TABLE 5.
First author [ref.] | Time of outcome | Definition of outcomes | Subjects n | Exacerbations per person year | Between group comparison | ICS use | Between group difference# |
Smith [24] | 3–12 months optimisation (exacerbation rates not reported for this period) plus 12 months titration | Minor: global daily asthma score¶ of two on ≥2 consecutive days | 94 | Intervention group+: 0.36 Control group+: 0.75 |
p=0.24 | Final value ICS use§ Intervention Baseline: mean 411 μg per day (95% CI 344–478) End of phase 2: mean 370 µg per day (95% CI 263–477) Control Baseline: mean 491 μg per day (95% CI 403–579) End of phase 2: mean 641 µg per day (95% CI 526–756) |
Mean difference −270 µg per day (95% CI −112– −430, p=0.003) |
Major: global daily asthma score¶ of three on ≥2 consecutive days (or in 1 day, in the context of a minor exacerbation) Major exacerbation or medical emergency: global daily asthma score¶ of four in 1 day |
Intervention group+: 0.13 Control group+: 0.14 |
p=0.91 | |||||
Any minor or major exacerbation | Intervention group: 0.49 (95% CI 0.20–0.78) Control group: 0.90 (95% CI 0.31–1.49) |
−45.6% (95% CI −78.6–54.5, p=0.27) NS | |||||
Course of oral prednisone | Intervention group: 0.48 Control group: 0.60 |
p=0.60 | |||||
Shaw [25] | 12 months | Course of OCS or antibiotics | 118 | Intervention group: 0.33 (sd 0.69) Control group: 0.42 (sd 0.79) |
−21% (95% CI −57–43%, p=0.43) | Final value ICS useƒ Intervention: 557 µg Control: 895 µg |
Mean difference −338 µg per day (95% CI −640– −37 µg, p= 0.028) Total used in study (AUC): 11% greater in FeNO group (95% CI −15–37%) |
Syk [14] | End-points analysed from visit 2 to visit 6 (2–4 weeks, 12 months) | Moderate exacerbation: need to step-up controller treatment for at least 2 days with or without clinic visit Prophylactic use before pollen season excluded |
165 | Intervention group: 0.1 Control group: 0.325 |
NR | ICS use¶¶ Intervention Median 0 (IQR −400–400) Baseline: mean 604 (se 370) Final value: 586 (se 454) Control 0 (IQR −200– 200) Baseline: mean 626 (se 391) Final value: 540 (se 317) |
0.945 |
Severe exacerbation ##: worsening requiring a course of OCS | Intervention group: 0.113 Control group: 0.0875 |
NS | |||||
Moderate or severe exacerbation | Intervention group: 0.22 Control group: 0.41 |
p=0.024 | |||||
Calhoun [13] | 9 months | Exacerbation: unscheduled medical contact for increased asthma symptoms that results in the use of OCS, increased ICS or additional medication for asthma | 229 | Intervention group: 0.21 (97.5% CI 0.1–0.32) Control group: 0.23 (97.5% CI 0.1–0.37) |
“Did not differ” | ICS use (unclear if mean over whole study or final value)ƒ Intervention Mean 1617 µg·month−1 Control Mean 1610 µg·month−1 |
NR |
Treatment failure defined as exacerbation or loss of control++ | Intervention group: 0.27 (97.5% CI 0.14–0.39) Control group: 0.43 (97.5% CI 0.23–0.64) |
“Were not different” | |||||
Honkoop [16] | 12 months | Severe exacerbation: course of oral prednisone, hospitalisation and/or emergency department visit | 611 | Intervention group: 0.19 (95% CI 0.11–0.29) Control group Strict: 0.29 (95% CI 0.17–0.40) Sufficient: 0.29 (95% CI 0.15–0.43) |
Odds ratio versus Strict: 0.64 (95% CI 0.27–1.56) Sufficient: 0.79 (95% CI 0.32–1.92) |
NR | NR |
Unscheduled healthcare utilisation: hospitalisation and/or emergency department visit | Number of visits Intervention group: 3 Controlled asthma: strict 5 Partly controlled asthma: sufficient 9 |
Odds ratio versus Strict: 0.61 (95% CI 0.14–2.58) Sufficient: 0.37 (95% CI 0.10–1.38) |
NS: nonsignificant difference; OCS: oral corticosteroid; AUC: area under curve; NR: not reported; IQR: interquartile range; PEFR: peak expiratory flow rate. #: Expressed as intervention minus control (negative values indicate lower FeNO). ¶: Asthma scores were as follows. 0 (stable): morning PEFR >75% of best PEFR in 14-day run-in period without deterioration in any symptom scores. 1 (mildly unstable): one or more of the following a) bronchodilator use on two or more occasions in 24 h more than the rounded mean number of occasions during the run-in period; b) increase in symptom score of 1 point or more as compared with rounded mean during run-in period; c) onset of or increase in nocturnal waking by one or more times in the previous seven nights more than rounded mean number of times during the run-in period, or morning PEFR of 61–75% without deterioration in any of the above categories. 2 (minor deterioration): morning PEFR of 61–75% of best PEFR during the run-in period and one or more criteria for an asthma score of 1; or morning PEFR of 41–60% without deterioration in any criteria for an asthma score of 1. 3 (major deterioration): morning PEFR of 41–60% of best PEFR during run-in period and one or more criteria for an asthma score of 1. 4 (major exacerbation or medical emergency): morning PEFR of 40% or less than best PEFR during run-in period regardless of symptoms, or attendance at clinician's office or emergency department because of severe asthma. +: Estimated off graph. §: Fluticasone or the equivalent. ƒ: Beclomethasone diproprionate or equivalent. ##: American Thoracic Society/European Respiratory Society Task Force Criteria 2009. ¶¶: Budesonide equivalent. ++: At-home measurements: 1) Pre-bronchodilator AM peak expiratory flow (PEF) of <65% of baseline on two consecutive mornings, scheduled measurements. 2) Post-bronchodilator PEF of <80% of baseline despite 60 min of rescue β-agonist treatment. 3) Post-bronchodilator PEF may be taken at any time of day, an increase in albuterol use of more than 8 puffs per 24 h over baseline use for a period of 48 h, or more than 16 puffs per 24 h for more than 48 h. In-clinic measurements: 1) Pre-bronchodilator forced expiratory volume in 1 s (FEV1) values on two consecutive sets of spirometric determinations, measured 24–72 h apart, that are <80% of the baseline pre-bronchodilator value (baseline value for adherence period: FEV1 value at visit 3; baseline for randomisation period: FEV1 value at visit 4). All participants found to have an FEV1 of <80% of baseline at any centre visit but who are not considered to meet treatment failure or exacerbation criteria must be seen again within 72 h to have FEV1 measured. 2) Physician judgment for patient safety. 3) Patient dissatisfaction with asthma control achieved by study regimen. 4) Requirement for open-label ICSs or another (nonsystemic corticosteroid) new asthma medication (e.g. montelukast) without the addition of systemic corticosteroids.