Timothy J. Wilt, MD, MPH; Dennis Niewoehner, MD; Roderick MacDonald, MS; Robert L. Kane, MD
Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Indy Rutks, who assisted in the literature search and creation of some figures.
Grant Support: Prepared by the Minnesota AHRQ Evidence-based Practice Center, Minneapolis, Minnesota, under AHRQ contract no. 290-02-0009 and a contract with the American College of Physicians.
Potential Financial Conflicts of Interest: Consultancies: D. Niewoehner (Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Sanofi Aventis, Schering-Plough, Adams Respiratory Therapeutics). Honoraria: D. Niewoehner (Pfizer Inc., Boehringer Ingelheim). Grants received: D. Niewoehner (Boehringer Ingelheim, GlaxoSmithKline).
Requests for Single Reprints: Timothy J. Wilt, MD, MPH, Veterans Affairs Medical Center (111-0), Minneapolis, MN 55417; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Wilt and Mr. MacDonald: University of Minnesota School of Medicine, Center for Chronic Disease Outcomes Research (111-0), Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
Dr. Niewoehner: University of Minnesota School of Medicine, Pulmonary Section (111A), Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.
Dr. Kane: Clinical Outcomes Research Center, School of Public Health, Health Policy and Management, University of Minnesota, Minneapolis, MN 55455.
Chronic obstructive pulmonary disease (COPD) is a common and disabling condition in adults. Information about therapeutic effectiveness and adverse effects of common treatment options and how clinical and spirometric characteristics affect outcomes is not well known but is important for clinicians caring for patients with stable COPD.
To evaluate the effectiveness of COPD management strategies.
English-language publications in MEDLINE and the Cochrane Library through March 2007.
Randomized, controlled trials (RCTs) and previous systematic reviews of inhaled therapies, pulmonary rehabilitation, disease management, and supplemental oxygen in adults with COPD.
Participant, study, and intervention characteristics; exacerbations; deaths; respiratory health status; exercise capacity; hospitalizations; and adverse effects.
Eight meta-analyses and 42 RCTs examined inhaled therapies: short-acting anticholinergics (n = 7), long-acting anticholinergics (n = 10), long-acting β2-agonists (n = 22), corticosteroids (n = 14), dual D2 dopamine receptor–β2-agonist (n = 3), or short-acting β2-agonist plus ipratropium (n = 3). Evidence for nonpharmacologic therapies included 3 reviews of 39 RCTs plus 6 additional RCTs of pulmonary rehabilitation, 2 reviews of 13 RCTs plus 2 additional RCTs of disease management, and 8 RCTs of oxygen. Overall, long-acting inhaled therapies, used alone or in combination, reduced exacerbations more than placebo by 13% to 25% and had similar effectiveness to each other. Average improvements in health status scores were less than what is considered to be clinically noticeable. Inhaled monotherapy did not reduce mortality rates. Inhaled corticosteroids plus long-acting β2-agonists reduced deaths in relative terms compared with placebo (relative risk, 0.82 [95% CI, 0.69 to 0.98]) and inhaled corticosteroids alone (relative risk, 0.79 [CI, 0.67 to 0.94]) but not compared with long-acting β2-agonists alone (relative risk, 0.82 [CI, 0.52 to 1.28]). Absolute reductions were 1% or less and were not statistically significant. Pulmonary rehabilitation improved health status and dyspnea but not walking distance. Neither disease management nor ambulatory oxygen improved measured outcomes. Supplemental oxygen reduced mortality rates among symptomatic patients with resting hypoxia (relative risk, 0.61 [CI, 0.46 to 0.82]). Insufficient evidence supports using spirometry to guide therapy.
Articles were limited to those in the English language. Treatment adherence, adverse effects, and effectiveness may differ among clinical settings. Short-acting inhalers for “rescue therapy” were not evaluated.
Long-acting inhaled therapies, supplemental oxygen, and pulmonary rehabilitation are beneficial in adults who have bothersome respiratory symptoms, especially dyspnea, and FEV1 less than 60% predicted.
Data search and selection.
RCT = randomized, controlled trial.
Appendix Table 1. Treatments, Baseline Characteristics, and Study Quality of Individual Trials of Treatments for Chronic Obstructive Pulmonary Disease
Table. Summary of Evidence and Conclusions Related to Each Clinical Question
Number of participants who had at least 1 exacerbation: inhalation treatments versus placebo.
LABA = long-acting β2-agonist; RR = relative risk.
Number of participants who had at least 1 exacerbation: inhalation treatments versus active control.
LABA = long-acting β2-agonist; NA = not applicable; RR = relative risk; SABA = short-acting β2-agonist.
Appendix Table 2. Inhaled treatments for Chronic Obstructive Pulmonary Disease versus Placebo and Control: Improvement in the St. George Respiratory Questionnaire or Chronic Respiratory Disease Questionnaire at Study End Point
Mortality: inhalation treatments versus placebo or combination long-acting β2-agonists and corticosteroid therapy versus monotherapy.
LABA = long-acting β2-agonist; LHS = Lung Health Study; RR = relative risk.
Appendix Table 3. Study Withdrawals and Adverse Effects for Trials Lasting 1 Year or More: Inhaled Treatment versus Placebo
Appendix Table 4. Summary of Outcomes for Clinical Trials of Pulmonary Rehabilitation
Appendix Table 5. Summary of Outcomes for Clinical Trials of Disease Management
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Christian Medical College and Hospital Ludhiana,India
November 6, 2007
Compassionate care for COPD patients
Two major problems facing the clinician treating the stable COPD patient are diagnosis and attitude. First, COPD is underdiagnosed.1,2 Even when diagnosed, the clinical importance of the disease is often underestimated. 3 This underestimation might reflect, in part, an inappropriate inclination of many clinicians toward therapeutic nihilism for COPD patients. This attitude might be based on the historical approach toward such patients as stated by Williams in Middle and Old Age (Oxford Medical Publications), quoted by Fletcher and colleagues4: "Chronic bronchitis with it accompanying emphysema is a disease on which a good deal of wholly unmerited sympathy is frequently wasted. It is a disease of the gluttonous, bibulous, otiose, and obese and represents a well-deserved nemesis for these unlovely indulgences . . . the majority of cases are undoubtedly due to surfeit and self-indulgence." This attitude toward COPD patients is inappropriate not only for its lack of compassion, but, at the present time, because therapeutic interventions for stable patients can result in substantial clinical benefit.
1 Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988"“1994. Arch Intern Med 2000; 160: 1683"“89.
2 Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance"”United States, 1971- 2000. MMWR Surveill Summ 2002; 51: 1"“16.
3 Jones PW. Issues concerning health-related quality of life in COPD. Chest 1995; 107 (suppl): 187"“193.
4 Fletcher C, Peto R, Tinker C, Speizer FE. The natural history of chronic bronchitis and emphysema. New York: Oxford University Press, 1976.
Christian Medical College and Hospital, Ldh, Pb, In
November 9, 2007
Give Benefit of Doubt to Patients with COPD
COPD is a leading cause of morbidity and mortality in the adult population world-wide and affects 6% and 3% of the male and female population in the United States respectively 
Patients with COPD have frequent exacerbations that may require hospitalization. There are various reasons for this. Failure to comply with treatment plan, in the form of not taking the medications on time or not using the prescribed oxygen therapy for adequate no of hours at home, or not using the non invasive ventilation as prescribed to them at home. Domiciliary oxygen therapy improves survival, exercise performance, and daily activities,
Another reason is because of frequent lower respiratory tract infection, pneumonias and spontaneous pneumothorax, which is common in patients with advanced bullous disease. Timely intervention and diagnosis of treatable causes of COPD can help reduce morbidity and mortality. More over these patients may have co morbid conditions like diabetes mellitus, renal failure, hypertension, obesity and cardiac arrhythmias , cor pulmonale, septicemia.[4,5,6].
Patients with these above conditions can be easily mistaken for end stage respiratory failure, and the physician may not be aggressive in admitting the patient to intensive care unit (ICU) and resuscitating them. Poor financial condition of the patient may be an additional factor for their no getting admitted to ICU. While the fact is that they may respond and recover if vigorous ICU care is instituted, including elective intubation, ventilation and adequate coverage with broad spectrum antibiotics. Wise use of corticosteroids, bronchodilators and anticolinergics, physiotherapy, lung volume reduction surgery and bullectomy might help them recover fast. Infection, hypoxia, hypercarbia and co morbid conditions should be treated aggressively.
It would be wise to admit all COPD patients to ICU and investigate and treat. Guarded but not negative prognosis should be maintained. A poor outcome should not deter the physician from admitting and treating patients with COPD. Patients should be immediately hospitalised if there is an exacerbation complicated by severe dyspnoea or respiratory failure 
1 Celli B, Snider GL, Heffner J, et al. 1995. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:S77- S120.
2 Petty TL, Finigan MM. Clinical evaluation of prolonged ambulatory oxygen therapy in chronic airway obstruction. Am J Med 1968: 45:242-252.
3 FusoL, Incalzi RA, Pistclli R, et al. Predicting mortality of patients hospitalised for acutely exacerbated chronic obstructive pulmonary disease. Am J Med 1995;98:272-277.
4 Niederman MS, Bass JB Jr, Campbell GD, et al. Guidelines for the i n i t i a l management of adults with community acquired pneumonia. Am Rev Respir Dis 1993:148:1418-1426.
5 Tsang KWT, Lam WK. The management of community acquired pneumonia. HK Pract 1997:19:80-88.
6 B r i t i s h Thoracic Society. Public Health Laboratory Service. Community acquired pneumonia in adults in British hospitals in 1982-3: a survey of aetiology, mortality, prognostic factors and outcome. QJ Med 1987; 62:195-220.
7 Martin J Wildman et al. Implications of prognostic pessimism in patients with chronic obstructive pulmonary disease (COPD) or asthma admitted to intensive care in the UK within the COPD and asthma outcome study (CAOS): multicentre observational cohort study. BMJ, doi:10.1136/bmj.39371.524271.55 (published 1 November 2007)
University of Missouri-Columbia
November 11, 2007
A missing piece of the puzzle
Since no studies have shown a clear-cut survival benefit with any inhaled therapies in COPD, the next most important hard outcome would be hospitalization rates. Wilt et al concluded that the reductions in hospitalizations with inhaled therapies were inconsistent and evidence did not permit definitive conclusions about relative effectiveness. I agree that that is true with long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS). However, recent meta-analyses have shown that tiotropium consistently reduced hospitalization rates in moderate-to-severe COPD. (1,2) Pooled analyses including recent studies such as TORCH (3) were conducted to update previous studies and tiotropium is still the only inhaled therapy that consistently and significantly reduced hospitalizations. (Figures are available at http://pulmccm.blogspot.com) Although TORCH study showed a statistically significant reduction in hospitalizations with combined LABA and ICS, there aren't enough data to conduct a pooled analysis on COPD related hospitalizations. In a recent Canadian study, tiotropium also showed reduced need for hospitalization, when combined with an ICS and LABA, but not with a LABA alone. (4) In conclusion, currently available evidence suggests that tiotropium and/or combined ICA/LABA should be the drug of choice in stable moderate-to-severe COPD.
1. Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstructive pulmonary disease: A meta-analysis. Thorax. 2006;61:854-62.
2. Oba Y. Cost Effectiveness of Long-Acting Bronchodilators for Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease. Mayo Clin Proc 2007:82(5);575-82.
3. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89.
4. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545-55.
Timothy J. Wilt
Minneapolis VA Center for Chronic Disease Outcomes Research
December 21, 2007
Re: A missing piece of the puzzle
We thank Dr Oba for his comments on our paper on COPD. Dr. Oba concludes that tiotropium is the preferred therapy for management of chronic stable COPD based on a meta-analysis of 4 tiotropium studies demonstrating a 6% risk difference (RD) (95%CI,-10,-2) in the annual rate of hospitalizations compared to placebo as well as the lack of a statistically significant reduction against placebo for studies of inhaled corticosteroids (ICS) or long-acting inhaled beta agonists (LABA) that reported this outcome (1). We described similar findings in our manuscript. "The proportion of participants requiring hospitalization for COPD was lower with tiotropium than with placebo (RD, -2% [CI,-4 to -1%]" (2).
We identified 42 eligible RCTs of inhaled therapies. However, few reported on hospitalizations. When reported, reductions were not consistently observed and very few studies assessed comparative effectiveness across categories of long-acting inhalers. Of the 10 eligible tiotropium studies just 5 reported hospitalizations and 4 used placebo controls. Only 1 of these studies demonstrated statistically significant benefit. The difference in effectiveness estimates for annual rates compared to proportion of participants hospitalized is likely due to some individuals requiring recurrent hospitalizations. The clinical significance of these pooled reductions in hospitalizations and preferred analytic method are not known. Furthermore, investigators have demonstrated that selective study or outcome reporting (publication bias) results in biased (and more positive) effectiveness estimates (3). Therefore, we do not agree that the above findings are sufficient to draw comparative effectiveness conclusions.
Data for other outcomes did not support the superiority of a particular class of long-acting inhaler. Many patients with symptomatic COPD place an equal or greater value on obtaining a noticeable improvement in respiratory health status or reduction in exacerbations rather than hospitalizations. No studies directly compared tiotropium versus ICS. Tiotropium did not provide a clinically noticeable improvement in the average respiratory health status scores versus placebo and there were no statistical or clinical differences versus LABA. Based on pooled results of the 2 comparative studies, tiotropium did not reduce exacerbations compared to LABA. None of the inhaled monotherapies reduced mortality versus placebo (relative risk [RR], tiotropium=0.94 (CI,0.60-1.47). Combined LABA and ICS reduced mortality in relative terms (RR 0.82 (0.69- 0.98). The absolute reduction was 1% and not statistically significant.
Based on the available evidence, we conclude that the current level of evidence does not allow a determination of whether one long-acting inhaled therapy (or combinations of these therapies) is superior to another for management of chronic stable COPD (4). Additional large, long- term randomized trials comparing relative effectiveness and harms are needed.
1) Oba Y. A Missing piece of the puzzle. Ann Intern Med XXX
2) Wilt TJ, Niewoehner, MacDonald D, Kane RL. Management of Stable Chronic Obstructive Pulmonary Disase: A Systematic Review for a Clinical Practice Guideline. Ann Intern Med. 2007;147:639-653.
3) Lau J, Ioannidis JPA, Terrin N, Schmid CH, and Olkin I. The case of the misleading funnel plot BMJ. 2006;333:597-600.
4) Qaseem A, Snow V, Shekelle P, Sherif K, Weinberger S, Wilt TJ and Owens DK. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007;147:633-8.
Consultancies D. Niewoehner (Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Sanofi Aventis, Schering-Plough, Adams Respiratory THerapeutics). Honoraria: D. Niewoehner (Pfizer Inc., Boehringer Ingelheim). Grants received: D. Niewoehner (Boehringer Ingelheim, GlaxoSmithKline).
Timothy J. Wilt, Dennis Niewoehner, Roderick MacDonald, Robert L. Kane. Management of Stable Chronic Obstructive Pulmonary Disease: A Systematic Review for a Clinical Practice Guideline. Ann Intern Med. 2007;147:639–653. doi: 10.7326/0003-4819-147-9-200711060-00009
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Published: Ann Intern Med. 2007;147(9):639-653.
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