Figures
- FIGURE 1
Study selection process. RCT, randomised controlled trial.
Tables
- TABLE 1
Definitions of mild asthma: classification used in this review
Main criteria for mild asthma RCTs (n=54) Observational/other studies (n=10) All n (%) Studies permitting past history of exacerbations n (%) All n (%) Studies permitting past history of exacerbations n (%) 1) Treatment level 3 (5.6) 0 (0) 5 2 (20.0) 2) Symptom frequency criteria 3 (5.6) 3 (5.6) 0 – 3) FEV1 ≥80% pred and symptoms<daily 19 (35.2) 15 (27.8) 2 1 (10.0) 4) FEV1 >60–80% pred and symptoms<daily 15 (27.8) 13 (24.1) 1 1 (10.0) 5) Miscellaneous definitions# 9 (16.7) 8 (14.8) 0 – 6) Included patients aged <5 years 5 (9.3) 4 (7.4) 2 2 (20.0) RCT: randomised controlled trial; FEV1: forced expiratory volume in 1 s. # Miscellaneous definitions not captured by the other five categories (e.g. “doctor-diagnosed mild asthma”, or “mild asthma based on airway hyper-responsiveness” alone), or, studies that did not state that patients had “mild asthma” but included patients with disease characteristics similar to those in the other five categories.
- TABLE 2
Mild asthma studies grouped by study type (RCT or observational/other) and by definition of mild asthma
Study (year) [ref.] Age range or average age years Treatment duration Placebo Exacerbation definition Baseline exacerbation data Patients with history of exacerbation not excluded# Yes n, treatment allowed No RCTs Category 1: RCTs that primarily defined mild asthma by treatment level Bateman et al. (2018) [26] 12–83 52 weeks ✓ ✓ ✓ Camargos et al. (2018) [31] 10.6 (2.8)¶, 9.9 (2.7)¶ 6 weeks ✓ ✓ O’Byrne et al. (2018) [38] 12–85 52 weeks ✓ ✓ Category 2: RCTs that primarily defined mild asthma by symptom frequency Martinez et al. (2011) [36] 5–18 44 weeks 74
P bid + P/ALB rescue✓ ✓ ✓ Pauwels et al. (2003) [41] 5–66 3 years 3568
P + usual asthma medication✓ ✓ ✓ Wongtim et al. (1995) [80] 33.2 (7.46)¶, 32.8 (8.6)¶ 8 weeks 10 ✓ Category 3: RCTs that primarily defined mild asthma with a composite definition of FEV1 ≥80% pred and symptoms <daily Basyigit et al. (2004) [81] 38 (8.2)¶, 42.4 (9.6)¶, 45.5 (10.9)¶ 8 weeks ✓ ✓ Bousquet et al. (2005) [29] 15–80 48 weeks (12 DB, 36 OL) ✓ ✓ ✓ Chrousos et al. (2005) [82] 18–65 14 days ✓ ✓ Chuang et al. (2007) [83] 6–14 8 weeks ✓ ✓ Chuchalin et al. (2005) [33] 6–87 12 months ✓ ✓ ✓ Chuchalin et al. (2008) [32] 12–79 52 weeks 315 ✓ ✓ Currie et al. (2003) [84] 36 (4)+ 2×3 weeks ✓ ✓ Garcia Garcia et al. (2005) [35] 6–14 12 months ✓ ✓ ✓ Karaman et al. (2004) [85] 8–14 12 weeks ✓ ✓ Maiti et al. (2011) [86] 18–70 4 weeks ✓ ✓ Ng et al. (2007) [37] 6–14 2×8 weeks ✓ ✓ Reddel et al. (2008) [42] 18–80 11 months 21 ✓ Renzi et al. (2010) [43] ≥12 24 weeks ✓ ✓ ✓ Riccioni et al. (2002) [87] 26.9 (12.3)¶, 26.7 (8.6)¶, 28.2 (10.1)¶ 16 weeks ✓ Shimoda et al. (2005) [88] 36.2 (12.8)¶, 35.6 (14.4)¶ 6 months ✓ ✓ Tamaoki et al. (2008) [89] ≥21 8 weeks ✓ ✓ Vatrella et al. (2002) [90] 18–48 16 weeks ✓ ✓ Zeiger et al. (2005) [91] 15–85 48 weeks (12 DB, 36 OL)§ ✓ ✓ Zietkowski et al. (2006) [92] 45.2 (10.9)ƒ, 42 (14)ƒ, 51 (7.6)ƒ 12 weeks ✓ ✓ Category 4: RCTs that primarily defined mild asthma with a composite definition of FEV1 approximately >60–80% and symptoms <daily Berger et al. (2009) [48] ≥12 16 weeks 177 ✓ Boulet et al. (2000) [93] ≥12 12 weeks ✓ ✓ Drazen et al. (1996) [34] 12–55 20 weeks (16 weeks active treatment + 4 weeks withdrawal (OL ALB as needed)) 129
P + ALB as needed##✓ ✓ Herjavecz et al. (1999) [55] 17–67 22 weeks (6 DB; 16 OL) ✓ ✓ ✓ O'Byrne et al. (2001) [39] ≥12 1 year Group A: 239 ✓ ✓ O'Sullivan et al. (2003) [94] 19–50 2×8 weeks ✓ ✓ Papi et al. (2007) [40] 18–65 6 months 118
P bid + ALB 100 μg as needed✓ ✓ Peters et al. (2007) [56] ≥6 16 weeks ✓ ✓ ✓ Stone et al. (2001) [95] ≥16 4 weeks ✓ ✓ Tattersfield et al. (2001) [45] 20–60 2 years ✓ ✓ Tomlinson et al. (2005) [46] 20–60 12 weeks ✓ ✓ ✓ van Grunsven et al. (1996) [47] ≥30 2 years ✓ ✓ ✓ Verberne et al. (1996) [58] 7–16 4 months ✓ ✓ ✓ Vermetten et al. (1999) [96] 18–66 12 weeks ✓ ✓ Woodcock et al. (2002) [59] 18–65 6 weeks ✓ ✓ Category 5: RCTs that defined mild asthma by other/miscellaneous criteria Arets et al. (2002) [23] 5–10 12 weeks 33 ✓ ✓ Boushey et al. (2005) [28] 18–65 1 year ✓ ✓ ✓ Villaran et al. (1999) [97] 14–45 8 weeks ✓ ✓ Category 5: RCTs that did not describe their patients as having “mild asthma” but included patients with disease characteristics similar to the categories described above Bailey et al. (2008) [24] 12–65 52 weeks ✓ ✓ ✓ Barnes et al. (2007) [98] ≥12 12 weeks ✓ ✓ Bateman et al. (2012) [25] ≥12 8 weeks 94 ✓ ✓ ✓ Busse et al. (2001) [30] >15 24 weeks ✓ ✓ ✓ Busse et al. (2001) [53] 12–75 12 weeks 114 van der Molen et al. (1998) [99] 18–50 12 weeks ✓ ✓ Category 6: RCTs that included patients <5 years old Bisgaard et al. (2005) [27] 2–5 48 weeks 271 ✓ ✓ ✓ Shah et al. (2014) [100] 2–18 12 weeks ✓ ✓ Szefler et al. (2007) [44] 2–8 52 weeks ✓ ✓ ✓ Category 6: RCTs that included patients <5 years old that did not describe their patients as having “mild asthma” but included patients with disease characteristics similar to mild asthma Robertson et al. (2007) [21] 2–14 12 months 113 ✓ ✓ Skoner et al. (2005) [57] 2–5 3 weeks 50 ✓ Observational/other Category 1: Observational/other studies that primarily defined mild asthma by treatment level Ding and Small (2017) [49] ≥12 – NA ✓ ✓ Friedman et al. (2010) [50] 12–25 – NA ✓ Friedman et al. (2010) [51] 12–65 – NA ✓ McIvor et al. (2009) [22] ≥6 Survey + 6-week treatment NA ✓ ✓ Navaratnam et al. (2009) [52] 12–65 – NA ✓ Category 3: Observational/other studies that primarily defined mild asthma with a composite definition of FEV1 ≥80% and symptoms<daily Giraud et al. (2006) [54] ≥18 4–8 weeks NA ✓ ✓ Lai et al. (2003) [61] Total (not just mild asthma) Children: 7.4 (3.8)¶Adults: 40.5 (18.5)¶ – NA ✓ Category 4: Observational/other studies that primarily defined mild asthma with a composite definition of FEV1 approximately >60–80% and symptoms<daily Soyer et al. (2009) [60] 6–18 – NA ✓ Category 6: Observational/other studies that included patients <5 years old König et al. 1996 [62] ≤17 – NA ✓ ✓ Robertson et al. (1992) [63] ≤20 – NA ✓ RCT: randomised controlled trial; bid: twice daily; P: placebo; ALB: albuterol; DB: double-blind; OL: open-label; FEV1: forced expiratory volume in 1 s; NA: not applicable. # History of exacerbations considered to be exacerbation, hospitalisation or emergency department visit or oral corticosteroid use that occurred prior to enrolment/screening (RCTs or prospective observational studies) or in the pre-index period (retrospective studies); ¶: mean (sd) age in years; +: mean (se) age. §: 10% of participants (determined at randomisation) switched therapies to preserve the masking in the preceding period; ƒ: median (range) age; ##: no dose given.
- TABLE 3
Retrospectively collected data on asthma exacerbations, hospitalisation and emergency department admissions/visits
Study (year) [ref.] Age range years Study groups n Exacerbation parameter(s) Data for exacerbations by specified parameter, for each study group Exacerbations reported in ≤6 months prior to study entry Bateman et al. (2012) [25] ≥12 97, 100, 110, 95, 102, 94 Pts with ≥1 exacerbation in last 6 months 18%, 19%, 16%, 25%, 17%, 21% McIvor et al. (2009) [22]# ≥6 534 Patients with any exacerbation in 6 weeks prior to study entry 51.7% Skoner et al. (2005) [57] 2–5 58, 51, 52, 50 No. of exacerbations in last 30 days Mean: 1.8, 1.3, 1.5, 1.2 Median: 0,1,0, 0 Pts with ≥1 exacerbation in last 30 days 48.3%, 52.9%, 48.1%, 36.7% Woodcock et al. (2002) [59] 18–65 86, 86 Mean no. daytime asthma attacks in 7-day run-in 0.25, 0.18 Mean no. night-time asthma attacks in 7-day run-in 0.10, 0.10 Exacerbations reported in 12 months/1 year prior to study entry Bateman et al. (2018) [26] 12–83 2089, 2087 Pts with 1 severe exacerbation in last 12 months 17.5%, 17.3% Pts with ≥1 severe exacerbations in last 12 months 22%, 21.9% Pts with ≥2 severe exacerbations in last 12 months 4.5%, 4.7% Ding and Small (2017) [49] ≥12 524, 591 Pts with 1 exacerbation in last 12 months 9.0%, 13.1% Pts with ≥3 exacerbations in last 12 months 3.4%, 1.9% Mean (sd) no. of moderate-to-severe exacerbations in last 12 months 0.2 (0.6)¶ Mean (sd) no. of exacerbations treated in ED or hospital in last 12 months 0.1 (0.4), 0.1 (0.3) Mean (sd) no. of exacerbations treated with OCS, antibiotics, ED or hospital admission in last 12 months+ 0.1 (0.5), 0.2 (0.6) Pts with 1 exacerbation treated with OCS, antibiotics, ED or hospital admission in last 12 months+ 5.8%, 10.8% Pts with ≥3 exacerbations treated with OCS, antibiotics, ED or hospital admission in last 12 months+ 1.0%, 1.5% Giraud et al. (2006) [54] ≥18 94 Pts hospitalised for asthma in previous 12 months 4.3% Herjavecz et al. (1999) [55] 17–67 90, 91 Time since last exacerbation 12.5 months, 13.0 months Lai et al. (2003) [61] Mean 7.4–40.5 1709, 633 Pts with hospital admissions in last year 7.3%, 15.4% Pts with any hospital ED/unscheduled emergency visit in the last year 33.1%, 41.3% Martinez et al. (2011) [36] 5–18 71, 72, 71,74 Mean no. hospital visits for asthma in last 1 year 0.3, 0.3, 0.2, 0.2 O’Byrne et al. (2018) [38] ≥12 1277, 1277,1282 Pts with ≥1 severe exacerbation in last 12 months 20.0%, 20.1%, 18.8% Peters et al. (2007) [56] ≥6 166, 165, 169 Pts with ≥1 urgent visit for asthma in last 1 year 30.7%, 35.8%, 35.5% Robertson et al. (2007) [21]§ 2–14 97, 105 Median no. of ED attendances for asthma in last 1 year 1, 1 Median no. of hospital admissions for asthma in last 1 year 1, 1 Soyer et al. (2009) [60] 6–18 522 Mean (sd) no. of unscheduled visits per patient 1.2 (0.2) Mean (sd) no. of ED visits per patient 0.6 (0.05) Verbene et al. (1996) [58] 7–16 30 Pts hospitalised for asthma in last 1 year 0% All studies were randomised controlled trials except Giraud et al. [54], McIvor et al. [22], Ding and Small [49], Lai et al. [61] and Soyer et al. [60]. pts: patients; ED: emergency department; OCS: oral corticosteroids; no.: number. # Study included patients with a history of exacerbations (time frame not specified); ¶ n=1076; + time frame not specified in Results section of [49] although Methods section suggests 12-month timeframe; §: Study included only patients with a history of 3–6 exacerbations (hospitalisation or ED visit or general practitioner visits) in the 12 months prior to enrolment/screening.
- TABLE 4
Prospective data on exacerbations and exacerbation-related outcomes in mild asthma from placebo arms of RCTs of ≥24 weeks' duration
Study (year) [ref.] Age range years Placebo n Other asthma medication in placebo arm Treatment duration Exacerbation parameter Placebo arm Studies not excluding patients with exacerbation history+ Bisgaard et al. (2005) [27] 2–5 271 Rescue OCS or ICS or β2-agonist 48 wks Pts with exacerbation§ 56% Exacerbation rate/year (n=257)ƒ 2.34 Median time to first exacerbation 147 days Pts with ≥1 unscheduled visit to physician for asthmaƒ 42.4% Pts hospitalised for asthmaƒ 5.8% Rate of OCS courses/yearƒ 0.64 Chuchalin et al. (2008) [32] 12–79 315 Rescue ALB 52 wks Mean exacerbation rate per pt per year (mild, moderate, severe) 2.88 Moderate (OCS) or severe exacerbation (hospitalisation) rate/year 0.33 No. unscheduled asthma-related healthcare contacts 7 Pt withdrawal/discontinued due to exacerbation, n 8 Martinez et al. (2011) [36] 5–18 74 Rescue ALB 44 wks Probability (95% CI) of first exacerbation by end of trial requiring prednisone course 49 (37–61)% Proportion with treatment failure (all defined by requirement for a second course of prednisone) 23% O'Byrne et al. (2001) [39] ≥12 239 Yes - only after first exacerbation (n=104)¶¶ 1 yr Pts with severe exacerbation 33.3% No. of pts with severe exacerbation, pts treated with OCSs 70.9% Pts receiving systemic corticosteroids 23.6% Severe exacerbation rate per pt per year 0.77 O’Byrne et al. (2018) [38] ≥12 1277 TERB 0.5 mg as needed 1 yr Pts with ≥1 moderate or severe exacerbation 21.5% Pts with ≥1 severe exacerbation 11.9% Annualised severe exacerbation rate 0.20 Papi et al. (2007) [40] 18–65 118 ALB as-needed 6 months Pts with severe exacerbation 3.4% Pts with ≥1 exacerbation 17.80% Mean no. of exacerbations/pt/year 1.63 Pauwels et al. (2003) [41] 5–66 3568 Usual asthma treatment (SABA 64.6% of placebo pts) plus ICS or systemic corticosteroid if needed 3 yrs Pts with life-threatening exacerbation over 3 years, n 24 (0.67%) Pts with ≥1 SARE over 3 years, n 198 Pts with ≥2 SAREs over 3 years, n 49 Mean no. of courses of systemic corticosteroids per year 0.21 Pts using systemic corticosteroids 3 months: 4.1% 12 months: 3.1% 24 months: 3.3% 36 months: 2.0% Pts with ≥1 systemic corticosteroid course 23% Studies excluding patients with exacerbation history+ Reddel et al. (2008) [42] 18–80 21 ALB as-needed 11 months Pts with ≥1 mild exacerbation, n 13 Pts with severe exacerbation, n 3 Studies requiring patients to have a history of frequent exacerbations# Robertson et al. (2007) [21] 2–14 113 Inhaled β2-agonist or OCS for acute asthma episode 12 months Proportion of children with ≥1 episode treated with short course of randomised therapy, n (%) 105 (92.9%) Total number of treated episodes of asthma 336 Proportion of treated asthma episodes utilising ≥1 health resource, n (%) 134 (39.9%) Proportion of treated asthma episodes requiring ED visit, n (%) 46 (13.7%) Proportion of treated asthma episodes requiring hospitalisation, n (%) 13 (3.9%) Proportion of treated asthma episodes with OCS use, n/N pts with diary data (%) 78 of 321 (24.3%) RCT: randomised controlled trial; ED: emergency department; wks: weeks; pt: patient; OCS: oral corticosteroid; ICS: inhaled corticosteroid; CI: confidence interval; SABA: short-acting β2-agonist; SARE: severe asthma-related event; ALB: albuterol; TERB: terbutaline; GP: general practitioner; LABA: long-acting β2-agonist. # Study included only patients with a history of 3–6 exacerbations (hospitalisation or ED visit or GP visits) within 12 months prior to enrolment/screening); ¶ Unscheduled visits to GP, specialist paediatrician, ED or admission to hospital; +: Exacerbation history defined as an exacerbation, hospitalisation or ED visit or OCS use occurring ≥3 months prior to enrolment/screening; §: data appear to relate to 48-week double-blind period only (total study duration 1 year including screening and single-blind, placebo run-in period); ƒ: source publication refers to “yearly” data, but double-blind treatment period only 48 weeks (total study duration 1 year including screening and single-blind, placebo run-in period); ##: defined as the requirement for a second dose of prednisone within any 6-month period; ¶¶: most common extra medication in placebo group was systemic corticosteroids (n=56), ICS (n=15) and LABAs (n=11).
Supplementary Material
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Supplementary material 00359-2019.SUPPLEMENT
