Opinion
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Treating COPD in the Real World Peter M. A. Calverley, MBChB, DSc
Evidence-based medicine is central to modern medical practice and relies on the availability of data from appropriately conducted randomized clinical trials (RCTs). These studies establish whether treatment is effective and, when an Related article page 1114 active comparator group is included in the trial, whether the new therapy is better than currently used treatment. In some conditions such as chronic obstructive pulmonary disease (COPD) for which no single surrogate end point predicts response to treatment, multiple trials of varying duration are needed to convince physicians and regulators that drug therapy is beneficial. The mainstays of COPD management, including inhaled long-acting antimuscarinic agents or long-acting β-agonists (LABAs) alone or combined with inhaled corticosteroids (ICSs), have been shown in RCTs to improve lung function and quality of life and reduce exacerbation frequency.1-3 Patients included in these trials are selected on the basis of having stable COPD without serious diseases that would lead to premature death, and these studies are then incorporated into treatment guidelines that direct clinical practice.4 Although RCTs provide evidence that a drug works in a specific patient population, what happens when treatment is used in the general patient population seen in daily practice remains uncertain. Evidence from RCTs may be biased due to premature study withdrawal, which limits the ability of investigators to answer important supplementary questions about the effects of treatment on the natural history of the disease.5 Large clinical trials can identify unanticipated new adverse effects such as pneumonia with ICS use,6 although whether the new events have the same clinical importance as non–steroid-associated pneumonia is less clear.7,8 More importantly, the profile of patients included in RCTs differs in age and comorbidity from that of many patients with COPD who are seen by physicians in most settings. Hence, it is important to establish whether outcomes seen in clinical treatment trials apply in the so-called real world of clinical practice. Large administrative health care databases, statistical methods needed to interrogate these complex data sets, and, in some countries like Canada, comprehensive health care provision that reduces confounding due to socioeconomic treatment choices all provide the opportunity to study the effect of clinicians’ prescribing choices. In this issue of JAMA, Gershon and colleagues9 report the results of an investigation of the comparative efficacy of using a LABA alone or together with an ICS in elderly patients with COPD living in Ontario. The authors identified patient records for 38 266 individuals who met their database-validated diagnosis of COPD and had received a new prescription for a LABA or a LABA-ICS combina-
tion. Approximately 1 in 10 patients received a LABA as a monotherapy, possibly reflecting the influence of guidelines and pharmaceutical promotion on treatment choices. Patients were matched for confounding variables using a propensitymatching protocol, and the resulting 3160 LABA and 8712 LABA-ICS users were followed up for as long as 5 years, with the principal outcome being risk of death or hospitalization for COPD. The matched patients were older (mean age, 77 years) and had more comorbid diseases (median, 7) than is usual in RCT populations. Approximately 30% had been hospitalized in the previous 6 months and 28% had a diagnosis of asthma recorded at some time previously. Approximately 25% had not undergone spirometry to confirm the COPD diagnosis, but the demographic characteristics of this subgroup and its subsequent outcomes were similar to the group as a whole. Median life expectancy in these older patients was approximately 2.5 years, leading to an annual mortality rate almost 3 times higher than was seen in the TORCH study, the only RCT to study mortality with ICS-LABA therapy as its primary end point.1 In the study by Gershon et al,9 among patients prescribed ICS-LABA drugs, the relative risk of death or hospitalization was approximately 8% less than among those treated with LABAs alone. This is similar to the 6.8% reduction in relative risk of death reported with these drugs in the TORCH study, although that difference in the latter study was not statistically significant. This result may reflect the greater number of deaths reported in the study by Gershon et al compared with the TORCH study (4353 vs 398, respectively) and the use of a combined end point with COPD hospitalizations. As Gershon et al report, the benefit associated with ICS-LABA use was greatest among patients with a prior diagnosis of asthma and among patients without this diagnosis who did not receive a long-acting antimuscarinic agent. However, there was no difference between treatments in the incidence of pneumonia. This is in contrast both with previous RCTs2,6,7 and with a large database study from Quebec10 that reported a doubling of the incidence of pneumonia in COPD patients receiving ICSs. However, the population in the study by Gershon et al was defined differently, had a different baseline risk profile for pneumonia, and was followed up for longer than the 60 days reported in the Quebec study. Database studies always raise concerns about why a physician prescribed a particular drug for a specific patient, often leading to important differences between study groups. The size and scope of the report by Gershon et al provide some reassurance that this is not the main factor in explaining the differences they report. Their diagnostic criterion identified approximately 80% of patients correctly as having COPD, and in a series of modeled scenarios with increasing degrees of diag-
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JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
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Opinion Editorial
nostic error, the only changes in results occurred at improbably high rates of misdiagnosis. Adherence to treatment was less than half that seen in the treatment trials and was worse in the LABA alone group. Poor adherence is a marker of a worse outcome in COPD, even if the patient is receiving placebo.11 However, the degree of health care contact for these elderly patients was similar in each group, making differences in health care behavior a less likely explanation of the results. Immortal time bias, which occurs if only one comparator group must have used a treatment for some time to qualify for study inclusion, can confound some pharmacoepidemiological studies.12 In this study, patients were allocated to groups essentially on an intention-to-treat basis, avoiding such a bias. More patients in the LABA alone group had their treatment escalated to LABA-ICS over time, potentially reducing the differences between the study groups. However, the beneficial outcomes associated with LABA-ICS treatment persisted, possibly reflecting the high statistical power of this study. The findings reported by Gershon et al have implications for the management of patients with COPD and for the assessment of clinical trial data. The presence of blood eosinophilia in patients with COPD without asthma can identify those more ARTICLE INFORMATION Author Affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, England. Corresponding Author: Peter M. A. Calverley, Institute of Ageing and Chronic Disease, University of Liverpool, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, England (pmacal @liverpool.ac.uk). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Calverley reports board membership for GlaxoSmithKline, Boehringer Ingelheim, Takeda, and the UK Department of Health Respiratory Programme Board, lecture/speaker fees from Novartis, GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and travel reimbursement from Boehringer Ingelheim. REFERENCES 1. Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775789. 2. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol vs vilanterol only for prevention of exacerbations of COPD: 2 replicate double-blind,
1102
responsive to corticosteroids.13,14 How this relative eosinophilia relates to clinicians’ diagnosis of previous asthma should be explored. There has been much interest in this asthmaCOPD overlap syndrome,15 and these new data suggest that this is a common clinical problem among older COPD patients and merits treatment with a LABA-ICS combination. Conversely, patients without an asthma history taking a long-acting antimuscarinic agent may not benefit from ICS use. A large clinical trial comparing exacerbation rates in COPD patients using both long-acting antimuscarinic agents and LABAs who withdraw or continue ICS treatment should clarify the safety of ICS withdrawal in nonasthmatic COPD.16 Perhaps the most noteworthy feature of the new data reported by Gershon et al is the difference in the characteristics of the patients who use these treatments from those in whom therapy was validated in RCTs. The outcomes of treatment in these “real-world” patients were somewhat better than might have been expected from RCTs, but the patients were also much more diverse and often sicker. The study by Gershon et al shows that findings from appropriately conducted database analyses complement data from RCTs and should be considered when determining treatment algorithms.
parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1(3):210-223. 3. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. 4. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. 5. Vestbo J, Anderson JA, Calverley PM, et al. Bias due to withdrawal in long-term randomised trials in COPD: evidence from the TORCH study. Clin Respir J. 2011;5(1):44-49. 6. Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34(3):641-647. 7. Calverley PM, Stockley RA, Seemungal TA, et al; Investigating New Standards for Prophylaxis in Reduction of Exacerbations Investigators. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139(3):505-512. 8. Restrepo MI, Mortensen EM, Anzueto A. Are COPD patients with pneumonia who are taking inhaled corticosteroids at higher risk of dying? Eur Respir J. 2011;38(1):1-3. 9. Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting β-agonists and inhaled corticosteroids compared with long-acting
β-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA. doi:10.1001 /jama.2014.11432. 10. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036. 11. Vestbo J, Anderson JA, Calverley PM, et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009;64(11): 939-943. 12. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J. 2008;31(5):927-933. 13. Bafadhel M, Davies L, Calverley PM, Aaron SD, Brightling CE, Pavord ID. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis [published online June 12, 2014]. Eur Respir J. doi:10.1183/09031936.00062614. 14. Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2012;186(1):48-55. 15. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax. 2009;64(8):728-735. 16. Magnussen H, Watz H, Kirsten A, et al. Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale. Respir Med. 2014;108 (4):593-599.
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/17/2015
jama.com
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Treating COPD in the Real World Peter M. A. Calverley, MBChB, DSc
Evidence-based medicine is central to modern medical practice and relies on the availability of data from appropriately conducted randomized clinical trials (RCTs). These studies establish whether treatment is effective and, when an Related article page 1114 active comparator group is included in the trial, whether the new therapy is better than currently used treatment. In some conditions such as chronic obstructive pulmonary disease (COPD) for which no single surrogate end point predicts response to treatment, multiple trials of varying duration are needed to convince physicians and regulators that drug therapy is beneficial. The mainstays of COPD management, including inhaled long-acting antimuscarinic agents or long-acting β-agonists (LABAs) alone or combined with inhaled corticosteroids (ICSs), have been shown in RCTs to improve lung function and quality of life and reduce exacerbation frequency.1-3 Patients included in these trials are selected on the basis of having stable COPD without serious diseases that would lead to premature death, and these studies are then incorporated into treatment guidelines that direct clinical practice.4 Although RCTs provide evidence that a drug works in a specific patient population, what happens when treatment is used in the general patient population seen in daily practice remains uncertain. Evidence from RCTs may be biased due to premature study withdrawal, which limits the ability of investigators to answer important supplementary questions about the effects of treatment on the natural history of the disease.5 Large clinical trials can identify unanticipated new adverse effects such as pneumonia with ICS use,6 although whether the new events have the same clinical importance as non–steroid-associated pneumonia is less clear.7,8 More importantly, the profile of patients included in RCTs differs in age and comorbidity from that of many patients with COPD who are seen by physicians in most settings. Hence, it is important to establish whether outcomes seen in clinical treatment trials apply in the so-called real world of clinical practice. Large administrative health care databases, statistical methods needed to interrogate these complex data sets, and, in some countries like Canada, comprehensive health care provision that reduces confounding due to socioeconomic treatment choices all provide the opportunity to study the effect of clinicians’ prescribing choices. In this issue of JAMA, Gershon and colleagues9 report the results of an investigation of the comparative efficacy of using a LABA alone or together with an ICS in elderly patients with COPD living in Ontario. The authors identified patient records for 38 266 individuals who met their database-validated diagnosis of COPD and had received a new prescription for a LABA or a LABA-ICS combina-
tion. Approximately 1 in 10 patients received a LABA as a monotherapy, possibly reflecting the influence of guidelines and pharmaceutical promotion on treatment choices. Patients were matched for confounding variables using a propensitymatching protocol, and the resulting 3160 LABA and 8712 LABA-ICS users were followed up for as long as 5 years, with the principal outcome being risk of death or hospitalization for COPD. The matched patients were older (mean age, 77 years) and had more comorbid diseases (median, 7) than is usual in RCT populations. Approximately 30% had been hospitalized in the previous 6 months and 28% had a diagnosis of asthma recorded at some time previously. Approximately 25% had not undergone spirometry to confirm the COPD diagnosis, but the demographic characteristics of this subgroup and its subsequent outcomes were similar to the group as a whole. Median life expectancy in these older patients was approximately 2.5 years, leading to an annual mortality rate almost 3 times higher than was seen in the TORCH study, the only RCT to study mortality with ICS-LABA therapy as its primary end point.1 In the study by Gershon et al,9 among patients prescribed ICS-LABA drugs, the relative risk of death or hospitalization was approximately 8% less than among those treated with LABAs alone. This is similar to the 6.8% reduction in relative risk of death reported with these drugs in the TORCH study, although that difference in the latter study was not statistically significant. This result may reflect the greater number of deaths reported in the study by Gershon et al compared with the TORCH study (4353 vs 398, respectively) and the use of a combined end point with COPD hospitalizations. As Gershon et al report, the benefit associated with ICS-LABA use was greatest among patients with a prior diagnosis of asthma and among patients without this diagnosis who did not receive a long-acting antimuscarinic agent. However, there was no difference between treatments in the incidence of pneumonia. This is in contrast both with previous RCTs2,6,7 and with a large database study from Quebec10 that reported a doubling of the incidence of pneumonia in COPD patients receiving ICSs. However, the population in the study by Gershon et al was defined differently, had a different baseline risk profile for pneumonia, and was followed up for longer than the 60 days reported in the Quebec study. Database studies always raise concerns about why a physician prescribed a particular drug for a specific patient, often leading to important differences between study groups. The size and scope of the report by Gershon et al provide some reassurance that this is not the main factor in explaining the differences they report. Their diagnostic criterion identified approximately 80% of patients correctly as having COPD, and in a series of modeled scenarios with increasing degrees of diag-
jama.com
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/17/2015
1101
Opinion Editorial
nostic error, the only changes in results occurred at improbably high rates of misdiagnosis. Adherence to treatment was less than half that seen in the treatment trials and was worse in the LABA alone group. Poor adherence is a marker of a worse outcome in COPD, even if the patient is receiving placebo.11 However, the degree of health care contact for these elderly patients was similar in each group, making differences in health care behavior a less likely explanation of the results. Immortal time bias, which occurs if only one comparator group must have used a treatment for some time to qualify for study inclusion, can confound some pharmacoepidemiological studies.12 In this study, patients were allocated to groups essentially on an intention-to-treat basis, avoiding such a bias. More patients in the LABA alone group had their treatment escalated to LABA-ICS over time, potentially reducing the differences between the study groups. However, the beneficial outcomes associated with LABA-ICS treatment persisted, possibly reflecting the high statistical power of this study. The findings reported by Gershon et al have implications for the management of patients with COPD and for the assessment of clinical trial data. The presence of blood eosinophilia in patients with COPD without asthma can identify those more ARTICLE INFORMATION Author Affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, England. Corresponding Author: Peter M. A. Calverley, Institute of Ageing and Chronic Disease, University of Liverpool, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, England (pmacal @liverpool.ac.uk). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Calverley reports board membership for GlaxoSmithKline, Boehringer Ingelheim, Takeda, and the UK Department of Health Respiratory Programme Board, lecture/speaker fees from Novartis, GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and travel reimbursement from Boehringer Ingelheim. REFERENCES 1. Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775789. 2. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol vs vilanterol only for prevention of exacerbations of COPD: 2 replicate double-blind,
1102
responsive to corticosteroids.13,14 How this relative eosinophilia relates to clinicians’ diagnosis of previous asthma should be explored. There has been much interest in this asthmaCOPD overlap syndrome,15 and these new data suggest that this is a common clinical problem among older COPD patients and merits treatment with a LABA-ICS combination. Conversely, patients without an asthma history taking a long-acting antimuscarinic agent may not benefit from ICS use. A large clinical trial comparing exacerbation rates in COPD patients using both long-acting antimuscarinic agents and LABAs who withdraw or continue ICS treatment should clarify the safety of ICS withdrawal in nonasthmatic COPD.16 Perhaps the most noteworthy feature of the new data reported by Gershon et al is the difference in the characteristics of the patients who use these treatments from those in whom therapy was validated in RCTs. The outcomes of treatment in these “real-world” patients were somewhat better than might have been expected from RCTs, but the patients were also much more diverse and often sicker. The study by Gershon et al shows that findings from appropriately conducted database analyses complement data from RCTs and should be considered when determining treatment algorithms.
parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1(3):210-223. 3. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. 4. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. 5. Vestbo J, Anderson JA, Calverley PM, et al. Bias due to withdrawal in long-term randomised trials in COPD: evidence from the TORCH study. Clin Respir J. 2011;5(1):44-49. 6. Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34(3):641-647. 7. Calverley PM, Stockley RA, Seemungal TA, et al; Investigating New Standards for Prophylaxis in Reduction of Exacerbations Investigators. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139(3):505-512. 8. Restrepo MI, Mortensen EM, Anzueto A. Are COPD patients with pneumonia who are taking inhaled corticosteroids at higher risk of dying? Eur Respir J. 2011;38(1):1-3. 9. Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting β-agonists and inhaled corticosteroids compared with long-acting
β-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA. doi:10.1001 /jama.2014.11432. 10. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036. 11. Vestbo J, Anderson JA, Calverley PM, et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009;64(11): 939-943. 12. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J. 2008;31(5):927-933. 13. Bafadhel M, Davies L, Calverley PM, Aaron SD, Brightling CE, Pavord ID. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis [published online June 12, 2014]. Eur Respir J. doi:10.1183/09031936.00062614. 14. Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2012;186(1):48-55. 15. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax. 2009;64(8):728-735. 16. Magnussen H, Watz H, Kirsten A, et al. Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale. Respir Med. 2014;108 (4):593-599.
JAMA September 17, 2014 Volume 312, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/17/2015
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