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Table 1 Characteristics of included randomised, double blind, controlled trials of long acting β2 agonists in maintenance therapy for chronic obstructive pulmonary disease (COPD)

From: Long acting β2agonists for stable chronic obstructive pulmonary disease with poor reversibility: a systematic review of randomised controlled trials

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
  1. AUC = area under the curve; BDI = baseline dyspnoea index;[29] CBSQ = chronic bronchitis symptom questionnaire; [42] CRDQ = chronic respiratory disease questionnaire;[30] FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; HRQoL = health related quality of life; MMRC = Modified Medical Research Council; PEFR = peak expiratory flow rate; RV = residual volume; SF-36 = Medical Outcomes Study Short Form 36;[28] SGRQ = St. George's Respiratory Questionnaire;[27] TDI = transition dyspnoea index;[29] TLC = total lung capacity.