcomes: severe asthma exacerbations, asthma control (measured by the Asthma Control Questionnaire, ACQ-7, a seven-item list ranging from 0-6 with six being severely under-controlled and a minimally important difference being 0.5 points; median baseline score of 2.12), quality of life (measured by the Asthma-related Quality of Life questionnaire, AQLQ, score ranging from 1-7, with a higher score better and a minimally important difference of 0.5 points), mortality, and adverse events 

-- median study duration 19.5 weeks, though most statistical information from studies 24-54 weeks in duration 

 

Results: 

 -- triple therapy versus dual therapy: 

    -- reduction in severe exacerbations by 17% (nine trials, 9932 patients): 22.7% versus 27.4%, risk ratio 0.83 (0.77-0.90), high-certainty evidence 

        -- there was specific reduction in time to first severe exacerbation in six trials (8296 patients, 28.6% versus 24.7%, 16% reduction with HR 0.84 (0.77-0.92))

        -- similar findings were seen with milder exacerbations or with asthma worsening 

    -- improvement in asthma control (14 trials, 11,230 patients): standardized mean difference (SMD) in ACQ-7 scale, -0.06 (-0.10 to -0.02), high-certainty evidence 

    -- no significant difference in asthma-related quality of life (seven trials, 5247 patients), SMD 0.05 (-0.03 to 0.13), moderate-certainty evidence 

    -- mortality: no deaths reported in either group 

    -- spirometry measurements: 

        -- FEV1 was measured in 18 trials, mean difference of 0.08 L (0.07-0.10), high-certainty evidence 

            -- assuming a minimal important difference of 200 mL, triple therapy was significantly associated with a higher percentage of patients achieving a 200 mL increase from baseline versus dual therapy: 47% versus 37%, RR 1.27 (1.22-1.32) 

    -- subgroup/sensitivity analyses: no difference comparing those with <1 vs >1 previous severe asthma exacerbation, those <18yo vs >18yo, smoking history, ICS dose, type or dose of LAMA, or inflammatory phenotype (defined by peripheral eosinophil count) 

    -- adverse events: triple therapy associated with significantly more dry mouth and dysphonia, 10 trials (7395 patients): 3.0% versus 1.8%, risk ratio 1.65 (1.14-2.38), high-certainty evidence 

        -- no difference between groups in treatment-related and serious adverse events

 

Commentary: 

-- the study suggested that children and adults with moderate to severe asthma benefited from triple therapy with fewer severe asthma exacerbations and modest improvements in asthma control (though in the latter case it is not clear that these changes were clinically important), but without significant differences in quality of life or mortality. Changes in FEV1 were also small and may not translate into clinical significance (there is no well-defined minimal clinically significant threshold)

    -- this discordance between a significant decrease in severe asthma exacerbations but no clinically important improvements in asthma control has also been found in some of the studies with biologic therapies 

    -- and this discordance reinforces the importance of looking at both asthma control as well as asthma exacerbations as independent and important outcomes in evaluating asthma therapy 

        -- which is why the GINA guidelines (noted below) do not use the "mild intermittent asthma" term, since there can be quite severe exacerbations in those with baseline mild (step 1) asthma, and that title tends to undermine the significance of this

-- the value of triple therapy is that it might reduce the need for more intensive ICS or systemic steroids, with their attendant higher risk of adverse effects, or moving on to biologics with their potential issues of cost and potential adverse long-term effects (and LAMAs seem to work independent of inflammatory phenotype) 

--This study adds further to the deficiencies of the 2020 US asthma treatment guidelines (see http://gmodestmedblogs.blogspot.com/2020/12/new-us-asthma-guidelines.html ), which can be criticized for not including the really important SYGMA trials but now also with less emphatic recommendations on the utility of LAMAs 

    --the US guidelines concluded that triple therapy helped with asthma control and quality of life but had no effects on asthma exacerbations. This was based on their using a very small database (2-3 trials, 1304 patients). The current study involved many more trials and patients, reaching the opposite conclusions 

    --the 2019 GINA international guidelines seem to me to be much more robust : see http://gmodestmedblogs.blogspot.com/2019/10/new-and-improved-asthma-guidelines.html , which also references a 2019 lancet article (see asthma triple therapy lancet2019 in dropbox or doi.org/10.1016/ S0140-6736(19)32216-0), included in the systematic review above but not included in the US 2020 review, a multinational study of 2592 patients with uncontrolled asthma on medium- or high-dose ICS and LABA, then randomized to LAMA vs placebo, finding a 12-15% decrease in exacerbations in the LAMA group (similar to the overall findings in the above meta-analysis)

    --unfortunately, the US guidelines were not holistic: they only responded to 6 key questions and not to other important diagnostic or therapeutic issues. And, for unclear reasons, they did not evaluate newer studies after October 2018, which was unfortunate since several very important studies were after that cutoff (eg the SYGMA studies, the 2 in the lancet article above, the PRACTICAL and Novel START trials) 

        -- which means that the 2019 GINA guidelines were more up-to-date than the 2000 US guidelines

-- one concern with these new guidelines is where does Advair (fluticasone/salmeterol) fit in, since it does not have a short acting LABA such as formoterol as recommended in the newer guidelines. In this current review article there were four studies using salmeterol, two of which were comparison studies with another LABA (indacaterol, which also has a rapid onset with the peak serum concentration of 15 minutes post-dose), both finding that clinical efficacy was better with indacaterol. So, my personal bias is we should not be using salmeterol at all, and moving patients to a LABA with rapid onset of action (eg formoterol or vilanterol, with the SYGMA studies using formoterol, though in this review several used vilanterol). And there is the concern that patients may use increasing inhalations of salmeterol in order to get effect for an asthma exacerbation, with a long-term buildup of lots of beta-agonists in their bloodstream and potential deleterious cardiac effects (arrhythmias, ?takotsubo cardiomyopathy) 

-- a study in patients with COPD also found triple therapy to be superior, using fluticasone/ucmeclinidium/vilanterol: see http://gmodestmedblogs.blogspot.com/2018/05/copd-improvement-with-triple-inhaler.html 

 

Limitations: 

-- the biggest one in this type of study is the merging of data from disparate studies with disparate definitions, populations, medications used, methodologies overall, and outcomes funneled into a neat and coherent conclusion through the wonders of mathematics.  

    -- It is notable in this context that most of these conclusions found were considered to be a high quality of evidence 

    -- subgroup analyses overall did not show much difference in outcomes (eg by age, or type of LAMA), however subgroup analyses are open to their own unmeasured biases and non-equivalences 

 

So, this study does add to the current recommendations, especially from GINA, to add regular LAMA therapy in patients with uncontrolled asthma not responding sufficiently to ICS-LABA therapy. cost and insurance coverage can be a significant issue, however (eg see http://gmodestmedblogs.blogspot.com/2020/11/asthma-single-day-of.html for more info)

geoff

 

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