Single inhaler maintenance and reliever therapy (SMART) in general practice asthma management: where are we?

Despite effective pharmacological options for treating asthma, most patients fail to achieve good control.¹ Non-adherence is common, with over-reliance on short-acting P2-agonists (SABA) and under-use of inhaled corticosteroids (ICS) frequently being observed.² There is a real need to consider new approaches to improve outcomes.

One approach that has attracted attention and controversy is Single inhaler Maintenance And Reliever Therapy (SMART) using the budesonide-formoterol combination inhaler Symbicort™. SMART is advocated by proponents on both pragmatic and theoretical grounds,³ and its use in primary care is addressed by Riemersma et al. in this issue of the PCRJ.⁴

In the traditional ‘step-wise’ asthma guideline model, therapy classes are added and doses increased when control is not achieved. Most patients use regular ICS ‘preventer’ treatment and an additional SABA inhaler used on an ‘as-needed’ basis; but when patients remain uncontrolled on ICS, long-acting P2-agonist (LABA) treatment is added, increasingly in the form of a fixed-dose ICS/LABA combination inhaler. The traditional approach has been to prescribe an ICS/LABA combination inhaler providing sufficient doses of ICS and LABA to achieve control, and to provide additional SABA for ‘rescue’ use — so most patients will use at least two different inhalers. In the SMART model, however, the patient is only provided with an ICS/LABA inhaler, used both for maintenance treatment and for additional rescue use in place of SABA. This results in a variable ICS dose which is higher when the patient is more symptomatic. The rationale is that the higher ICS use at the time of increased symptoms improves outcomes by reducing exacerbation risk,⁵ and in fact allows lower total ICS exposure without compromising outcomes.

Although SMART has been advocated as being safe and more effective than traditional regimes, controversy persists concerning its relative effectiveness compared to guideline-based therapy, and when and in whom it should be used. Critics claim that the SMART trial programme has not actually compared SMART with current best practice, since the control arms (generally consisting of a fixed-dose regime) in the SMART studies are chronically under-treated.⁶ Recent Cochrane reviews of SMART have been published, one concluding that despite there being evidence that it reduces exacerbations compared to fixed-dose ICS monotherapy, current evidence of benefit over guideline-based treatment was lacking.⁷ A second review⁸ concluded that in mild asthma it is not yet known whether SMART use of a budesonide/formoterol inhaler for relief of asthma symptoms results in clinically important benefits (indicating that ICS monotherapy plus as required SABA likely still remains the right approach for most patients), but that in more severe patients at risk of exacerbations SMART combination ICS/LABA inhaler use reduced exacerbations.

SMART is currently only possible in inhalers containing the LABA formoterol, as its rapid onset of action (comparable to that of SABA preparations⁹) allows its use as a rapid-onset rescue bronchodilator, with a maximum dose of 72 mcg/day. (Symbicort™ formulations contain 6 or 12 mcg per actuation with SMART generally using 6mcg formulations, and total daily use should not usually exceed 8 puffs/day). Although theoretically possible to use this approach with other combination inhalers containing formoterol, the current evidence (and statutory licensing arrangements) only permits its use with Symbicort™. However, despite these limitations, the simplicity and ease of the SMART approach — and the extensive trial programme underpinning its use — make it popular with patients and clinicians, and its use is now widespread.

There remain some important gaps in our understanding of how SMART fits into our overall strategy, and in whom it should be used. ICS treatment is used to control airway inflammation, and effective inflammatory control will over time lead to a reduction in bronchial hyperresponsiveness (BHR), the ‘twitchiness’ in the airways smooth muscle that leads to episodes of bronchconstriction when exposure to triggers occurs. A possible concern with SMART is that inadequate anti-inflammatory treatment may be given to (at least some) patients, resulting in persistent inflammation and increased BHR. A recent study compared airways inflammation in patients randomly allocated to SMART or a fixed-dose combination regime of 4-times the daily ICS dose.¹⁰ It reported less inflammation in the fixed-dose group, although inflammation levels in the majority of the SMART group were within the range associated with stable clinical control, so the clinical significance is not clear.

In Riemersma et al.'s primary care study of patients with mild-to-moderate asthma,⁴ stable patients were randomised to SMART or ‘usual care’, and a range of control measures was observed over 12 months, with BHR measured at baseline and after 12 months. The study showed that although the SMART group received 59% less ICS, the change in BHR over the study was not significantly different between groups, and clinical outcomes were likewise similar. This is a very reassuring finding for patients and clinicians using the SMART regime, although some slight cautionary notes can be sounded. Firstly, this was a relatively small study recruiting stable patients, and there may be a sub-group of patients with more severe inflammation in whom BHR could have increased with the lower ICS load. Secondly, although this was a 12-month study, BHR may vary over prolonged time periods, and a longer study might show differences. Thirdly, the results cannot be extrapolated to unstable patients or to those with less well-controlled disease, (or indeed to those using other formoterol-containing combination inhalers).

Where does this leave us? SMART is now a realistic strategy for adults at ‘step 3’ of the BTS/SIGN guidelines, i.e. those requiring treatment with LABA in addition to ICS, and who use budesonide-formoterol fixed-dose combination inhalers. It has the advantage of simplicity, and in stable patients with mild-to-moderate asthma is unlikely to lead to deterioration in BHR and may allow lower cumulative ICS doses to be used without a loss of control. SMART may be particularly useful in patients who adhere poorly to their regular preventer therapy; ICS use has been shown to increase in such patients randomised to SMART therapy.¹¹ Whether there are other groups of patients who should or shouldn't be treated with SMART, and whether it can be used with other combination inhalers, remains to be clarified.