Asthma affects over 5 million patientsin the UK and has an annual treat-

ment cost exceeding £1 billion per year.1

Poorly controlled asthma leads to signifi-cant morbidity, and results in 4.1 millionGP consultations per year and 1.1 millionwork days lost. The recent confidentialenquiry, National Review of AsthmaDeaths (NRAD), highlighted a number ofdeficiencies in asthma care that might becontributing to the still significant mortal-ity associated with asthma.2

Despite good pharmacological treat-ments for asthma symptoms, manypatients have symptoms that remainpoorly controlled. There are several rea-sons that might contribute to this thatinclude poor treatment adherence, underrecognition of signs and symptoms ofpoor asthma control, and inappropriateprescribing practices.

The NRAD report highlighted bothunder prescribing of preventer medicationsand inappropriate long-acting beta2 agonist(LABA) prescriptions as contributory factorsin a number of the asthma deathsreviewed. A total of 80 per cent of casesreviewed had received fewer than 12 pre-venter medication prescriptions in the yearpreceding their death. A total of 14 per centof patients who died had been prescribeda single agent LABA at the time of deathand at least 3 per cent were on LABAmonotherapy without inhaled corticosteroid(ICS) preventer therapy. The key recommen-dations associated with these findings werethat adherence to medication should be

routinely checked and that where LABAbronchodilators are prescribed for peoplewith asthma, they should be prescribed ina single combination inhaler with an ICS.

One possible treatment strategy thatmight address both of these concerns isthe use of combination ICS and LABA ina single inhaler as both maintenance andreliever therapy (SMART).

There is evidence that ICS useincreases in patients who are prescribedSMART therapy implying that SMART maybe a useful strategy to overcome pooradherence with ICS.3 Clinical trial datahave also shown that the benefits ofSMART go beyond improved adherenceand the convenience of a single inhalerdevice: reduced frequency of severe exac-erbations and reduced hospitalisationrates have been seen in SMART-treatedpopulations on lower ICS doses thanfixed-dose inhaler comparator groups.

The place for SMARTGuideline-based asthma management,such as described in the British Thoracic Society/Scottish IntercollegiateGuidelines Network (BTS/SIGN) asthmaguideline (2014), advocates the use ofSMART therapy in patients whose asthmaremains poorly controlled despite the reg-

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Benefits of SMART therapyfor asthma managementWilliam M Storrar MRCP and Anoop J Chauhan PhD, FRCP

A combination ICS and LABAin a single inhaler canimprove adherence, and data suggest it can alsoreduce frequency of severeexacerbations.

Figure 1. Combination ICS and LABA in a single inhaler as maintenance and reliever therapy

SPL

ular use of an ICS (step 3).4 At this step,prescription of a combination inhaler con-taining both ICS and LABA is recom-mended in order to aid treatmentcompliance and ensure that the LABA isnot being taken without the ICS. Mostpatients at Step 3 will be on at least twoinhalers – a combination ICS/LABAinhaler and a short-acting beta2 agonist(SABA) inhaler – so using a single inhalerfor maintenance and reliever therapy hasthe additional benefit of simplifying thetreatment regimen for patients.

The pan-European INSPIRE study(n=3415), which looked at the attitudesand actions of asthma patients on regularmaintenance therapy, found that mostpatients felt confident that they couldself-manage their asthma (88 per cent).5

Most patients wanted treatment givingimmediate relief of symptoms (90 percent), but were concerned about takingtoo much medication when they felt well(54 per cent). The self-control offered bySMART therapy would be particularly suit-able for this cohort of patients.

As with any symptom-directed ther-apy, there will be patients for whomSMART therapy is not suitable, such ashabitual users of reliever medication andunder perceivers of asthma symptoms. Itis important that all patients being con-sidered for SMART therapy have anunderstanding of the maximum dailyallowance of additional reliever use andit is recognised that SMART therapy is nota treatment for all.

We would recommend that patientson SMART therapy use an appropriateself-management plan (see Figure 2).

Licensed productsBudesonide/formoterol combinationproducts Symbicort and more recentlyDuoResp are licensed for use as SMARTtherapy in adult patients (>18 years). Thebeclometasone/formoterol combinationinhaler, Fostair, has also recently beenlicensed for use as SMART therapy inadult patients (>18 years).

Both combinations of ICS and LABAare suitable for use as maintenance andreliever therapy as they contain the LABAformoterol. Formoterol is a potent beta2

agonist that is well suited to maintenanceand reliever therapy by virtue of its rapidonset of action (within one to three min-utes of inhalation), required for quicksymptom relief, and a lack of tolerabilityissues enabling repeated dosing.

DosingThe maximum daily dose of formoterol is72µg, which limits the number of inhala-tions that can be used in a single day.Symbicort SMART regimens use the 6µg formulations (200/6 or 100/6).Symbicort inhalers containing 12µg arenot licensed for use as SMART. SymbicortSMART can be prescribed as 100/6 or200/6 two to four puffs in two divideddoses for maintenance with up to eightadditional puffs daily as required for reliefof symptoms.

DuoResp 200/6 is also licensed atthe same dose; two to four puffs in twodivided doses for maintenance with up toeight additional puffs daily as required forrelief of symptoms. The DuoResp inhalercontaining 12µg is not licensed for use asSMART. Fostair 100/6 contains 6µg of

formoterol and can be prescribed as100/6 two puffs daily in two divideddoses for maintenance with up to six addi-tional puffs daily as required for relief ofsymptoms.

It should be noted that patientsrequiring ≥1 puff/day for the relief ofsymptoms should have their mainte-nance treatment reviewed and escalatedif appropriate, as this would suggest thattheir asthma control is sub-optimal. It isalso worth noting that Fostair, DuoRespand Symbicort inhalers all contain 120actuations; a patient using the maximumdaily dose for maintenance and relievertherapy will use a Symbicort or DuoRespinhaler in 10 days and a Fostair inhalerin 15 days.

Product choiceThe decision to prescribe Symbicort,DuoResp or Fostair should take accountof the following.

Inhaler deviceSymbicort and DuoResp are delivered bydry-powder inhaler (DPI) devices.Symbicort uses a Turbohaler device,while DuoResp uses the breath-activatedinhaler device, Spiromax. Fostair is deliv-ered via a metered-dose inhaler (MDI).The MDI is compatible with spacerdevices. Patient preference for differentinhaler devices and competence at usingthe device will influence choice.6

Particle sizeFostair delivers beclometasone/for-moterol as an extra fine hydrofluo-roalkane particle formulation, targeting

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Table 1. Combination inhaler preparations licensed for use as SMART therapy

Product ICS LABA Inhaler device SMART dosing Max dailydose

30 day costequivalent (1 puff bd)

Symbicort 200/6 Budesonide200µg

Formoterol6µg

DPI Turbohaler 1–2 puffs bd + up to additional8 puffs/24hrs

12 puffs £19.00

Symbicort 100/6 Budesonide100µg

Formoterol6µg

DPI Turbohaler 1–2 puffs bd + up to additional8 puffs/24hrs

12 puffs £16.50

DuoResp 200/6 Budesonide200µg

Formoterol6µg

DPI Spiromax 1–2 puffs bd + up to additional8 puffs/24hrs

12 puffs £14.98

Fostair 100/6 Beclometasone100µg

Formoterol6µg

MDI 2 puffs bd + up to additional 6 puffs/24hrs

10 puffs £14.66

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both large and small airways withimproved deposition in the smaller air-ways compared with the other combina-tion inhalers. Patients with small airwaysdysfunction (reduced forced expiratoryflow25–75%) might benefit from Fostair tar-geting the smaller airways.7

Clinical evidenceIn 2005, evidence was published tosupport the use of budesonide/for-moterol as both maintenance andreliever medication in asthma.8 Thisdouble-blind, randomised controlledtrial of 2760 patients using low mainte-nance dose budesonide/formoterolshowed that in those patients whereSABA was replaced with budesonide/formoterol as reliever medication therewas an increased time to first severeexacerbation (p<0.001) resulting in a45–47 per cent lower exacerbation risk

compared to budesonide/formoterolwith SABA reliever.

A Cochrane Review published in2013 assessed the efficacy and safety of SMART (budesonide/formoterol) incomparison with maintenance treatmentprovided by combination inhalers withhigher ICS dose and SABA for relief ofsymptoms.9 Four studies with a total of9130 patients were included. All of thestudies were funded by the pharmaceu-tical company AstraZeneca. The reviewconcluded that SMART therapy reducesthe number of patients having an asthmaexacerbation requiring oral steroids andthe number requiring hospitalisation oremergency department visit comparedwith those treated with fixed-dose combi-nation inhalers.

The mean daily dose of ICS required inthe SMART therapy group was lower thanin the fixed-dose combination inhaler

group, suggesting that increasing the ICSin response to symptoms, but keeping thedose lower when stable, is more effectiveand leads to lower overall ICS require-ments. The review was unable to commenton several secondary outcomes such aslung function measures, quality of life andasthma symptom control.

In order to address the issue ofwhether SMART therapy improves asthmacontrol, a large post hoc analysis was car-ried out on five clinical trials (>12,000patients) of budesonide/formoterolSMART treatment.10 This concluded thatthe proportion of patients achieving targetlevels of current clinical control were sim-ilar or higher with SMART compared withthe same or a higher fixed-dose combina-tion inhaler plus SABA as reliever.

A recent study that evaluated the useof beclometasone/formoterol as SMARTtherapy supporting its licence for this treat-

Three single medication inhaler approach (no longer recommended)

Two inhaler approach (combination inhaler preventer and SABA reliever)

One inhaler ‘SMART’ approach (Single inhaler maintenance and reliever therapy)

Figure 2. Three approaches to inhaler medication prescription at BTS Step 3 asthma treatment; BDP = beclometasone dipropionate

SABAStep 1Mild intermittent asthmaInhaled SABA as required for symptom relief

ICSStep 2Regular preventer therapyAdd ICS (200–800µg BDP or equivalent) as regular preventer

LABAStep 3Initial add-on therapyAdd LABA to ICS and continue SABA reliever

SABAStep 1Mild intermittent asthmaInhaled SABA as required for symptom relief

ICSStep 2Regular preventer therapyAdd ICS (200–800µg BDP or equivalent) as regular preventer

Combination ICS+LABAStep 3Initial add-on therapyAdd combination inhalerICS+LABA and continue SABAreliever

SABAStep 1Mild intermittent asthmaInhaled SABA as required for symptom relief

ICSStep 2Regular preventer therapyAdd ICS (200–800µg BDP or equivalent) as regular preventer

SMART Step 3Initial add-on therapyUse combination inhaler ICS+formoterol LABA as single inhalermaintenance and reliever therapy

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ment regimen extended the results seenwith budesonide/formoterol SMART.11 Atotal of 1714 patients were randomised toreceive either beclometasone/formoterolplus SABA as required or beclometasone/formoterol plus beclometasone/formoterolas required (up to eight inhalations perday). Beclometasone/formoterol SMARTsignificantly prolonged the time to firstexacerbation (by 75 days; p=0.0003) andsignificantly reduced the risk of experienc-ing a severe exacerbation by 36 per cent(95% CI 18 to 51 per cent; p=0.0005).

Beclometasone/formoterol SMARTalso reduced the yearly rate of severe exac-erbations by 34 per cent, hospitalisationsand emergency department visits by 33per cent and oral corticosteroid courses by35 per cent (all p<0.001) when comparedto beclometasone/formoterol and SABA.

ConclusionThe use of a single combination ICS andrapid-onset LABA for maintenance andreliever therapy in patients with moder-ate-to-severe asthma has a number ofattractions. It may not be suitable for all

patients, but for selected patients thereare clear advantages.

Owing to its simplicity, the treatmentregimen may help to improve adherencewhile reducing the overall ICS doserequired to achieve asthma control. Thismay have an impact on long-term treat-ment side-effects and their associatedmorbidity.

Several studies have now shownthat SMART treatment can increase thetime to first exacerbation, and reducethe frequency of severe exacerbationsand asthma hospitalisations. Asthmaexacerbations place a significant bur-den on healthcare resources andmeans of controlling symptoms toimprove patient’s quality of life whilereducing healthcare expenditure shouldbe embraced.

References1. asthma UK. Asthma facts and FAQs.http://bit.ly/U5IJXI.2. RCP. Why asthma still kills. National Reviewof Asthma Deaths (NRAD). May 2014http://bit.ly/1wVCnMy.

3. Sovani MP, et al. Br J Gen Pract 2008;58;37–43.4. BTS/SIGN. British guideline on the manage-ment of asthma. A national clinical guideline.October 2014 .5. Partridge MR, et al. BMC Pulm Med2006;6:13.6. Chrystyn H, Price D. Prim Care Resp J2009;18:243–9.7. De Backer W, et al. J Aerosol Med and PulmDrug Deliv 2010;23:137–48.8. O’Byrne PM, et al. Am J Respir Crit Care Med2005;171;129–36.9. Kew KM, et al. Cochrane Database Syst Rev2013;12:CD00901910. Bateman ED, et al. Respir Res2011;12:38.11. Papi A, et al. Lancet Respir Med2013;1:23–31.

Declaration of interestsNone to declare.

Dr Storrar is Senior Clinical ResearchFellow and Professor Chauhan is con-sultant respiratory physician at theQueen Alexandra Hospital, Portsmouth,UK, part of the Wessex Asthma Network