Andrea Gershon, MD, MSc; Ruth Croxford, MSc, PStat; Teresa To, PhD; Matthew B. Stanbrook, MD, PhD; Ross Upshur, MD, MSc; Paula Sanchez-Romeu, BMath, MMath; Thérèse Stukel, PhD
Chronic obstructive pulmonary disease (COPD), a largely preventable and manageable respiratory condition, affects an estimated 12% to 20% of adults. Long-acting inhaled β-agonists and anticholinergics have both been shown to improve COPD outcomes and are recommended for moderate to severe disease; however, little is known about their comparative effectiveness.
To compare survival in older patients with COPD who initially receive inhaled long-acting β-agonists with that of patients who receive anticholinergics.
Population-based, retrospective cohort study.
Patients aged 66 years or older (who carry the largest burden of COPD and for whom data were available) who met a validated case definition of COPD on the basis of health administrative data and were newly prescribed an inhaled long-acting β-agonist or a long-acting anticholinergic (but not both) between 2003 and 2007. Patients were followed for up to 5.5 years.
The primary outcome was all-cause mortality.
A total of 46 403 patients with COPD (mean age, 77 years; 49% women) were included. Overall mortality was 38.2%. Mortality was higher in patients initially prescribed a long-acting anticholinergic than in those initially prescribed a long-acting inhaled β-agonist (adjusted hazard ratio, 1.14 [95% CI, 1.09 to 1.19]). Rates of hospitalizations and emergency department visits were also higher in those initially prescribed a long-acting anticholinergic.
Patients were classified as having COPD on the basis of health administrative records, which did not contain information about lung function.
Older adults initially prescribed long-acting inhaled β-agonists for the management of moderate COPD seem to have lower mortality than those initially prescribed long-acting anticholinergics. Further research is needed to confirm these findings in younger patients and in a randomized, controlled trial.
Government of Ontario, Canada.
Long-acting inhaled β-agonists and anticholinergic agents are both used to treat chronic obstructive pulmonary disease (COPD). Whether one or the other is better for initial therapy is not known.
Patients with physician-diagnosed COPD were identified in a public health administrative database by using a computer algorithm. Patients initially prescribed a long-acting anticholinergic agent had more hospital visits and higher mortality rates than those initially prescribed a long-acting β-agonist.
Patients were identified as having COPD according to administrative data, not clinical guidelines. Lung function testing was not available.
Further study regarding the relative benefits of long-acting anticholinergics and β-agonists for treatment of COPD is warranted.
Appendix Table 1.
COPD = chronic obstructive pulmonary disease.
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Leonardo M. Fabbri
Department of Oncology, Hematology and Respiratory Diseases, University of Modena & Reggio Emilia, M
May 27, 2011
SAFETY OF INHALED LONG-ACTING ANTICHOLINERGICS
Based on data from health administrative databases in Ontario, Canada, and in contrast to their previous findings (1), Gershon et al (2) describe an increase in mortality and hospitalization in chronic obstructive pulmonary disease (COPD) patients aged 66 years or older receiving the long-acting anticholinergic tiotropium as a first prescription compared with patients starting with long-acting beta- agonists (LABAs). Acknowledging the inherent limitations of this retrospective database analysis, the authors conclude that "further research is needed to confirm these findings in randomized controlled trials". We would like to note that this suggested further research has already been performed and published in the Prevention Of Exacerbations with Tiotropium in COPD (POET) study (3), a randomized, controlled, double- blind trial directly comparing tiotropium with the LABA salmeterol for one year. This trial is the largest head-to-head comparison of these two therapeutic regimens comprising approximately 7400 patients with COPD. The POET study (3) showed that tiotropium was significantly more effective than salmeterol in all assessed COPD exacerbation endpoints. In addition, the incidence of serious adverse events, and of adverse events leading to the discontinuation of treatment, was shown to be similar in the two treatment arms, and outcomes were consistent across age and COPD severity groups and concomitant medication. Specifically, all-cause mortality (vital status follow-up to day 360, 99.1% complete) was not significantly different between tiotropium (64 deaths [1.7%]) and salmeterol (78 deaths [2.1%]). This was independent of sub-group according to age, and including patients aged >65 years. In a pre-specified sub-group analysis, the hazard ratio (HR) for all-cause mortality was numerically in favor of tiotropium (HR, 0.84, 95% confidence interval [CI], 0.47-1.51 for patients aged between 65 and <75 years; HR, 0.78, 95% CI, 0.39-1.59 for patients aged 75 years or more) (4). This is another example illustrating that observations of associations in retrospective cohort studies are not necessarily confirmed in randomized controlled trials, which remain the gold standard for proving causality (5).
1. Gershon AS, Wang L, To T, Luo J, Upshur RE. Survival with tiotropium compared to long acting Beta-2-agonists in Chronic Obstructive Pulmonary Disease. COPD. 2008;5:229-34. [PMID: 18671148]
2. Gershon A, Croxford R, To T, Stanbrook MB, Upshur R, Sanchez-Romeu P, et al. Comparison of Inhaled Long-Acting beta-Agonists and Anticholinergic Effectiveness in Older Patients with Chronic Obstructive Pulmonary Disease: A Cohort Study. Ann Intern Med. 2011;154:583-92. [PMID: 21536937]
3. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van M?lken MP, Beeh KM, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093-103. [PMID: 21428765]
4. Boehringer Ingelheim, data on file.
5. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300:2407-16. Erratum in: JAMA. 2009;301:1024. [PMID: 19033591]
Dr Vogelmeier has received consulting fees/honoraria and support for travel to meetings from Boehringer Ingelheim; is a board member for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, Novartis and Nycomed; and has received fees for expert testimony and grants from Talecris and payment for lectures/speaking from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Nycomed, and Talecris. Dr Rabe has received consultancy fees and honoraria from, and is a board member for, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Nycomed, Pfizer; and has received grants from Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche. Dr Fabbri has received consultancy fees from Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Elevation Pharmaceuticals, Merck Sharp & Dohme, Novartis, Nycomed, Pearl Therapeutics, Roche and Sigma-Tau; payment for lectures and support for travel expenses from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Euromediform SrL, GlaxoSmithKline, German Centre for Lung Research, Merck Sharp & Dohme,Menarini, Mundipharma International, Novartis, Nycomed, TEVA Pharmaceuticals, Pfizer, and Sigma-Tau; and LMF's institution has received grants from Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Italian Ministry of Health, Italian Ministry for University and Research, Merck Sharp & Dohme, Nycomed, and Sigma-Tau.
Hitachinaka Education and Research Center, The University of Tsukuba
June 29, 2011
Older adults initially prescribed LABA, but not long-acting anticholinergics, may be asthmatic rather than pure COPD patients
It has been recently reported that long-acting inhaled ?-agonists (LABA) for the management of moderate COPD seem to have lower mortality than those initially prescribed long-acting anticholinergics in older adults with COPD(1). The study is sensational, but may be wrong. First. Elderly COPD is very complex. Pure COPD without asthmatic component airways in older adults are fairly difficult to be diagnosed by general physicians (2). The definition of the COPD, asthma, COPD with asthma, and COPD with heart failure is very poorly written in the study. Second. COPD mortality is considerably affected by age and acute exacerbation history (3). The initially prescribed long-acting anticholinergics groups have a significantly greater rate of acute exacerbation number, indicating that these patients are prone to acute exacerbators among COPD patients. Third. We always think the LABA prescription for wheeze asthmatic rather than dry cough type COPD initially (4). That is why the LABA prisrcctors may somehow imply the COPD patients with asthmatic domain. Importantly, the mortality is greater in asthma patients rather than COPD patients. Thus, the results of the current study may be just based on the therapeutic/diagnostic decision bias between asthma and COPD. The results may not be associated with agent superiority for the mortally on COPD itself. The bias is likely to be introduced in many trials on widely prescribed treatments in patients with chronic disease (5). Furthermore, elderly patients with COPD have an increased risk of systemic events including heart attacks, bone fractures, and depression. A multidisciplinary approach for the systemic complication, not just for airway bronchodilators, may determine the prognosis of the older COPD patients.
1) Gershon A, Croxford R, To T, Stanbrook MB, Upshur R, Sanchez-Romeu P, Stukel T. Comparison of inhaled long-acting ?-agonist and anticholinergic effectiveness in older patients with chronic obstructive pulmonary disease: a cohort study. Ann Intern Med. 2011 May 3;154(9):583-92. PMID:21536937
2) McDonald VM, Higgins I, Simpson JL, Gibson PG. The importance of clinical management problems in older people with COPD and asthma: do patients and physicians agree? Prim Care Respir J. 2011 Mar 29. pii: pcrj- 2009-12-0100-R3. doi: 10.4104/pcrj.2011.00025. [Epub ahead of print] PMID:21448550
3) Hurst JR, Vestbo J, Anzueto A, Locantore N, M?llerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-38. PMID:20843247
4) Gooneratne NS, Patel NP, Corcoran A. Chronic obstructive pulmonary disease diagnosis and management in older adults. J Am Geriatr Soc. 2010 Jun;58(6):1153-62.
5) Vollenweider D, Boyd CM, Puhan MA. High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease. BMC Med. 2011 Jun 13;9(1):73. [Epub ahead of print]
Matthew B. Stanbrook
Institute for Clinical Evaluative Sciences in Ontario, University of Toronto
September 7, 2011
Author's response to Fabbri, et al.
To The Editor:
We thank Fabbri et al. for their comments and congratulate them on successfully conducting the POET-COPD study,(1) which was published when our paper was in press. While POET-COPD adds valuable new evidence to our understanding of the comparative efficacy of long-acting bronchodilators in COPD, it is important to recognize that its findings do not necessarily contradict the findings of our paper because of key differences between the two studies--most notably differences in study population, design, and outcomes.
The most salient difference is in study populations. The POET-COPD study, like virtually all such randomized trials in COPD but unlike our study, excluded patients with congestive heart failure, arrhythmias, and recent MI,(1) who may be the very individuals most at risk for adverse events. Also, while our study observed patients from the time of their first use of a long-acting bronchodilator, a majority of patients in POET- COPD were already receiving a long-acting bronchodilator at baseline. By virtue of the fact that they tolerated their regimen and volunteered to take it in a study, this group was more likely to have favorable outcomes. A treatment-naive subgroup of POET-COPD patients was reported to be similar to the overall cohort with respect to exacerbations, but mortality in this subgroup was not reported.(1)
A second difference is that participants in the POET-COPD study who were randomized to tiotropium were precluded from adding or switching to a long-acting beta-agonist, and vice versa,(1) while in our study there was no such restriction. In real-life practice, such switches and additions happen routinely, in keeping with recommendations of current COPD guidelines.(2) Therefore, while the findings of POET-COPD study may apply to specific clinical situations, our study is likely more representative of what usually happens in actual clinical practice.
Lastly, mortality was the primary outcome in our study, while in POET -COPD the primary outcome was exacerbations. POET-COPD was not adequately powered to find small differences in mortality, having enrolled 7376 patients in contrast to the 46,403 patients included in our study.
We agree with Fabbri et al. that a randomized trial provides the highest level of evidence for causal associations, but observational research often plays an essential role in identifying unintended consequences of therapy that may differ in actual practice from findings observed in the idealized context of a randomized trial.(3) We remain concerned that, in current clinical practice, the choice of initial long- acting bronchodilator therapy may lead to different outcomes, including mortality. The POET-COPD study does not fully allay these concerns for the reasons described above. We think that to confirm or refute our findings would instead require a pragmatic randomized trial in which patients were assigned to either class of long-acting bronchodilator (and ideally also a group assigned to both) and allowed to add or cross over to other therapies without restriction. However, we anticipate that such a trial would be very large and expensive, which would present substantial feasibility barriers.
Matthew B. Stanbrook, MD PHD
Andrea Gershon, MD, MSc Institute for Clinical Evaluative Sciences in Ontario University of Toronto
1. Vogelmeier C, Hederer B, Glaab T, et al. for the POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-1103.
2. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available from: http://www.goldcopd.org/.
3. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51.
Gershon A, Croxford R, To T, et al. Comparison of Inhaled Long-Acting β-Agonist and Anticholinergic Effectiveness in Older Patients With Chronic Obstructive Pulmonary Disease: A Cohort Study. Ann Intern Med. 2011;154:583–592. doi: 10.7326/0003-4819-154-9-201105030-00003
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Published: Ann Intern Med. 2011;154(9):583-592.
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