Table 1 Characteristics of included randomised, double blind, controlled trials of long acting β2 agonists in maintenance therapy for chronic obstructive pulmonary disease (COPD)
First author, year of publication, design | Trial quality | Patients meeting inclusion criteria | Interventions | Outcomes investigated | Notes |
|---|---|---|---|---|---|
Ulrik, 1995[16] Crossover | 3 | 66 current smokers with FEV1 of 1–2 L (< 60% of predicted) and FEV1/FVC < 60% of predicted. FEV1of <15% or 300 ml after salbutamol | Salmeterol (50 μg twice daily) or placebo for 4+4 weeks; no crossover washout. | FEV1, PEFR, daytime and night-time symptom scores, rescue use of salbutamol. | Two week run in. Methylxanthines, corticosteroids (short oral courses) allowed. |
Newman, 1996[22] (abstract) Crossover | 2 | 42 patients with mean FEV1 of 0.93 L (35% of predicted) and no response to oral steroids. | Salmeterol (100 μg twice daily) or placebo for 8+8 weeks. | FEV1, FVC, six minute walk test and Borg dyspnoea assessment,[26] daytime and night-time symptom scores, rescue use of salbutamol, proportion of days unable to perform normal activity, incidence of adverse events and COPD exacerbations. | Two week run in. Salbutamol rescue allowed. |
Grove, 1996[15] Crossover | 3 | 29 patients with FEV1 25%–75% of predicted and 5%–15% reversibility with 200 μg of salbutamol. | Salmeterol (50 μg twice daily) or placebo for 4+4 weeks; one1 week crossover washout. | FEV1, FVC, TLC, RV, 6 minute walk test and exertion on Borg scale, oxygen uptake. | At least one week run in. Inhaled corticosteroids, anticholinergics, oral theophylline allowed. |
Boyd, 1997[10] Parallel | 2 | 674 patients with FEV1 ≤ 70% and FEV1/FVC ratio ≤ 60% of predicted and 5%–15% reversibility of FEV1 with 400 or 800 μg of salbutamol. | Salmeterol (50 or 100 μg twice daily) or placebo for 16 weeks. | FEV1, six minute walk test and Borg dyspnoea assessment, daytime and night-time symptom scores, rescue use of salbutamol. | Two week run in. Medications other than β2 agonists allowed. |
Jones, 1997[14] Parallel | 2 | 283 patients with FEV1 ≤ 70% and FEV1/FVC ratio ≤ 60% of predicted; 5%–15% reversibility of FEV1 with 400 or 800 μg of salbutamol. | Salmeterol (50 or 100 μg twice daily) or placebo for 16 weeks. | HRQoL with SGRQ27 and SF-36[28]. | Two week run in. Medications other than β2 agonists allowed. |
Mahler, 1999[8] Parallel | 3 | 145 patients with FEV1 ≤ 65% and FEV1/FVC ratio ≤ 70% of predicted; ≤ 15% reversibility of FEV1 with short acting β2agonist; grade 1 baseline severity of breathlessness. | Salmeterol (42 μg twice daily) or ipratropium bromide (36 μg four times daily) or placebo for 12 weeks. | FEV1 AUC, six minute walk test, daytime and night-time symptom scores, dyspnoea on BDI and TDI,[29] supplemental use of salbutamol, HRQoL on CRDQ,[30] COPD exacerbations. | Run in six hours to three days. Prednisone (≤ 10 mg) or equivalent or inhaled corticosteroids allowed. |
Rennard, 2001[23] Parallel | 3 | 179 patients with FEV1 ≤ 65% and FEV1/FVC ratio ≤ 70% of predicted; ≤ 12% reversibility of FEV1 with salbutamol; score ≥ 1 on MMRC five point dyspnoea scale. | Salmeterol (42 μg twice daily) or ipratropium (36 μg four times daily) or placebo for 12 weeks. | FEV1 and FVC AUC, dyspnoea on BDI and TDI, six minute walk test and Borg dyspnoea assessment, symptom scores, QoL on CRDQ, COPD exacerbations. | Corticosteroids, inhaled and oral (< 10 mg/d), allowed. |
Rossi, 2002[27] Parallel | 3 | 418 patients with FEV1 < 70% and FEV1/FVC ratio ≤ 88% of predicted; < 15% reversibility of FEV1 with short acting β2agonist; grade 1 baseline severity of breathlessness. | Formoterol (12 or 24 μg twice daily) or placebo or oral slow release theophylline for 12 months. | FEV1 AUC. | Inhaled corticosteroids and rescue use of salbutamol allowed. |
Stahl, 2002[26] Parallel | 3 | 183 patients with FEV1 < 60% and FEV1/FVC < 70% of predicted; < 12% reversibility of FEV1 after single dose of formoterol. | Formoterol (18 μg twice daily) or ipratropium (80 μg three times daily) or placebo for 12 weeks. | FEV1, FVC, PEFR, shuttle walking test, morning and evening symptom scores, HRQoL on SGRQ. | Inhaled corticosteroids at constant doses and rescue use of short acting β2 agonists allowed. |
Gupta, 2002[29] Parallel | 4 | 33 patients with FEV1 < 60 % predicted and FEV1/FVC ≤ 70%; reversibility <12 % improvement of FEV1 after 400 μg salbutamol | Salmeterol (50 μg twice daily) or placebo twice daily for 8 weeks | FEV1, FVC, six minute walk test, HRQoL on SF-36[28], dyspnoea on BDI, patient self-assessment, and rescure inhaler usage | Two week run in period. Patients required to take beclomethasone 400 μg twice daily and ipratropium 20 μg four times daily. |
Mahler, 2002[30] Parallel | 2 | 158 patients with FEV1 < 65 % predicted and FEV1/FVC ≤ 70%; reversibility <12 % improvement of FEV1 after 400 μg salbutamol | Salmeterol (50 μg twice daily) or placebo twice daily for 24 weeks | FEV1, morning PEF, dyspnoea on BDI and TDI; rescue salbutamol use; HRQoL on CRDQ [30]; symptoms on CBSQ | Randomization stratified by reversibility. |
Calverly, 2003[28] Parallel | 5 | 733 patients with FEV125–70% predicted and FEV1/FVC ≤ 70%; reversibility <10 % of predicted FEV1 after salbutamol | Salmeterol (50 μg twice daily) or placebo twice daily for 52 weeks | FEV1, FVC, relief medication, symptom scores, night-time awakenings, exacerbation rates, HRQoL on SGRQ | Two week run in and two week follow up |
Hanania, 2003[31] Parallel | 2 | 163 patients with FEV1 < 65% predicted but > 700 ml (or if ≤ 700 ml > 40 % predicted) and FEV1/FVC < 65%; reversibility < 12 % of predicted FEV1 after salbutamol | Salmeterol (50 μg twice daily) or placebo twice daily for 24 weeks | FEV1, morning PEF, dyspnoea on BDI and TDI; rescue salbutamol use; HRQoL on CRDQ [30]; symptoms on CBSQ, exacerbation rates (all severities) | Randomization stratified by reversibility |