- Email: [email protected]
Treatment with the immunomodulator AM3 improves the health-related quality of life of patients with COPD
ARTICLE IN PRESS 66
V.A. Kiri et al.
Inhaled corticosteroids in chronic obstructive pulmonary disease: Results from two observational designs free of immortal time bias Am J Respir Crit Care Med 172:460–4. First published online as doi:10.1164/rccm.200502210OC.
Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): A randomised placebo-controlled trial The Lancet 2005;365(9470):1552–60
V.A. Kiri, N.B. Pride, J.B. Soriano, J. Vestbo
M. Decramer, M. Rutten-van Mo ¨lken, P.N.R. Dekhuijzen, T. Troosters, C. van Herwaarden, R. Pellegrino, C.P. Ovan Schayck, D. Olivieri, M. Del Donno, W. De Backer, et al.
Worldwide Epidemiology, GlaxoSmithKline R&D, Greenford Road, Greenford, Middlesex UB6 0HE, UK E-mail address: [email protected] (V.A. Kiri).
Rationale: Recent cohort studies in chronic obstructive pulmonary disease (COPD) have questioned the validity of previously reported associations between inhaled corticosteroids (ICS) and reductions in mortality and rehospitalization in observational studies. Using time-dependent versions of statistical survival models, these studies have suggested immortal time bias as responsible for the proposed beneficial association. Objectives: We explored the extent of this bias in a study of patients with COPD monitored for a year from COPD discharge with two designs free of any immortal time bias in the General Practice Research Database in the United Kingdom. Methods: In Design 1, we used only patients whose treatment status was defined on the same day of discharge to obtain a matched cohort based on propensity scores, which were derived from the patient-level baseline characteristics. In Design 2, we identified all in the study cohort who experienced death or rehospitalization and then matched each case to up to four noncases by randomly sampling from the cohort risk sets without regard to treatment status. Measurements and main results: The propensity scores matched cohort analysis of 786 patients without a wait time found a significant risk reduction associated with use of ICS: hazard ratio, 0.69 (95% confidence interval, 0.52–0.93). The matched nested case–control analysis of 2222 patients, designed without regard to exposure status and hence free of immortal time bias, gave a similar association with exposure to ICS in the last 6-month period: hazard ratio, 0.71 (0.56–0.90). Conclusions: We conclude that immortal time bias cannot account for the risk reduction associated with ICS exposure in observational studies.
Reproduced with permission from the American Thoracic Society. doi: 10.1016/j.rmedu.2005.09.020
Background: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. Methods: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. Findings: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs. 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI 25 to 10). The number of exacerbations per year did not differ between groups (1 25 [SD 1 35] vs. 1 29 [SD 1 46]; hazard ratio 0 99 [95% CI 0 89–1 10, P ¼ 0 85). Subgroup analysis suggested that the exacerbation rate might be reduced with N-acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. Interpretation: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD. & 2005 Published by Elsevier Ltd doi: 10.1016/j.rmedu.2005.09.021
Treatment with the immunomodulator AM3 improves the health-related quality of life of patients with COPD Chest 2005;127(4):1212–8. M. Alvarez-Mon, M. Miravitlles, J. Morera, L. Callol, J.L. Alvarez-Sala Departmento de Medicina, Universidad de Alcala, Carretera Madrid-Barcelona, Km 33,600, E-28871 Alcala de Henares (Madrid), Spain E-mail address: [email protected] (M. Alvarez-Mon).
ARTICLE IN PRESS Smoking and COPD
67
Background: COPD has a severe impact on patient quality of life. AM3 is an orally effective immunomodulator that can normalize the defective antimicrobial functions of the immune system effector cells of COPD patients. Objectives: We analyzed the effect of AM3 on exacerbation frequency and health-related quality of life (HRQL) of COPD patients with moderate disease. Design: A randomized, double-blind, placebo-controlled trial. Setting: Outpatient departments of 21 hospitals. Methods: A total of 253 COPD patients with a mean age of 67.7 years (SD, 8.1 years) and mean FEV(1) percentage of predicted of 49.6% (SD, 10.2%) were evaluated. Patients received (orally) either 3 g/d AM3 or a matched placebo for 180 consecutive days. Patient quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ). Results: There were no differences in the exacerbation frequency of the two groups (0.82 episodes per patient in the AM3 arm vs. 0.84 in the placebo arm), and 55.3% of patients were exacerbation free in the AM3 arm compared to 48.8% in the placebo arm ðP ¼ 0:11Þ: At the end of treatment, quality of life was significantly better in the AM3 arm than in the placebo arm (SGRQ total score, 32.9; SD, 16.4, compared to 37.5; SD, 17.5 [Po0.05]: activity score, 47.5; SD, 22.4, compared to 54.6; SD, 20.5 [Po0.05]). The improvements in total SGRQ scores were 8.9 U (SD, 13.4 U) in the AM3 arm and 5.6 U (SD, 15.9 U) in the placebo arm ðP ¼ 0:076Þ: Improvements on the symptoms subscale were 15.9 U (SD, 20.7 U) for the AM3 arm and 10.2 U (SD, 21.3 U) for the placebo arm (Po0.05). Both AM3 and the placebo were clinically, biochemically, and hematologically well tolerated. Conclusions: AM3 is a safe, easily tolerated, effective treatment that improves the quality of life of COPD patients as measured by SGRQ scores. This effect was observed with no significant reduction in the frequency of exacerbations.
Background: Combined treatment with inhaled corticosteroids and long acting b2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. Methods: Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. Results: PEF was significantly higher after 1 day in patients treated with salmeterol 50 mg twice daily or the salmeterol/fluticasone propionate combination 50/ 500 mg twice daily than placebo. In patients treated with fluticasone propionate 500 mg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11–21), 11 l/min (95% CI 6–16), and 27 l/min (95% CI 22–33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/ fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 s (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long-term response in individual patients. Conclusions: The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.
& 2005 American College of Chest Physicians. Reproduced with permission.
Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: A randomised controlled trial Thorax 2005;60:480–7.
doi: 10.1016/j.rmedu.2005.09.022
Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Thorax 2005;60:301–4 J. Vestbo, R. Pauwels, J.A. Anderson, P. Jones, P. Calverley, on behalf of the TRISTAN study group
Reproduced with permission from the BMJ Publishing Group. doi: 10.1016/j.rmedu.2005.09.023
E.F.M. Wouters, D.S. Postma, B. Fokkens, W.C.J. Hop, J. Prins, A.F. Kuipers, H.R. Pasma, C.A.J. Hensing, E.C. Creutzberg, for the COSMIC (COPD and Seretide: a Multi-Center Intervention and Characterization) Study Group
North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK
Department of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
E-mail address: [email protected] (J. Vestbo).
E-mail address: [email protected] (E.C. Creutzberg).
V.A. Kiri et al.
Inhaled corticosteroids in chronic obstructive pulmonary disease: Results from two observational designs free of immortal time bias Am J Respir Crit Care Med 172:460–4. First published online as doi:10.1164/rccm.200502210OC.
Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): A randomised placebo-controlled trial The Lancet 2005;365(9470):1552–60
V.A. Kiri, N.B. Pride, J.B. Soriano, J. Vestbo
M. Decramer, M. Rutten-van Mo ¨lken, P.N.R. Dekhuijzen, T. Troosters, C. van Herwaarden, R. Pellegrino, C.P. Ovan Schayck, D. Olivieri, M. Del Donno, W. De Backer, et al.
Worldwide Epidemiology, GlaxoSmithKline R&D, Greenford Road, Greenford, Middlesex UB6 0HE, UK E-mail address: [email protected] (V.A. Kiri).
Rationale: Recent cohort studies in chronic obstructive pulmonary disease (COPD) have questioned the validity of previously reported associations between inhaled corticosteroids (ICS) and reductions in mortality and rehospitalization in observational studies. Using time-dependent versions of statistical survival models, these studies have suggested immortal time bias as responsible for the proposed beneficial association. Objectives: We explored the extent of this bias in a study of patients with COPD monitored for a year from COPD discharge with two designs free of any immortal time bias in the General Practice Research Database in the United Kingdom. Methods: In Design 1, we used only patients whose treatment status was defined on the same day of discharge to obtain a matched cohort based on propensity scores, which were derived from the patient-level baseline characteristics. In Design 2, we identified all in the study cohort who experienced death or rehospitalization and then matched each case to up to four noncases by randomly sampling from the cohort risk sets without regard to treatment status. Measurements and main results: The propensity scores matched cohort analysis of 786 patients without a wait time found a significant risk reduction associated with use of ICS: hazard ratio, 0.69 (95% confidence interval, 0.52–0.93). The matched nested case–control analysis of 2222 patients, designed without regard to exposure status and hence free of immortal time bias, gave a similar association with exposure to ICS in the last 6-month period: hazard ratio, 0.71 (0.56–0.90). Conclusions: We conclude that immortal time bias cannot account for the risk reduction associated with ICS exposure in observational studies.
Reproduced with permission from the American Thoracic Society. doi: 10.1016/j.rmedu.2005.09.020
Background: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. Methods: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. Findings: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs. 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI 25 to 10). The number of exacerbations per year did not differ between groups (1 25 [SD 1 35] vs. 1 29 [SD 1 46]; hazard ratio 0 99 [95% CI 0 89–1 10, P ¼ 0 85). Subgroup analysis suggested that the exacerbation rate might be reduced with N-acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. Interpretation: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD. & 2005 Published by Elsevier Ltd doi: 10.1016/j.rmedu.2005.09.021
Treatment with the immunomodulator AM3 improves the health-related quality of life of patients with COPD Chest 2005;127(4):1212–8. M. Alvarez-Mon, M. Miravitlles, J. Morera, L. Callol, J.L. Alvarez-Sala Departmento de Medicina, Universidad de Alcala, Carretera Madrid-Barcelona, Km 33,600, E-28871 Alcala de Henares (Madrid), Spain E-mail address: [email protected] (M. Alvarez-Mon).
ARTICLE IN PRESS Smoking and COPD
67
Background: COPD has a severe impact on patient quality of life. AM3 is an orally effective immunomodulator that can normalize the defective antimicrobial functions of the immune system effector cells of COPD patients. Objectives: We analyzed the effect of AM3 on exacerbation frequency and health-related quality of life (HRQL) of COPD patients with moderate disease. Design: A randomized, double-blind, placebo-controlled trial. Setting: Outpatient departments of 21 hospitals. Methods: A total of 253 COPD patients with a mean age of 67.7 years (SD, 8.1 years) and mean FEV(1) percentage of predicted of 49.6% (SD, 10.2%) were evaluated. Patients received (orally) either 3 g/d AM3 or a matched placebo for 180 consecutive days. Patient quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ). Results: There were no differences in the exacerbation frequency of the two groups (0.82 episodes per patient in the AM3 arm vs. 0.84 in the placebo arm), and 55.3% of patients were exacerbation free in the AM3 arm compared to 48.8% in the placebo arm ðP ¼ 0:11Þ: At the end of treatment, quality of life was significantly better in the AM3 arm than in the placebo arm (SGRQ total score, 32.9; SD, 16.4, compared to 37.5; SD, 17.5 [Po0.05]: activity score, 47.5; SD, 22.4, compared to 54.6; SD, 20.5 [Po0.05]). The improvements in total SGRQ scores were 8.9 U (SD, 13.4 U) in the AM3 arm and 5.6 U (SD, 15.9 U) in the placebo arm ðP ¼ 0:076Þ: Improvements on the symptoms subscale were 15.9 U (SD, 20.7 U) for the AM3 arm and 10.2 U (SD, 21.3 U) for the placebo arm (Po0.05). Both AM3 and the placebo were clinically, biochemically, and hematologically well tolerated. Conclusions: AM3 is a safe, easily tolerated, effective treatment that improves the quality of life of COPD patients as measured by SGRQ scores. This effect was observed with no significant reduction in the frequency of exacerbations.
Background: Combined treatment with inhaled corticosteroids and long acting b2 agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. Methods: Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. Results: PEF was significantly higher after 1 day in patients treated with salmeterol 50 mg twice daily or the salmeterol/fluticasone propionate combination 50/ 500 mg twice daily than placebo. In patients treated with fluticasone propionate 500 mg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11–21), 11 l/min (95% CI 6–16), and 27 l/min (95% CI 22–33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/ fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 s (FEV1). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV1 was only partly indicative of a long-term response in individual patients. Conclusions: The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.
& 2005 American College of Chest Physicians. Reproduced with permission.
Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: A randomised controlled trial Thorax 2005;60:480–7.
doi: 10.1016/j.rmedu.2005.09.022
Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Thorax 2005;60:301–4 J. Vestbo, R. Pauwels, J.A. Anderson, P. Jones, P. Calverley, on behalf of the TRISTAN study group
Reproduced with permission from the BMJ Publishing Group. doi: 10.1016/j.rmedu.2005.09.023
E.F.M. Wouters, D.S. Postma, B. Fokkens, W.C.J. Hop, J. Prins, A.F. Kuipers, H.R. Pasma, C.A.J. Hensing, E.C. Creutzberg, for the COSMIC (COPD and Seretide: a Multi-Center Intervention and Characterization) Study Group
North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK
Department of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
E-mail address: [email protected] (J. Vestbo).
E-mail address: [email protected] (E.C. Creutzberg).