new and improved asthma guidelines

new and improved asthma guidelines

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New international asthma guidelines were released from GINA (Global Initiative for Asthma), with many significant changes: see asthma guidelines GINA2019 in dropbox, or https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf ), a 201 page document that is quite accessible/readable

Background:

--GINA was started in 1993 by the NHLBI in the US along with the WHO, with GINA guidelines based on their twice-yearly cumulative literature review

--the US guidelines (NAEPP) is from 2007 and outdated, many new studies (eg SYGMA 1 and 2) have been done recently and are incorporated into the GINA recommendations

    --Sygma1: see asthma SYGMA1 nejm2018 in dropbox, or DOI: 10.1056/NEJMoa1715274

    --Sygma 2: see asthma SYGMA2 nejm2018 in dropbox, or DOI: 10.1056/NEJMoa1715275

--GINA bases recommendations on the level of therapy needed to control symptoms and prevent exacerbations (and future risk of adverse outcomes)

--they do stress non-pharmacologic therapy: smoking session/avoiding exposure, regular physical activity, avoidance of occupational exposures, avoid meds that can make asthma worse (eg NSAIDs and aspirin in some patients, oral or intra-ocular b-agonists in some), diet emphasizing fruits and vegetables, weight reduction if obese, avoid indoor and outdoor pollution/allergens/molds as well as dampness indoors/pets and house dust mites, try to decrease emotional stess. An important goal is to prevent asthma exacerbations by decreasing the patient's asthma triggers

--followup should be within 2 days after ED or hospital visit 

--make sure to confirm diagnosis of asthma (25-35% of people labeled as having asthma do not have it confirmed on testing; for PFTs they use cutpoint of 12% improvement in FEV1, noting that 15% provides greater confidence)

--vitamin D levels of at least 30ng/ml seems to be important in pregnant women to reduce the risk of asthma/recurrent wheezing in their infants at 0-3 yo

Major revisions:

--they no longer recommend SABA (short-acting b-agonists) alone for the treatment of asthma in adults and adolescents

--GINA's stepped therapy (they have a summary table on page 56, or Box 3-5A on page 46):

    --step-1 recommendations for patients with symptoms <2x/month and no exacerbation risk factors: use of low-dose ICS-formoterol (ICS=inhaled corticosteroids; formoterol is a long-acting b-agonist, LABA) as needed for symptom relief (ie not regularly), supported by indirect evidence from a large double-blind study (SYGMA1) comparing that to SABA alone as well as to routine low dose ICS plus as-needed SABA

        --the issue is that patients with even few exacerbations can still have severe ones (they have therefore eliminated the "intermittent" asthma category as being useful). and the use of SABA alone, though effective short-term, is associated with increased risk of death

        --formoterol is a great LABA since it has rapid onset of action (as effective as a SABA) but is also long-acting

        --adding formoterol allows for a decrease in steroid dose (ie, a lower dose steroid can be effectively used)

             --the relevant study (SYGMA 2) was done with budesonide/formoterol, and budesonide does have the advantage of less systemic steroid absorption/effects as compared to other ICS; the combo is available in the US as Symbicort

             --the maximum dose of formoterol is 72 mcg/day. in this study, they used the Symbicort Turboinhaler with 6 mcg of fomoterol and 200 mcg of budesonide, thereby allowing up to 12 inhalations/d. they found that though use of the inhaler averaged about 0.5 inhalations/d, 10% of patients used it >8 inhalations as their max as rescuer inhaler, and 4% >12 inhalations

        --and this works as step 2 therapy and is better adhered to than daily steroids, esp in patients with very intermittent symptoms

        --a study also showed that this combo works well for exercise-induced asthma, similar to daily ICS with SABA for symptom relief

   --step 2 options:

        --either dailiy low-dose ICS or as needed ICS-formoterol

            --combo of low-dose budesonide-formoterol as needed is better than SABAs and not worse than ICS taken regularly daily with rescue meds

        --leukotriene receptor antagonists (LTRAs, eg monteleukast) are less effective than ICS

        --for children 6-11: best option is low dose ICS, though LTRAs are option, albeit less effective

    --do not use theophylline (weak effect, but adverse effects), chromones such as cromolyn (low efficacy, but safe), or taking low-dose ICS whenever SABA used

    --step 3 options:

        --always check inhaler technique (see their page 69), adherence, environmental exposures, and make sure symptoms are from asthma before proceeding to this level

        --preferred: either low dose ICS-LABA as maintenance plus as-needed SABA, or low dose ICA-formoterol (particularly combo with budesonide or beclometasone, the latter combined with formoterol as "fostair inhaler") as both maintenance and reliever treatment (ie, use addional inhalations of ICS-formoterol to relieve symtoms)

            --can also consider: sublingual allergen immunotherapy (SLIT) if patient is symptomatic on low dose ICS, has allergic rhinitis and sensitized to house dust mites, and FEV1>70% predicted; or increase to medium dose ICS, though this tends to less effective than adding a LABA

        --kids 6-11yo:  preferred is to increase ICS to medium dose or change to ICS-LABA, with as needed SABA

    --step 4 options:

        --preferred, if at least one exacerbation/yr: combo of low dose ICS-formoterol as maintenance and reliever treatment (more effective than continuing same ICS-LABA dose or increasing ICS dose)

        --can try increasing ICS to medium potency

        --other options: adding tiotropium if >6yo. insufficient evidence about tiotropium-ICS vs ICS-LABA; consider SLIT as per Step 3; consider dosing budesonide at medium or high dose even 4x/d (not so for other ICS: keep at 2x/d)

    --step 5 options:

        --consider high dose ICS-LABA (this step is the only one with high dose ICS recommended) though not lots of increased efficacy and more adrenal suppression. would consider for 3-6 months trial

        --other options: add tiotropium; add azithromycin 3x/week (off-label use); try anti-IgE therapy with omalizumab; try anti-interleukin-5/SR parenterally if severe eosinophilic asthma; add anti-IL-4R alpha with subcutaneous dupilumab if requiring maintenance oral steroids; add-on oral steroids (no more than 7.5 mg/d prednisone) in adults with severe asthma

--try to step-down treatment, based on individual patient assessment (eg moving to lower potency ICS), can use LTRA

--outpatient management of children <5yo with mild-to-moderate acute exacerbation: try to avoid oral steroids. initial albuterol treatment, repeat every 20 minutes for 1st hour if needed, monitor closely; if symptoms recur within 3-4 hours, give more albuterol and prednisolone at 2mg/kg (max of 20mg if <2yo; 30mg if 2-5). for most children, albuterol delivery is more efficient with a pressurized MDI (pMDI) with a spacer than using a nebulizer. ipratropium may be added in kids with poor response to initial SABA. 

--for their assessment of total daily steroid dosing, see Box 3-6 on page 48: but a few examples (see table for kids below this one):

    --budesonide: low dose 200-400mcg/d, medium >400-800, high >800

    --beclometasone: low dose 100-200mcg/d, medium >200-400, high >400

    --fluticasone: low dose 100-250mcg/d, medium >250-500, high >500

overall for kids:

--i did no go into as much detail in treating kids (the document is quite accessible and has very clear categories and well-organized information). And, the changes for adults and adolescents are much more extensive than for kids

--see Box 3-5B on page 47, which reviews the approach to kids age 6-11; and Box 4-2 page107, which incorporates these changes into an asthma action plan

--when meds are too expensive, consider higher dose ICS; consider earlier add-ons of LABA, tiotropium, LTRA; consider low dose oral steroids trying to minimize adverse effects; and stop ineffective therapies

Further Commentary:

--vilanterol (the LABA in Breo ellipta and Trelegy ellipta) does have quicker action than salmeterol and should work well: per table 51 in https://www.ncbi.nlm.nih.gov/books/NBK409764/table/T59/?report=objectonly , vilanterol seems to be at least as good as formoterol, though direct comparisons are lacking

    --see http://gmodestmedblogs.blogspot.com/2018/05/copd-improvement-with-triple-inhaler.html for blog on triple long-acting therapy for copd with the Trelegy Ellipta, which is a single inhalation daily, including a LABA (fluticasone), a LAMA (long acting muscarinic antagonist umeclinidium, similar to tiotropium), and an ICS (vilanterol). Not commented on in GINA, but as noted above this LABA is likely as good as formoterol. may be quite effective for asthmatics who are in the step 4-5 range, and has a very easy, once-daily delivery system. i personally have had several COPD patients do really well with this med

--ADDENDUM: The Lancet just published a somewhat complex study, combining 2 similar international studies. they used a single-inhaler triple therapy for adult patients with uncontrolled asthma, a history of at least 1 exacerbation in past year and previously on a medium or high dose ICS and LABA, then randomized to a combo of beclometasone and formoterol, with addition of glycopyrronium (a LAMA, like tiopropium) vs placebo (see asthma triple therapy lancet2019 in dropbox or doi.org/10.1016/ S0140-6736(19)32216-0), finding:

    --2592 patients from 392 sites in 16-17 countries (varied a bit between the 2 studies)

    -- at 26 weeks: FEV1 improved 57 ml in one study at 73 ml in the other

    -- at 52 weeks: rate of moderate and severe exacerbations decreased 12% and 15%

   --so, this study reinforces the utility of LAMAs as add-on therapy. it does raise a couple of issues. it seems that LAMAs are quite safe and do not cross the blood-brain barrier. there was some concern about increased mortality, but that was apparently only associated with the tiotropium Respimat but not with the tiotropium HandiHaler (eg, all-cause mortality in the UPLIFT trial found that 4 years of tiotropium was associated with a 14% decrease, see Celli B. Am J Resp Crit Care Med 2009; 180 (10): 948). so, should a LAMA be added even earlier? might it lead to decreased ICS dosages, esp if combined with a fast-acting LABA as formoterol?

so, needless to say, the above is a very brief summary of this quite long document. There are some important points that i think are worth integrating into our practice:

--we really should try to minimize the ICS potency to the lowest that works. in general, we should start with a low-dose ICS for initial theapy. but some patients do require higher doses (their "step 5" above) to achieve stable asthma control. and, as with PPIs for GERD/gastritis, it is too easy to just keep refilling the prescriptions and focus on the patients' other, likely more pressing issues. In both cases, if the patient is requiring a high dose of meds, it may be useful to try to step-down therapy when the patient is stable.  And, there are likely advantages to using budesonide over fluticasone, for example, since the former has lower systemic steroid absorption and effects

--the LABA of choice seems to be formoterol, since it has such a rapid effect and can also be used as a rescue agent in combo with an ICS.  likely that vilanterol is similarly effective, but actual studies are lacking. I wonder if those on ICS-salmeterol might be able to lower their ICS dose if they were on ICS-formoterol?? And, perhaps we should use less Advair, since it combines fluticasone and salmeterol, neither of which seem to be the ideal components

--i do have several patients with very mild and very intermittent asthma or mild exercise-induced asthma, who have not had a significant asthma exacerbation for many years, and have used only occasional SABAs with excellent results. i am not convinced that they should be changed to a low dose ICS-LABA to use prn with the likely unnecessary exposure to inhaled steroids (and I do not plan to change their management). But, overall and in new patients, it really does make sense to minimize SABA use

--but overall, this GINA document on asthma management and prevention provides valuable guidance with suggestions related to important newer studies, and (i think) should supplant the quite old US recommendations from 2007

geoff​

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