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Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
Tiotropium Letter
Response
Two Major Bias in this Study
Is This Study Design Ethical?
Tiotropium for COPD
A Therapeutic Gain?
Do bronchodilators produce a clinically meaningful reduction in COPD-related exacerbations?
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Nadia K. Janjua, MD University of Louisville, Kendra D. Sheppard MD
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n0khan01{at}gwise.louisville.edu Nadia K. Janjua, et al.
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To The Editor, The article designed by Niewoehner et al was presented at University of Louisville Internal Medicine Journal Club. This study indicated that tiotropium use significantly reduced the number of COPD exacerbations. According to study design patients were allowed to continue inhaled steroid use. There was no data disclosing the number of patients who benefited from tiotroprium who were also on inhaled steroids. It was unclear whether the benefit was from inhaled steroids or tiotroprium use. Several trials with patients that have a mean FEV1 less than 2L (or less than 70% predicted) almost uniformly demonstrated a positive effect of inhaled corticosteroids on (reducing) exacerbations regardless of the duration of the study or the specific formulation used (2). Based on Figure 3, it was shown that there was statistical benefit of tiotropium in patients with FEV1<35%, no prednisone use in the past year, no inhaled steroid or theophylline use, and age<61 yrs. However, standard of care denotes that patients with FEV1<35% should be on inhaled steroids per GOLD criteria (3). Regarding patients who withdrew from the study and were counted as having no event (table 1); it would be helpful if there was data provided that delineated the day of withdrawal from the study, as it would impact the relevance of exacerbation free events. Finally, perhaps an independent review of the study would have provided more validity as this study was designed by the pharmaceutical sponsors of tiotroprium and reviewed by an author who discloses affiliation with the same pharmaceutical sponsor. We would appreciate the authors' response. Kendra Sheppard, MD, Nadia Khan Janjua, MD, on behalf of University of Louisville Internal Medicine Journal Club References: 1 Niewoehner et al. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator. Ann Intern Med, Sep 2005; 143: 317 - 326. 2 Sin et al. Contemporary Management of Chronic Obstructive Pulmonary Disease Scientific Review. JAMA, 2003; 290: 2301-2312. 3 Global Initiative for Chronic Obstructive Pulmonary Disease. Global Strategy for the Diagnosis Management and Prevention of COPD; NHLBI/WHO Workshop, Bethesda, MD: National Heart Lung and Blood Institute, April 2001, updated 2003. Accessed at www.goldcopd.com on 29 Jan 2006. Conflict of Interest:None declared |
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Dennis E Niewoehner, MD Minneapolis VA Medical Center, Kathryn Rice, Stephen Kesten
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niewo001{at}umn.edu Dennis E Niewoehner, et al.
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The authors of both letters express concerns relating to the fact that we discontinued ipratropium in many subjects. They view ipratropium as a standard of care in the community. Therefore, stopping the drug makes the trial both clinically irrelevant and unethical. We will briefly review the scientific basis for their claims. Two large three-arm trials compared the bronchodilator effects of ipratropium, of albuterol, and of their combination [1,2]. Both trials clearly demonstrated that ipratropium is an effective bronchodilator in COPD, but albuterol produces almost identical responses. Combined treatment produces better bronchodilation than either drug alone, but the additive effect is small and is not associated with overall differences in symptom scores among the three treatment arms. These results indicate that albuterol and ipratropium can be used interchangeably for short-term control of symptoms, a conclusion in full accord with current expert recommendations [3]. The clinical utility of combined therapy for this purpose remains unproven [4]. Additionally, there is very good evidence that regular use of ipratropium does not affect long-term changes in lung function [5]. Drs. Good and Longo make the additional claim that ipratropium reduces exacerbation rates by 32% when added to a short-acting beta agonist. The basis for this assertion is a meta-analysis of three trials [6], with the overall conclusion residing largely with the two studies cited above [1,2]. Exacerbation rates in those two trials were inferred from changes in prednisone use, which was reduced when ipratropium was added to albuterol. However, prednisone use was only one of numerous other secondary efficacy and safety variables showing no treatment effects. Claims based on secondary or post-hoc analysis must be recognized for their limitations and often prove incorrect when appropriate prospective testing is performed. Moreover, authors of a another review identified four trials, comprising more than 1,000 patients, which showed no significant advantage of ipratropium over placebo in reducing exacerbations (RR, 0.95, 95% CI, 0.78 - 1.16) [7]. Drs. Good and Longo ask that we provide a table comparing health care events for COPD prior to the study with the same events during the trial to determine whether stopping ipratropium had adverse effects in the placebo group. These data are to be found in Tables 1 (Baseline Characteristics) and Table 3 (Secondary Outcomes) of our article. We obtained retrospective information from patient self-report and prospective information from monthly interviews and medical records. We express frequencies in both tables in common units of mean events per patient-year. Some comparisons are not possible (e.g, "courses of antibiotics" vs "days of antibiotics"). We can compare COPD hospitalization rates by summing the two categories for hospitalization in Table 1 with the single category in Table 3. Thus, the 915 patients in the placebo arm reported a mean rate of 0.24 COPD hospitalizations per patient-year in the previous year and we identified a mean rate of 0.25 hospitalizations per patient-year during the six months of the trial. We can similarly compare the sum of "urgent physician visits" and "ED visits" in Table 1 (mean of 0.59 per patient-year) with the umbrella term of "unscheduled visits" in Table 3 (mean of 0.49 per patient year). These comparisons are deeply flawed for obvious reasons, but we can fairly conclude that they raise no red flags. For the reasons detailed above, we strongly refute the suggestions that we conducted an irrelevant or unethical trial, either willfully or through ignorance. Our decision to allow albuterol as sole "rescue" therapy is fully consistent with the scientific evidence. Our study highlights the importance of conducting prospective clinical trials with pre-defined primary endpoints and thereby provides definitive evidence of the effect of tiotropium on COPD exacerbations. Dennis E. Niewoehner, MD Kathryn Rice, MD Veterans Affairs Medical Center Minneapolis, MN 55417 Stephen Kesten, MD Boehringer Ingelheim Pharmaceuticals Ridgefield, CT 06877 References 1. COMBIVENT Inhalation Aerosol Study Group. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. Chest 1994;105:1411-9. 2. COMBIVENT Inhalation Solution Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest 1997;112:1514-21. 3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. NHLBI/WHO workshop report. Bethesda, National Heart, Lung and Blood Institute, April 2001; Update of the Management Sections 2003, GOLD website (www.goldcopd.com). 4. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, et al. State of the Art Compendium: Canadian Thoracic Society recommendations for the management of chronic obstructive pulmonary disease. Can Respir J 2004;11(Suppl B):7B-59B. 5. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994;272:1497-1505. 6. Sin DD, McAlister FA, Man SFP, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease. Scientific review. JAMA 2003;290:2301-12. 7. Wilt TJ, Niewoehner D, Kim C, Kane RL, Linabery A, Tacklind J, et al. Use of Spirometry for Case Finding, Diagnosis, and Management of Chronic Obstructive Pulmonary Disease (COPD). Evidence Report/Technology Assessment No. 121 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-02-0009.) AHRQ Publication No. 05-E017-2. Rockville, MD. Agency for Healthcare Research and Quality. September 2005. Conflict of Interest:Dennis Niewoehner - Consultancies and honoraria (Boehringer Ingelheim Pharmaceuticals) Kathryn Rice - Honoraria (Boehringer Ingelheim Pharmaceuticals) Stephen Kesten - Employee (Boehringer Ingelheim) Pharmaceuticals |
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Oreste Capelli, MD CeVEAS (Center for the Evaluation of Effectiveness of Health Care) - Modena - Italy, Armando Capelli, Giulio Formoso, Nicola Magrini.
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o.capelli{at}ausl.mo.it Oreste Capelli, et al.
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Niewoehner and Colleagues evaluate the effectiveness of a long- acting inhaled anticholinergic bronchodilator, tiotropium, in reducing chronic obstructive pulmonary disease (COPD) exacerbations and exacerbation-related health care utilization (1). The study was a parallel -group, randomized, double-blind, placebo-controlled trial in patients with moderate to severe COPD. The authors conclude that tiotropium reduces COPD exacerbations and may reduce related health care utilization. The study is well done but in our opinion it is not “designed to reflect community practice as closely as possible” as sustained by the authors; in fact we think that there are two biases in this trial: a) In community practice only from 5 to 30 % of COPD patients are treated with short-acting anticholinergics (ipratropium or oxitropium) (2-4); on the contrary in Niewoehwnwe and Colleagues’ trial 80% of the patients enrolled were under current treatment with these drugs. In our opinion the study population was a “selected population” of COPD patients with a high compliance for the anticholinergic drug. This type of bias is present also in other studies on tiotropium efficacy and safety (5-7) and so it is difficult to generalize the results of these trials to the general COPD population as, on the contrary, seems to be sustained in the editorial by Turino. (8) b) The second bias concerns the ethical problem to suspend therapy with short-acting anticholinergic drugs in the placebo group. It is well known that in some patients anticholinergics are more effective than beta2- agonists and it is well known that these two types of bronchodilator have a synergic effect (9): to suspend the short-acting anticholinergic drug in the treatment of the placebo group could have worsening effects on the clinical and physiopathological conditions of patients, statistically increasing the tiotropium effects in the treated group. In fact the subgroup analysis shows more efficacy of tiotropium in those patients treated with corticosteroids or theophylline and where, probably, the short-acting anticholinergic was the most important treatment. In any case, as underlined also in the Editorial, the benefit obtained with tiotropium seems clinically poor. In our opinion the study would have been ethically and methodologically more correct and more in line with community practice if tiotropium had been compared not only with placebo but also with the usual therapy, including short-acting anticholinergic drug. 1. Niewoehner DE, Kathryn Rice, Claudia Cote, Daniel Paulson, J. Allen D. Cooper, Jr., Larry Korducki, Cara Cassino, and Steven Kesten Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator: A Randomized Trial Ann Intern Med 2005; 143: 317-326 2. Rudolf M The Reality of Drug Use in COPD The European Perspective CHEST 2000; 117:29S–32S 3. Ramsey SD Suboptimal medical therapy in COPD. Exploring the causes and consequences CHEST 2000; 117:33S-37S 4. Soriano JB, Vestbo J Pride NB, Kiri V, Maden C , Maier WC. Survival in COPD patients after regular use of Fluticasone propionate and salmeterol in general practice. Eur Respir J. 2002; 20: 819 - 825. 5. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002 Feb;19(2):217-24. 6. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, Cornelissen PJ; Dutch/Belgian Tiotropium Study Group. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J. 2002 Feb;19(2):209-16. 7. Donohue JF, van Noord JA, Bateman ED, Langley SJ, Lee A, Witek TJ Jr, Kesten S, Towse L. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest. 2002 Jul;122(1):47-55. 8. Turino GM Therapeutic gains of prolonged bronchial dilatation in chronic obstructive pulmonary disease. Ann Intern Med. 2005 Sep 6;143(5):386-7. 9. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest. 1994 May;105(5):1411-9. Conflict of Interest:None declared |
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Alec B. O'Connor, MD University of Rochester
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alec_oconnor{at}urmc.rochester.edu Alec B. O'Connor
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The clinical trial described in “Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator” (1) is concerning because it does not satisfy either of the two basic moral considerations governing the ethics of clinical trial design (2). The first consideration dictates that the research must strive to answer clinically important questions using scientifically valid methods. Inhaled ipratropium can be considered a standard of care for patients with moderate to severe COPD; as evidence, the great majority of patients in the tiotropium trial had been prescribed and were actively taking it upon enrollment in the trial. As such, the trial does not answer the questions of importance to clinicians: is tiotropium more effective than ipratroprium? Since tiotropium is more convenient for patients than ipratropium, is tiotroprium as effective as ipratropium? How does tiotropium compare in a cost-effectiveness analysis? While a standard of care control is not necessarily required for a trial to be considered ethical, it is often needed to ensure that the trial results have clinical utility (2). The second moral consideration governing the design of clinical trials dictates that research subjects must be protected from exploitation or harm. In the tiotropium trial, 80% of the subjects were taken off of ipratropium therapy; the safety of discontinuing ipratropium in this patient population is unknown. The use of a standard of care arm would have allowed the researchers to ensure the safety of subjects in the non-standard of care arm(s) (2). The trial design does not allow us to feel comfortable that either group of subjects in the trial was adequately protected from harm, let alone had better outcomes than “usual care.” It is possible that prescribers changing practice based on the results of this trial may actually be harming patients. 1. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper AD, Korducki L, et al. Prevention of exacerbations of chronic obstructive disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator. A randomized trial. Ann Intern Med 2005;143:317-326. 2. Miller FG, Silverman HJ. The ethical relevance of the standard of care in the design of clinical trials. Am J Respir Crit Care Med 2004;169;562-4. Conflict of Interest:None declared |
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Chester B Good, MD, MPH VA Pittsburgh Healthcare System and the University of Pittsburgh, Lisa Longo
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chester.good{at}med.va.gov Chester B Good, et al.
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The decision of Niewoehner and colleagues (1) to compare tiotropium to placebo rather than ipratropium for prevention of exacerbations of chronic obstructive pulmonary disease (COPD) is problematic for several reasons. The authors state they “designed the study to reflect community practice…” However, community practice of COPD includes the use of anticholinergic bronchodilators, evidenced by the fact that 80% of study participants received this therapy at baseline. Thus, the comparison group (placebo) actually was getting less than accepted community practice. It is difficult to determine the significance of the study findings when an appropriate comparator (ipratropium) was not used. Furthermore, studies of ipratropium in patients with COPD and similar FEV1’s (approximately 1L) as in the Niewoehner study have demonstrated a 32% decrease in exacerbations (2). These studies were all published long before patients were recruited for the present study. This raises the real possibility that patients in the placebo arm could have been harmed as a result of participating in the clinical trial. We ask that the authors provide a table comparing mean COPD health care events (as detailed in Table 1) for the placebo group at baseline, and during the study period, after excluding those patients who withdrew from the study before reaching study conclusion or a clinical endpoint. Chester B. Good, MD, MPH VA Pittsburgh Healthcare System Lisa Longo, Pharm D VA Pittsburgh Healthcare System 1) Niewoehner DE, Rice K, Cote C, Paulson D, Cooper AD, Korducki L, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator. Ann Intern Med. 2005; 143:317-326. 2) Sin DD, McAlister FA, Paul Man, SF, Anthonisen NR: Contemporary management of chronic obstructive pulmonary disease. JAMA 2003; 290:2301- 2312. Conflict of Interest:No competing interests |
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Michael H. Monroe, MD Carolinas Medical Center, J. Matthew Blackwell and Arnold Frazier
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mmonroe{at}carolinas.org Michael H. Monroe, et al.
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To the Editor: In their recent article on tiotropium use in COPD, Niewoehner et al. concluded ”that tiotropium reduces exacerbations and may reduce health care utilization in patients with moderate to severe COPD who are already receiving most elements of usual care.”(1) We disagree with this conclusion. While the results initially appear promising, serious questions arise regarding the methodology. The population studied consisted of advanced COPD patients with more than 90% on a beta-agonist at baseline, 80% on ipratropium, and close to 60% on inhaled steroids. These medications were likely being utilized to suppress disease manifestations and were certainly in line with clearly expressed standards of care. (2) The study design discontinued ipratropium in 728 patients and replaced it with placebo effectively disadvantaging them relative to the 735 patients who were given tiotropium in place of ipratropium. That there would be a difference in symptom based outcomes at 6 months comes as no surprise. Turino in his editorial explains that, “[i]ncreased cholinergic tone mediated through the vagus nerve is a clinically significant factor in bronchial obstruction in COPD, and anticholinergic therapy is beneficial” but fails to comment on the potential implications of the substitution of placebo for a chronic anticholinergic therapy that has previously been shown to reduce exacerbations. (3,4) That the “percentage of reductions in exacerbations and hospitalizations reported. . . may seem modest” appears quite an understatement given this switch. Although initial studies with tiotropium show promise in terms of improving lung function and reducing exacerbations with COPD, this trial adds little to the established knowledge base. (5) It would have been much more instructive to compare tiotropium not with the substitution of placebo for effective therapy but with the continued use of ipratropium. Only then would we have clarification whether we are truly looking at a therapeutic gain as opposed to a therapeutic switch, and perhaps a more expensive one at that. 1. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA Jr, Korducki L, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotroprium, a once-daily inhaled anticholinergic bronchodilator. A randomized trial. Ann Intern Med. 2005;143:317-26. 2. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global initiative for chronic obstructive lung disease (GOLD) workshop summary. Am J Respir Crit Care Med. 2001;163:1256-76. 3. Turino GM. Therapeutic gains of prolonged bronchial dilatation in chronic obstructive pulmonary disease. Ann Intern Med. 2005;143:386-7. 4. Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek TJ. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest.1999;115:635-41. 5. Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest. 2004;125:249-59. Conflict of Interest:None declared |
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S. Troy McMullin, Pharm.D. Purkinje Clinical Decision Support
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tmcmullin{at}purkinje.com S. Troy McMullin
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As pointed out in the study by Niewoehner et al,[1] COPD-related exacerbations and hospitalizations are associated with a significant impact on patients’ quality of life and their cost of care. Unfortunately, it is unclear at this point whether tiotropium (or any other available treatment) has been shown to produce a clinically meaningful improvement in COPD-related exacerbations. Although tiotropium was associated with statistically fewer exacerbations (0.85 vs. 1.05 per patient per year), fewer unscheduled healthcare visits (0.39 vs. 0.45 per patient per year), and fewer COPD- related hospitalizations (0.18 vs. 0.25 per patient per year) than placebo, the absolute difference between groups appears to be relatively modest.[1] Assuming the rates of exacerbation remain constant over time, these results suggest that patients treated with tiotropium would experience on average one fewer exacerbation every 5 years and one fewer hospitalization every 14 years when compared to patients treated with other available therapies. These results are consistent with other long-term studies comparing tiotropium to placebo, ipratropium, or salmeterol. [2-4] In all of these studies (2,663 participants), the absolute difference in event rates suggest that patients treated with tiotropium would experience approximately one fewer exacerbation every 4 to 6 years and one fewer hospitalization every 14 to 17 years when compared to patients treated with other available therapies. These relatively disappointing results are not limited to tiotropium studies. Of six long-term placebo-controlled studies assessing the impact of long-acting beta agonists (5,920 participants),[4-9] only one has found a statistically significant impact on the rate of exacerbations. The results from that study [7]suggest that patients would need to be treated with salmeterol for approximately 4 years to prevent one exacerbation. Salmeterol had no significant impact on the rate of COPD-related hospitalizations. Although many patients in these trials received concomitant therapy with inhaled steroids, the impact of these agents is also questionable. In clinical trials, the combination of a long-acting beta agonist and an inhaled steroid has not been consistently superior to monotherapy with a long-acting beta agonist for reducing the rate of exacerbations. Of five long-term studies comparing monotherapy with a long-acting beta agonist to combination therapy (4,713 participants), only two [8-9] reported a statistically significant difference in the rate of exacerbations. The rates of hospitalization were not reported in these trials. As Niewoehner et al point out, the relative impact of treatments on the exacerbations and hospitalizations should be weighed against other considerations, including cost. The monthly costs of treatment with tiotropium ($165), fluticasone/salmeterol ($150), salmeterol ($100), formoterol ($100), and ipratropium ($90) are substantial, especially given the frequency with which these agents are used in combination. We look forward to formal cost effectiveness analyses that address the true impact of these agents on exacerbation-related costs. It is also important to note that all long-term comparative trials have primarily enrolled patients with severe COPD (mean FEV1 < 50% predicted), and therefore, it is difficult to draw firm conclusions regarding the relative efficacy of these agents in patients with less severe disease. Future studies should attempt to determine whether these treatments have any impact on exacerbation rates in patients with mild or moderate COPD. 1. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: A randomized trial. Ann Intern Med. 2005; 143:317-26. 2. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Resp J. 2002; 19:217-24. 3. Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J. 2002; 19:209-16, 4. Brusasco V, Hodder R. Miravitlles M. et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2003; 58:399- 404. 5. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 mcg)/salmeterol (50 mcg) combined in the discus inhaler for the treatment of COPD. Chest. 2003; 124:834-43. 6. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the discus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002; 166:1084-91. 7. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet. 2003; 361:449-56 8. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003; 21:74-81. 9. Calverley PM, Boonswat W, Cseke Z. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003; 22:912-9. Conflict of Interest:None declared |
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