Therapeutics
Review: In COPD, fluticasone or budesonide increases serious pneumonia but not mortality
Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;3:CD010115.
Clinical impact ratings: F ★★★★★✩✩ p ★★★★★✩✩ Question
Main results
In chronic obstructive pulmonary disease (COPD), does fluticasone or budesonide, alone or combined with long-acting β2-agonists (LABAs), increase risk for pneumonia?
The main results are in the Table. Fluticasone (unweighted event rates 29% vs 34%, P < 0.001) and budesonide (23% vs 28%, P < 0.001) each reduced treatment withdrawals compared with control. Fluticasone (0.3% vs 0.2%) and budesonide (0.1% vs 0%) did not differ from control for pneumonia mortality.
Review scope Included studies compared fluticasone or budesonide with placebo, or either drug {in a LABA combination inhaler}* with LABA monotherapy, in patients with COPD (FEV1–FVC ratio < 0.7 and ≥ 1 of the following: chronic cough, chronic sputum production, progressive or persistent dyspnea, or past exposure to risk factors); and had study duration ≥ 12 weeks. Outcomes were nonfatal serious pneumonia needing hospitalization, all-cause and pneumonia mortality, nonfatal serious adverse events {as defined by trial authors}*, any pneumonia, and treatment withdrawal.
Review methods Cochrane Airways Group Specialized Register of trials to Sep 2013, which includes searches of MEDLINE, EMBASE/ Excerpta Medica, Cochrane Central Register of Controlled Trials, CINAHL, AMED, PsycINFO, and conference abstracts; ClinicalTrials.gov to Sep 2013; reference lists; and drug manufacturer Web sites were searched for parallel-group, randomized, controlled trials (RCTs). 43 RCTs met the selection criteria: 26 evaluated fluticasone (n = 21 247, mean age 47 to 67 y, 52% to 92% men, weighted mean duration 18 mo) and 17 budesonide (n = 10 150, mean age 52 to 67 y, 54% to 100% men, weighted mean duration 14 mo). 17 RCTs had low risk for bias in allocation concealment, 39 in blinding patients and investigators, and 10 in blinding outcome assessment. For completeness of outcome data, 21 studies had low risk for bias, 16 had high risk for bias because of high or uneven dropout rates, and 6 had undetermined risk. 34 RCTs received funding from drug manufacturers.
Conclusion In chronic obstructive pulmonary disease, fluticasone or budesonide, alone or with long-acting β2-agonists, increases serious pneumonia needing hospitalization but not mortality. *Information provided by author.
Source of funding: No external funding. For correspondence: K.M. Kew, St. George’s University of London, London, England, UK. E-mail [email protected]. ■
Commentary
The decision of whether to use an inhaled corticosteroid (ICS) in COPD must weigh the increased risk for pneumonia against the benefits (when combined with LABAs) of fewer exacerbations, higher lung function, and better quality of life (1). Because benefits of ICS/LABA over LABA alone are small and have been shown mostly in patients with severe COPD or a history of exacerbations (1), ICS/LABA should be preferred primarily in such patients. This approach is concordant with current guidelines (2). In the review by Kew and colleagues, pneumonia risk seemed to be dosedependent for budesonide. As ICS benefits in COPD have not shown the same dose dependency (1), moderate-dose ICS may be a better choice than higher-dose ICS for COPD patients. Although the review by Kew and colleagues evaluated only budesonide and fluticasone, a recent large observational study (3) also found an increased dose-dependent risk for pneumonia requiring hospitalization in patients receiving other ICSs and a higher risk with fluticasone than budesonide. Kew and colleagues also found a higher risk Fluticasone or budesonide vs placebo, and fluticasone or budesonide plus LABAs vs with fluticasone than budesonide but only for all LABA monotherapy in COPD† pneumonias, not serious cases. Such differences must be interpreted with caution because baseSteroid Outcomes‡ Number of Weighted RRI/RRR (95% CI) NNH/NNT (CI) trials (n) event rates line risk for pneumonia varied across trials, many did not report pneumonia events, and most did Fluticasone Nonfatal serious 17 (19 504) 4.3% vs 2.5% RRI 73% (47 to 104) NNH 56 (39 to 86) not report how pneumonia was identified. A pneumonia§ randomized trial directly comparing regimens Nonfatal SAE 19 (20 381) 24% vs 23% RRI 4% (−1 to 9) NS with different inhaled steroids is needed to Any pneumonia|| 11 (15 377) 11% vs 7.2% RRI 57% (41 to 75) NNH 25 (19 to 34) determine whether they confer different pneuAll-cause mortality 22 (20 861) 5.76% vs 5.82% RRR 1% (−11 to 11) NS monia risks in COPD. Budesonide
Nonfatal serious pneumonia§||
7 (6472)
1.5% vs 0.9%
RRI 60% (1 to 155)
NNH 184 (71 to 10 989)
Nonfatal SAE||
12 (10 009)
14.6% vs 14.5%
RRI 1% (−14 to 18)
NS
Any pneumonia||
6 (7011)
3.1% vs 2.8%
RRI 12% (−16 to 48)
NS
All-cause mortality||
12 (10 009)
1.5% vs 1.7%
RRR 10% (−24 to 35)
NS
†COPD = chronic obstructive pulmonary disease; LABA = long-acting β2-agonist; NS = not significant; SAE = serious adverse event; other abbreviations defined in Glossary. Weighted event rates, RRI, RRR, NNH, and CI calculated from data in article using random-effects (budesonide for nonfatal SAEs) or fixed-effect (all other outcomes) models. ‡Quality of evidence was high based on Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria unless indicated otherwise. §Pneumonia needing hospitalization. ||Quality of evidence was moderate based on GRADE criteria.
JC8
© 2014 American College of Physicians
Matthew B. Stanbrook, MD, PhD University Health Network, University of Toronto Toronto, Ontario, Canada References 1. Nannini LJ, Lasserson TJ, Poole P. Cochrane Database Syst Rev. 2012;9: CD006829. 2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the diagnosis, management, and prevention of COPD. 2014. www.goldcopd.org/ (accessed 6 Jun 2014). 3. Suissa S, Patenaude V, Lapi F, Ernst P. Thorax. 2013;68:1029-36. 19 August 2014 | ACP Journal Club | Volume 161 • Number 4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a NYU Medical Center Library User on 02/16/2017
Review: In COPD, fluticasone or budesonide increases serious pneumonia but not mortality
Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;3:CD010115.
Clinical impact ratings: F ★★★★★✩✩ p ★★★★★✩✩ Question
Main results
In chronic obstructive pulmonary disease (COPD), does fluticasone or budesonide, alone or combined with long-acting β2-agonists (LABAs), increase risk for pneumonia?
The main results are in the Table. Fluticasone (unweighted event rates 29% vs 34%, P < 0.001) and budesonide (23% vs 28%, P < 0.001) each reduced treatment withdrawals compared with control. Fluticasone (0.3% vs 0.2%) and budesonide (0.1% vs 0%) did not differ from control for pneumonia mortality.
Review scope Included studies compared fluticasone or budesonide with placebo, or either drug {in a LABA combination inhaler}* with LABA monotherapy, in patients with COPD (FEV1–FVC ratio < 0.7 and ≥ 1 of the following: chronic cough, chronic sputum production, progressive or persistent dyspnea, or past exposure to risk factors); and had study duration ≥ 12 weeks. Outcomes were nonfatal serious pneumonia needing hospitalization, all-cause and pneumonia mortality, nonfatal serious adverse events {as defined by trial authors}*, any pneumonia, and treatment withdrawal.
Review methods Cochrane Airways Group Specialized Register of trials to Sep 2013, which includes searches of MEDLINE, EMBASE/ Excerpta Medica, Cochrane Central Register of Controlled Trials, CINAHL, AMED, PsycINFO, and conference abstracts; ClinicalTrials.gov to Sep 2013; reference lists; and drug manufacturer Web sites were searched for parallel-group, randomized, controlled trials (RCTs). 43 RCTs met the selection criteria: 26 evaluated fluticasone (n = 21 247, mean age 47 to 67 y, 52% to 92% men, weighted mean duration 18 mo) and 17 budesonide (n = 10 150, mean age 52 to 67 y, 54% to 100% men, weighted mean duration 14 mo). 17 RCTs had low risk for bias in allocation concealment, 39 in blinding patients and investigators, and 10 in blinding outcome assessment. For completeness of outcome data, 21 studies had low risk for bias, 16 had high risk for bias because of high or uneven dropout rates, and 6 had undetermined risk. 34 RCTs received funding from drug manufacturers.
Conclusion In chronic obstructive pulmonary disease, fluticasone or budesonide, alone or with long-acting β2-agonists, increases serious pneumonia needing hospitalization but not mortality. *Information provided by author.
Source of funding: No external funding. For correspondence: K.M. Kew, St. George’s University of London, London, England, UK. E-mail [email protected]. ■
Commentary
The decision of whether to use an inhaled corticosteroid (ICS) in COPD must weigh the increased risk for pneumonia against the benefits (when combined with LABAs) of fewer exacerbations, higher lung function, and better quality of life (1). Because benefits of ICS/LABA over LABA alone are small and have been shown mostly in patients with severe COPD or a history of exacerbations (1), ICS/LABA should be preferred primarily in such patients. This approach is concordant with current guidelines (2). In the review by Kew and colleagues, pneumonia risk seemed to be dosedependent for budesonide. As ICS benefits in COPD have not shown the same dose dependency (1), moderate-dose ICS may be a better choice than higher-dose ICS for COPD patients. Although the review by Kew and colleagues evaluated only budesonide and fluticasone, a recent large observational study (3) also found an increased dose-dependent risk for pneumonia requiring hospitalization in patients receiving other ICSs and a higher risk with fluticasone than budesonide. Kew and colleagues also found a higher risk Fluticasone or budesonide vs placebo, and fluticasone or budesonide plus LABAs vs with fluticasone than budesonide but only for all LABA monotherapy in COPD† pneumonias, not serious cases. Such differences must be interpreted with caution because baseSteroid Outcomes‡ Number of Weighted RRI/RRR (95% CI) NNH/NNT (CI) trials (n) event rates line risk for pneumonia varied across trials, many did not report pneumonia events, and most did Fluticasone Nonfatal serious 17 (19 504) 4.3% vs 2.5% RRI 73% (47 to 104) NNH 56 (39 to 86) not report how pneumonia was identified. A pneumonia§ randomized trial directly comparing regimens Nonfatal SAE 19 (20 381) 24% vs 23% RRI 4% (−1 to 9) NS with different inhaled steroids is needed to Any pneumonia|| 11 (15 377) 11% vs 7.2% RRI 57% (41 to 75) NNH 25 (19 to 34) determine whether they confer different pneuAll-cause mortality 22 (20 861) 5.76% vs 5.82% RRR 1% (−11 to 11) NS monia risks in COPD. Budesonide
Nonfatal serious pneumonia§||
7 (6472)
1.5% vs 0.9%
RRI 60% (1 to 155)
NNH 184 (71 to 10 989)
Nonfatal SAE||
12 (10 009)
14.6% vs 14.5%
RRI 1% (−14 to 18)
NS
Any pneumonia||
6 (7011)
3.1% vs 2.8%
RRI 12% (−16 to 48)
NS
All-cause mortality||
12 (10 009)
1.5% vs 1.7%
RRR 10% (−24 to 35)
NS
†COPD = chronic obstructive pulmonary disease; LABA = long-acting β2-agonist; NS = not significant; SAE = serious adverse event; other abbreviations defined in Glossary. Weighted event rates, RRI, RRR, NNH, and CI calculated from data in article using random-effects (budesonide for nonfatal SAEs) or fixed-effect (all other outcomes) models. ‡Quality of evidence was high based on Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria unless indicated otherwise. §Pneumonia needing hospitalization. ||Quality of evidence was moderate based on GRADE criteria.
JC8
© 2014 American College of Physicians
Matthew B. Stanbrook, MD, PhD University Health Network, University of Toronto Toronto, Ontario, Canada References 1. Nannini LJ, Lasserson TJ, Poole P. Cochrane Database Syst Rev. 2012;9: CD006829. 2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the diagnosis, management, and prevention of COPD. 2014. www.goldcopd.org/ (accessed 6 Jun 2014). 3. Suissa S, Patenaude V, Lapi F, Ernst P. Thorax. 2013;68:1029-36. 19 August 2014 | ACP Journal Club | Volume 161 • Number 4
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a NYU Medical Center Library User on 02/16/2017
