Table 2.
Representative Randomized Controlled Trials in Moderate-to-Severe Asthma of Maintenance Therapy + Reliever Inhaled Corticosteroid–β-agonist Therapy versus Maintenance Therapy + Reliever β2-agonist Therapy
| Trial Name | Trial Design | Primary Inclusion Criteria | Participants (n) | Treatment Arms | Primary Outcome | Conclusion(s) |
|---|---|---|---|---|---|---|
| SMILE (Lancet 2006) (66) | Double-blinded, multicenter, parallel-group RCT over 12 mo | ⩾12 yr old with asthma and ⩾1 exacerbation in the prior yr, pre-BD FEV1 50–100% with ⩾12% reversibility, received ICS for 3 mo before entry yet remained symptomatic | 3,394 | Budesonide–formoterol (160/4.5 μg) twice-daily + reliever: 1. SABA 2. Formoterol (4.5 μg), or 3. Budesonide–formoterol (160/4.5 μg) |
Time to first severe exacerbation: SMART therapy with reliever budesonide–formoterol resulted in a longer time to first severe exacerbation than twice-daily budesonide–formoterol and reliever SABA (P = 0.005; log-rank test) or reliever formoterol (P = 0.005) |
1. On the basis of time to first exacerbation, SMART therapy was superior to maintenance budesonide–formoterol with reliever SABA or reliever formoterol. 2. SMART therapy with reliever budesonide–formoterol resulted in a 48% reduction in the rate of severe exacerbations compared with the same maintenance therapy with reliever SABA usage. |
| COMPASS (IJCP 2007) (67) | Double-blinded, multicenter, parallel-group RCT over 6 mo | ⩾12 yr old with asthma and ⩾1 exacerbation in the prior yr, pre-BD FEV1 50–100% with ⩾12% reversibility, received ICS for 3 mo before entry yet remained symptomatic | 3,335 | 1. SMART therapy with maintenance budesonide–formoterol (160/4.5 μg) twice daily and as a reliever 2. Budesonide–formoterol (320/9 μg) twice daily and reliever SABA 3. Fluticasone–salmeterol (125/25 μg) twice daily and reliever SABA |
Time to first severe exacerbation: SMART resulted in a longer time to first severe exacerbation than twice-daily budesonide–formoterol and reliever SABA (P = 0.02; log-rank test) or twice-daily fluticasone/salmeterol and reliever SABA (P = 0.003) |
1. On the basis of time to first exacerbation, SMART therapy was superior to maintenance budesonide–formoterol and reliever SABA or fluticasone/salmeterol and reliever SABA. 2. SMART therapy resulted in a 28% reduction (rate ratio, 0.72; 95% CI, 0.57–0.90) and 39% (rate ratio, 0.61; 95% CI, 0.49–0.76) reduction in the rate of severe exacerbations compared with maintenance budesonide–formoterol with reliever SABA or fluticasone–salmeterol with reliever SABA. |
| PREPARE (NEJM 2021) (68, 69) | Open-label, pragmatic, multicenter, parallel-group RCT for 52 wk | 18–75 yr old, self-identified as Black or Latinx, clinician-diagnosed asthma, prescribed ICS ± LABA, uncontrolled on the basis of ACT score | 1,201 | Usual clinical care with maintenance ICS ± LABA and reliever: 1. SABA, or 2. SABA + beclomethasone (80 μg) if using MDI or SABA + beclomethasone (400 μg) if using a nebulizer |
Annualized rate of severe exacerbations: As-needed SABA + beclomethasone resulted in a decreased rate of severe exacerbations vs. SABA alone (0.82 vs. 0.69 severe exacerbations/yr; hazard ratio, 0.85; 95% CI, 0.72–1.00; P = 0.048) |
In an open-label trial in Black and Latinx adults, on the severe exacerbation rate, the addition of an as-needed ICS to usual clinician care was superior to reliever SABA alone. |
| MANDALA (NEJM 2022) (70) | Double-blinded, multicenter, parallel-group RCT over 24 wk | ⩾4 yr old with either a diagnosis of asthma and ⩾1 exacerbation in the prior yr, pre-BD FEV1% 40–90% with ⩾12% reversibility, prescribed medium-to-high dose ICS ± LABA, uncontrolled on the basis of ACQ score | 3,132 | Usual clinical care with maintenance ICS ± LABA and reliever: 1. SABA (albuterol 180 μg) 2. Budesonide–albuterol (80/180 μg)* 3. Budesonide–albuterol (160/180 μg) |
First event of severe exacerbation: Reliever use of high-dose budesonide–albuterol resulted in a decreased rate of severe exacerbations (hazard ratio, 0.74, 95% CI, 0.62–0.89) as compared with albuterol alone, but low-dose budesonide/albuterol did not (hazard ratio, 0.84; 95% CI, 0.71–1.00; P = 0.052) |
Reliever budesonide–albuterol (160/180 μg) resulted in a lower rate of severe exacerbations than as-needed albuterol alone. |
Definition of abbreviations: BD = bronchodilator; CI = confidence interval; COMPASS = effect of budesonide–formoterol maintenance and reliever therapy on asthma exacerbation; ICS = inhaled corticosteroid; LABA = long-acting β2 agonist; MANDALA = as-needed albuterol/budesonide versus albuterol in adults and children aged at least 4 years with moderate-to-severe asthma; MDI = metered dose inhaler; OR = odds ratio; PREPARE = PeRson EmPowered Asthma Relief study; RCT = randomized controlled trial; SABA = short-acting β2 agonist; SMART = Single Maintenance and Reliever Therapy; SMILE = effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomized controlled, double-blind study.
Throughout multiple randomized controlled trials, the reliever use of an ICS with formoterol or albuterol has shown superiority to similar maintenance therapy with reliever SABA therapy. The above represents only a small sample of these results and is not inclusive of all studies of a SMART approach. Systematic reviews and meta-analyses of SMART can be found by Cates and colleagues (142) and Sobieraj and colleagues (22). Notably, the PREPARE and MANDALA trials are not considered SMART but are shown to demonstrate data regarding the result of concomitant ICS and SABA reliever usage when prescribed with a separate maintenance inhaler.
Only low-dose budesonide–albuterol was examined in children under 12 years old.