- Email: [email protected]
Bronchiectasis trials: losing the battle but winning the war?
Comment
smoking during pregnancy.16 Incorporating issues of empowerment and the social context of women into gender-based strategies for tobacco control could be an effective strategy to reduce smoking during pregnancy13 and to promote the health, development, and wellbeing of women and children. Maureen M Black,* Prasanna Nair, Adam J Spanier Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA [email protected] We declare no competing interests.
7 8
9
10 11
12
Copyright © Black et al. Open Access article distributed under the terms of CC BY. 1 2
3
4
5
6
Simpson WJ. A preliminary report on cigarette smoking and the incidence of prematurity. Am J Obstet Gynecol 1957; 12: 868–69. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 2012; 129: 735–44. Motlagh MG, Sukhodolsky DG, Landeros-Weisenberger A, et al. Adverse effects of heavy prenatal maternal smoking on attentional control in children with ADHD. J Atten Disord 2011; 15: 593–603. Gaysina D, Fergusson DM, Leve LD, et al. Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry 2013; 70: 956–63. Weissman MM, Warner V, Wickramaratne PJ, Kandel DB. Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. J Am Acad Child Adolesc Psychiatry 1999; 38: 892–89. Buka SL, Shenassa ED, Niaura R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study. Am J Psychiatry 2003; 160: 1978–84.
13
14
15
16
Behnke M, Smith VC. Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 2013; 131: e1009–24. Bublitz MH, Stroud LR. Maternal smoking during pregnancy and offspring brain structure and function: review and agenda for future research. Nicotine Tob Res 2012; 14: 388–97. Cooper S, Taggar J, Lewis S, et al. Effect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomised, double-blind, placebo-controlled SNAP trial. Lancet Respir Med 2014; published online Aug 11. http://dx.doi.org/10.1016/S22132600(14)70157-2. Slotkin TA. Fetal nicotine or cocaine exposure: which one is worse? J Pharmacol Exp Ther 1998; 285: 931–45. US Department of Health and Human Services. The Health Consequences of Smoking - 50 Years of Progress. A Report of the Surgeon General. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. WHO. WHO Report on the Global Tobacco Epidemic, 2009: Implementing Smoke-Free Environments. Geneva: World Health Organization, 2009. Smedberg J, Lupattelli A, Mardby AC, Nordeng H. Characteristics of women who continue smoking during pregnancy: a cross-sectional study of pregnant women and new mothers in 15 European countries. BMC Pregnancy Childbirth 2014; 14: 213. Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Rockville: Substance Abuse and Mental Health Services Administration, 2011. Duke JC, Lee YO, Kim AE, et al. Exposure to electronic cigarette television advertisements among youth and young adults. Pediatrics 2014; 134: e29–36. Nichter M, Greaves L, Bloch M, et al. Tobacco use and secondhand smoke exposure during pregnancy in low- and middle-income countries: the need for social and cultural research. Acta Obstet Gynecol Scand 2010; 89: 465–77.
The past several years have seen a growing interest in bronchiectasis from clinicians, academia, and industry. Having previously relied on extrapolating evidence from cystic fibrosis, this renewed interest is now translating into a number of large randomised trials, specifically in bronchiectasis. These efforts include recently published phase 3 trials of dry powder mannitol,1 colistin,2 and now in the Lancet Respiratory Medicine, inhaled aztreonam for patients with chronic Gram-negative airway infection.3 This landmark study is the largest randomised trial in bronchiectasis so far conducted. 266 patients in AIRBX1 and 274 patients in AIR-BX2 were included in two identical double-blind placebo-controlled trials to assess the efficacy and safety of two 28-day courses of inhaled aztreonam. The authors chose health-related quality of life as the primary outcome, using the newly developed Quality of Life-Bronchiectasis (QOL-B) questionnaire. The study seemed set to provide both a new treatment www.thelancet.com/respiratory Vol 2 September 2014
for bronchiectasis and a new validated clinical trial endpoint. Sadly, the trial’s primary endpoint was not met, and 22% of aztreonam-treated patients (29 of 134) discontinued treatment because of intolerance in AIR-BX1 (vs 3% [four of 132] in the placebo group), and 8% (11 of 135) discontinued aztreonam in AIRBX2 (vs 3% [four of 137] in the placebo group.3 Adverse effects were mostly respiratory (dyspnoea and cough), mirroring effects noted with previous inhaled agents such as tobramycin.4 Despite extensive subgroup analyses, a clear responder population could not be identified. Why did this therapy, which is effective in cystic fibrosis,5 not benefit patients with bronchiectasis? Some aspects of the study design might have contributed. The study included a broad, heterogeneous population of patients, including a mix of aetiologies, different Gramnegative pathogens, and a range of severities. What
GJLP/Science Photo Library
Bronchiectasis trials: losing the battle but winning the war?
Published Online August 19, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70181-X See Articles page 738
679
Comment
could have been a great strength of the study in its broad generalisability, in hindsight appears to be a weakness. Nearly a third of patients in the aztreonam group had COPD, compared with 19% in the placebo group, a population we might speculate could be more prone to bronchospasm with inhaled antibiotics. The study was underpowered to detect a difference in the frequency of exacerbations because of its short duration and because a third of patients at baseline had had no exacerbations in the previous year. Amidst the disappointment, we should learn the lessons for future trials. The reasons for a lack of success with aztreonam seem to differ from those of other phase 3 studies. Colistin narrowly failed to meet its primary endpoint of time to next exacerbation, probably because of the absence of statistical power since the placebo group had fewer exacerbations than expected.2 Colistin was nevertheless well tolerated and achieved a clinically relevant improvement in quality of life. Inhaled mannitol met one of its primary endpoints of improved sputum weight, but did so through an unexpected reduction in sputum weight in the placebo group and did not improve quality of life.1 A unifying factor in each of these trials was unexpected behaviour of the placebo group; Barker and colleagues noted a relatively large improvement in quality of life from baseline in the placebo group. This greatly reduced the power of aztreonam to achieve a significant improvement in quality of life. A consistent finding of improved quality of life, lower than expected exacerbation rates, and other placebo group effects noted across several bronchiectasis trials requires further study.1–3,6,7 Aztreonam achieved significant reductions in bacterial load, and a key message of this study is that clearance of bacteria does not always translate into clinical benefit. In experimental studies, antibiotic therapy reduces airway neutrophilic inflammation, but this finding has not translated into significant patient benefits in the aztreonam or colistin studies.8 These data indicate we might need to re-assess colony forming units per g as the key phase 2 endpoint in bronchiectasis clinical trials. Together, these trials have taught us that bronchiectasis is a heterogeneous disease and that high quality phenotyping of patients is needed to identify populations that can benefit from and tolerate new treatments. The need for a better understanding of the natural history of this disease reinforces the 680
value of international registries such as the COPD Foundation’s Bronchiectasis research registry in the USA and the European Respiratory Society’s EMBARC registry. COPD-related bronchiectasis needs to be better defined and characterised. Targeting treatments to more severe patients most likely to benefit is a logical step, and we hope the recently developed bronchiectasis severity index will have an important role in facilitating this.9 Finally, we have learned comprehensively that bronchiectasis is not cystic fibrosis. In 1998, O’Donnell and colleagues noted that DNase, an effective treatment in cystic fibrosis, caused an increase in exacerbations and reduced FEV1 when applied to bronchiectasis.10 Clear parallels exist between the study by O’Donnell and colleagues10 and the present study of aztreonam,3 in which the investigators used a dose developed for cystic fibrosis (75 mg three times daily) and noted that this dose was poorly tolerated. Many possible reasons could explain the differing drug responses noted between cystic fibrosis and non-cystic fibrosis bronchiectasis, and they have been nicely explored by Barker and colleagues.3 Whatever the reason, it is clear that future studies should establish the appropriate tolerated dose specifically in bronchiectasis patients rather than extrapolating from cystic fibrosis. Although disappointing, a series of negative of trials have taught us important lessons that will lead to better trials and a better understanding of bronchiectasis in the future. In working towards an effective treatment for bronchiectasis, we have lost a number of recent battles, but we might just win the war. James D Chalmers Tayside Respiratory Research Group, University of Dundee, Dundee, DD1 9SY, UK [email protected] I declare no competing interests. 1
2
3
4
Bilton D, Daviskas E, Anderson SD, et al, B301 Investigators. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis. Chest 2013; 144: 215–25. Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2014; 189: 975–82. Barker AF, O’Donnell AE, Flume P, et al. Aztreonam for inhalation solution (AZLI) in patients with non-CF bronchiectasis: the results from two randomized double blind placebo controlled phase 3 trials. Lancet Respir Med 2014; published online Aug 19. http://dx.doi. org/10.1016/S2213-2600(14)70165-1. Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481–85.
www.thelancet.com/respiratory Vol 2 September 2014
Comment
5
6
7
McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008; 178: 921–28. Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA 2013; 309: 1251–59. Chalmers JD, Smith MP, McHugh B, Doherty C, Govan JRW, Hill AT. Short and long term antibiotic therapy reduces airway and systemic inflammation in non-CF bronchiectasis. Am J Respir Crit Care Med. 2012; 186: 657–65.
8
9
10
Murray MP, Govan JRW, Docherty CJ, et al. A randomised controlled trial of nebulised gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; 183: 491–99. Chalmers JD, Goeminne P, Aliberti S, et al. Derivation and validation of the bronchiectasis severity index: an international multicentre observational study. Am J Respir Crit Care Med 2014; 189: 576–85. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998; 113: 1329–1334.
Why doesn’t reducing exacerbations decrease COPD mortality?
C CO OPD PD Gen coh e, ort
Clinic-based
SE
on
LIP
nd
EC
s
agen Stu dies
ine
Stu
dy
Copenh
CI
L ife
S, L
m
Claims d
PCRD, IP
, FH
HS
Ro tte rda
Lo
CPRD, O
Populationbased
atabases
Primary care-based
,C
www.thelancet.com/respiratory Vol 2 September 2014
RCTs use stringent selection criteria, such as including only exacerbators or excluding patients with COPD with prespecified comorbidities. Therefore, patients with COPD who are enrolled in RCTs are younger, predominantly male, have worse lung function and quality of life, and have higher rates of exacerbations than do patients with COPD seen in primary care.6 These differences in patient characteristics challenge the external validity of RCTs for most patients with COPD who are managed in primary care settings. The frequency of COPD exacerbations has been overestimated. In the ECLIPSE (evaluation of COPD longitudinally to identify predictive surrogate endpoints) study,7 a clinic-based cohort that recruited patients with COPD from secondary and tertiary care, severe exacerbations occurred in 7% of GOLD stage 2 and in 18% of GOLD stage 3 patients in a year, whereas the prevalence of frequent exacerbator phenotype was
IC AR
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are acute events characterised by a worsening of patient respiratory symptoms beyond normal day-to-day variations, leading to a change in their drug regimen.1 In randomised controlled trials (RCTs), moderate exacerbations are defined as episodes of COPD worsening that need antibiotics or systemic corticosteroids, whereas severe exacerbations need treatment in hospital.2 Acute exacerbations of COPD have been associated with deterioration of lung function and an increased risk of death.3 In patients with moderate-to-severe COPD, maintenance therapy with inhaled long-acting muscarinic antagonists, longacting beta-2-agonists, inhaled corticosteroids, or macrolides reduces the risk of exacerbations. However, these drugs do not convincingly decrease mortality. Despite reductions in exacerbations, why treatments for COPD do not decrease mortality is not known but could be attributable to several, not mutually exclusive, findings. First, COPD exacerbations and patients with COPD are heterogeneous, encompassing several phenotypes.4,5 Cohort studies of COPD are also heterogeneous, with differences in age and sex distribution, ethnic origin, smoking history, symptoms, severity of airflow limitation, comorbidities, and frequency of exacerbations. In accordance with methods of recruitment and level of care (no care [if undiagnosed], primary, secondary, or tertiary care), COPD cohorts can be subdivided into three categories: population-based cohorts, cohort studies done mainly in primary care, and cohorts in secondary or tertiary care (figure). RCTs in COPD are the fourth category of cohort studies, in which patients are randomly assigned to maximise the internal validity of the study results. However,
Classic
RCTs in
COPD
Figure: Examples of the heterogeneity of chronic obstructive pulmonary disease (COPD) cohort studies Excluding RCTs, at least three different types of cohort studies in COPD can be discerned: population-based cohorts; primary care-based cohorts based on general practitioners’ medical record databases; and clinic-based cohorts. For clarity, only a few examples of cohort studies are mentioned per category. ARIC=atherosclerosis risk in communities study. CHS=cardiovascular health study. FHS=framingham heart study. CPRD=clinical practice research datalink. OPCRD=optimal patient care research database. IPCI=integrated primary care information database. ECLIPSE=evaluation of COPD longitudinally to identify predictive surrogate endpoints. RCT=randomised controlled trial.
681
smoking during pregnancy.16 Incorporating issues of empowerment and the social context of women into gender-based strategies for tobacco control could be an effective strategy to reduce smoking during pregnancy13 and to promote the health, development, and wellbeing of women and children. Maureen M Black,* Prasanna Nair, Adam J Spanier Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA [email protected] We declare no competing interests.
7 8
9
10 11
12
Copyright © Black et al. Open Access article distributed under the terms of CC BY. 1 2
3
4
5
6
Simpson WJ. A preliminary report on cigarette smoking and the incidence of prematurity. Am J Obstet Gynecol 1957; 12: 868–69. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 2012; 129: 735–44. Motlagh MG, Sukhodolsky DG, Landeros-Weisenberger A, et al. Adverse effects of heavy prenatal maternal smoking on attentional control in children with ADHD. J Atten Disord 2011; 15: 593–603. Gaysina D, Fergusson DM, Leve LD, et al. Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry 2013; 70: 956–63. Weissman MM, Warner V, Wickramaratne PJ, Kandel DB. Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. J Am Acad Child Adolesc Psychiatry 1999; 38: 892–89. Buka SL, Shenassa ED, Niaura R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study. Am J Psychiatry 2003; 160: 1978–84.
13
14
15
16
Behnke M, Smith VC. Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 2013; 131: e1009–24. Bublitz MH, Stroud LR. Maternal smoking during pregnancy and offspring brain structure and function: review and agenda for future research. Nicotine Tob Res 2012; 14: 388–97. Cooper S, Taggar J, Lewis S, et al. Effect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomised, double-blind, placebo-controlled SNAP trial. Lancet Respir Med 2014; published online Aug 11. http://dx.doi.org/10.1016/S22132600(14)70157-2. Slotkin TA. Fetal nicotine or cocaine exposure: which one is worse? J Pharmacol Exp Ther 1998; 285: 931–45. US Department of Health and Human Services. The Health Consequences of Smoking - 50 Years of Progress. A Report of the Surgeon General. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. WHO. WHO Report on the Global Tobacco Epidemic, 2009: Implementing Smoke-Free Environments. Geneva: World Health Organization, 2009. Smedberg J, Lupattelli A, Mardby AC, Nordeng H. Characteristics of women who continue smoking during pregnancy: a cross-sectional study of pregnant women and new mothers in 15 European countries. BMC Pregnancy Childbirth 2014; 14: 213. Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Rockville: Substance Abuse and Mental Health Services Administration, 2011. Duke JC, Lee YO, Kim AE, et al. Exposure to electronic cigarette television advertisements among youth and young adults. Pediatrics 2014; 134: e29–36. Nichter M, Greaves L, Bloch M, et al. Tobacco use and secondhand smoke exposure during pregnancy in low- and middle-income countries: the need for social and cultural research. Acta Obstet Gynecol Scand 2010; 89: 465–77.
The past several years have seen a growing interest in bronchiectasis from clinicians, academia, and industry. Having previously relied on extrapolating evidence from cystic fibrosis, this renewed interest is now translating into a number of large randomised trials, specifically in bronchiectasis. These efforts include recently published phase 3 trials of dry powder mannitol,1 colistin,2 and now in the Lancet Respiratory Medicine, inhaled aztreonam for patients with chronic Gram-negative airway infection.3 This landmark study is the largest randomised trial in bronchiectasis so far conducted. 266 patients in AIRBX1 and 274 patients in AIR-BX2 were included in two identical double-blind placebo-controlled trials to assess the efficacy and safety of two 28-day courses of inhaled aztreonam. The authors chose health-related quality of life as the primary outcome, using the newly developed Quality of Life-Bronchiectasis (QOL-B) questionnaire. The study seemed set to provide both a new treatment www.thelancet.com/respiratory Vol 2 September 2014
for bronchiectasis and a new validated clinical trial endpoint. Sadly, the trial’s primary endpoint was not met, and 22% of aztreonam-treated patients (29 of 134) discontinued treatment because of intolerance in AIR-BX1 (vs 3% [four of 132] in the placebo group), and 8% (11 of 135) discontinued aztreonam in AIRBX2 (vs 3% [four of 137] in the placebo group.3 Adverse effects were mostly respiratory (dyspnoea and cough), mirroring effects noted with previous inhaled agents such as tobramycin.4 Despite extensive subgroup analyses, a clear responder population could not be identified. Why did this therapy, which is effective in cystic fibrosis,5 not benefit patients with bronchiectasis? Some aspects of the study design might have contributed. The study included a broad, heterogeneous population of patients, including a mix of aetiologies, different Gramnegative pathogens, and a range of severities. What
GJLP/Science Photo Library
Bronchiectasis trials: losing the battle but winning the war?
Published Online August 19, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70181-X See Articles page 738
679
Comment
could have been a great strength of the study in its broad generalisability, in hindsight appears to be a weakness. Nearly a third of patients in the aztreonam group had COPD, compared with 19% in the placebo group, a population we might speculate could be more prone to bronchospasm with inhaled antibiotics. The study was underpowered to detect a difference in the frequency of exacerbations because of its short duration and because a third of patients at baseline had had no exacerbations in the previous year. Amidst the disappointment, we should learn the lessons for future trials. The reasons for a lack of success with aztreonam seem to differ from those of other phase 3 studies. Colistin narrowly failed to meet its primary endpoint of time to next exacerbation, probably because of the absence of statistical power since the placebo group had fewer exacerbations than expected.2 Colistin was nevertheless well tolerated and achieved a clinically relevant improvement in quality of life. Inhaled mannitol met one of its primary endpoints of improved sputum weight, but did so through an unexpected reduction in sputum weight in the placebo group and did not improve quality of life.1 A unifying factor in each of these trials was unexpected behaviour of the placebo group; Barker and colleagues noted a relatively large improvement in quality of life from baseline in the placebo group. This greatly reduced the power of aztreonam to achieve a significant improvement in quality of life. A consistent finding of improved quality of life, lower than expected exacerbation rates, and other placebo group effects noted across several bronchiectasis trials requires further study.1–3,6,7 Aztreonam achieved significant reductions in bacterial load, and a key message of this study is that clearance of bacteria does not always translate into clinical benefit. In experimental studies, antibiotic therapy reduces airway neutrophilic inflammation, but this finding has not translated into significant patient benefits in the aztreonam or colistin studies.8 These data indicate we might need to re-assess colony forming units per g as the key phase 2 endpoint in bronchiectasis clinical trials. Together, these trials have taught us that bronchiectasis is a heterogeneous disease and that high quality phenotyping of patients is needed to identify populations that can benefit from and tolerate new treatments. The need for a better understanding of the natural history of this disease reinforces the 680
value of international registries such as the COPD Foundation’s Bronchiectasis research registry in the USA and the European Respiratory Society’s EMBARC registry. COPD-related bronchiectasis needs to be better defined and characterised. Targeting treatments to more severe patients most likely to benefit is a logical step, and we hope the recently developed bronchiectasis severity index will have an important role in facilitating this.9 Finally, we have learned comprehensively that bronchiectasis is not cystic fibrosis. In 1998, O’Donnell and colleagues noted that DNase, an effective treatment in cystic fibrosis, caused an increase in exacerbations and reduced FEV1 when applied to bronchiectasis.10 Clear parallels exist between the study by O’Donnell and colleagues10 and the present study of aztreonam,3 in which the investigators used a dose developed for cystic fibrosis (75 mg three times daily) and noted that this dose was poorly tolerated. Many possible reasons could explain the differing drug responses noted between cystic fibrosis and non-cystic fibrosis bronchiectasis, and they have been nicely explored by Barker and colleagues.3 Whatever the reason, it is clear that future studies should establish the appropriate tolerated dose specifically in bronchiectasis patients rather than extrapolating from cystic fibrosis. Although disappointing, a series of negative of trials have taught us important lessons that will lead to better trials and a better understanding of bronchiectasis in the future. In working towards an effective treatment for bronchiectasis, we have lost a number of recent battles, but we might just win the war. James D Chalmers Tayside Respiratory Research Group, University of Dundee, Dundee, DD1 9SY, UK [email protected] I declare no competing interests. 1
2
3
4
Bilton D, Daviskas E, Anderson SD, et al, B301 Investigators. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis. Chest 2013; 144: 215–25. Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2014; 189: 975–82. Barker AF, O’Donnell AE, Flume P, et al. Aztreonam for inhalation solution (AZLI) in patients with non-CF bronchiectasis: the results from two randomized double blind placebo controlled phase 3 trials. Lancet Respir Med 2014; published online Aug 19. http://dx.doi. org/10.1016/S2213-2600(14)70165-1. Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481–85.
www.thelancet.com/respiratory Vol 2 September 2014
Comment
5
6
7
McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008; 178: 921–28. Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA 2013; 309: 1251–59. Chalmers JD, Smith MP, McHugh B, Doherty C, Govan JRW, Hill AT. Short and long term antibiotic therapy reduces airway and systemic inflammation in non-CF bronchiectasis. Am J Respir Crit Care Med. 2012; 186: 657–65.
8
9
10
Murray MP, Govan JRW, Docherty CJ, et al. A randomised controlled trial of nebulised gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; 183: 491–99. Chalmers JD, Goeminne P, Aliberti S, et al. Derivation and validation of the bronchiectasis severity index: an international multicentre observational study. Am J Respir Crit Care Med 2014; 189: 576–85. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998; 113: 1329–1334.
Why doesn’t reducing exacerbations decrease COPD mortality?
C CO OPD PD Gen coh e, ort
Clinic-based
SE
on
LIP
nd
EC
s
agen Stu dies
ine
Stu
dy
Copenh
CI
L ife
S, L
m
Claims d
PCRD, IP
, FH
HS
Ro tte rda
Lo
CPRD, O
Populationbased
atabases
Primary care-based
,C
www.thelancet.com/respiratory Vol 2 September 2014
RCTs use stringent selection criteria, such as including only exacerbators or excluding patients with COPD with prespecified comorbidities. Therefore, patients with COPD who are enrolled in RCTs are younger, predominantly male, have worse lung function and quality of life, and have higher rates of exacerbations than do patients with COPD seen in primary care.6 These differences in patient characteristics challenge the external validity of RCTs for most patients with COPD who are managed in primary care settings. The frequency of COPD exacerbations has been overestimated. In the ECLIPSE (evaluation of COPD longitudinally to identify predictive surrogate endpoints) study,7 a clinic-based cohort that recruited patients with COPD from secondary and tertiary care, severe exacerbations occurred in 7% of GOLD stage 2 and in 18% of GOLD stage 3 patients in a year, whereas the prevalence of frequent exacerbator phenotype was
IC AR
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are acute events characterised by a worsening of patient respiratory symptoms beyond normal day-to-day variations, leading to a change in their drug regimen.1 In randomised controlled trials (RCTs), moderate exacerbations are defined as episodes of COPD worsening that need antibiotics or systemic corticosteroids, whereas severe exacerbations need treatment in hospital.2 Acute exacerbations of COPD have been associated with deterioration of lung function and an increased risk of death.3 In patients with moderate-to-severe COPD, maintenance therapy with inhaled long-acting muscarinic antagonists, longacting beta-2-agonists, inhaled corticosteroids, or macrolides reduces the risk of exacerbations. However, these drugs do not convincingly decrease mortality. Despite reductions in exacerbations, why treatments for COPD do not decrease mortality is not known but could be attributable to several, not mutually exclusive, findings. First, COPD exacerbations and patients with COPD are heterogeneous, encompassing several phenotypes.4,5 Cohort studies of COPD are also heterogeneous, with differences in age and sex distribution, ethnic origin, smoking history, symptoms, severity of airflow limitation, comorbidities, and frequency of exacerbations. In accordance with methods of recruitment and level of care (no care [if undiagnosed], primary, secondary, or tertiary care), COPD cohorts can be subdivided into three categories: population-based cohorts, cohort studies done mainly in primary care, and cohorts in secondary or tertiary care (figure). RCTs in COPD are the fourth category of cohort studies, in which patients are randomly assigned to maximise the internal validity of the study results. However,
Classic
RCTs in
COPD
Figure: Examples of the heterogeneity of chronic obstructive pulmonary disease (COPD) cohort studies Excluding RCTs, at least three different types of cohort studies in COPD can be discerned: population-based cohorts; primary care-based cohorts based on general practitioners’ medical record databases; and clinic-based cohorts. For clarity, only a few examples of cohort studies are mentioned per category. ARIC=atherosclerosis risk in communities study. CHS=cardiovascular health study. FHS=framingham heart study. CPRD=clinical practice research datalink. OPCRD=optimal patient care research database. IPCI=integrated primary care information database. ECLIPSE=evaluation of COPD longitudinally to identify predictive surrogate endpoints. RCT=randomised controlled trial.
681