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Articles: Shawn D. Aaron, Katherine L. Vandemheen, Dean Fergusson, Franois Maltais, Jean Bourbeau, Roger Goldstein, Meyer Balter, Denis O'Donnell, Andrew McIvor, Sat Sharma, Graham Bishop, John Anthony, Robert Cowie, Stephen Field, Andrew Hirsch, Paul Hernandez, Robert Rivington, Jeremy Road, Victor Hoffstein, Richard Hodder, Darcy Marciniuk, David McCormack, George Fox, Gerard Cox, Henry B. Prins, Gordon Ford, Dominique Bleskie, Steve Doucette, Irvin Mayers, Kenneth Chapman, Noe Zamel, Mark FitzGerald for the Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial Ann Intern Med 2007; 146: 545-555 [Abstract] [Full text] [PDF]

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Electronic letters published:

Author's response to Dr. Brown's letter

Shawn D. Aaron   (29 May 2007)

Power calculations

Ejvind Frausing Hansen   (29 May 2007)

Re: Inhaled Corticosteroid in COPD: safety vs efficacy

jaspreet Singh   (15 May 2007)

Possible confounding effect of withdrawal of pre-existing therapy

Samuel M. Brown   (1 May 2007)

Editor's reply to Dr. Porat

Harold C. Sox   (30 April 2007)

Conflicts of Interest

Gil Porat   (27 April 2007)

Inhaled Corticosteroid in COPD: safety vs efficacy

Akashdeep Singh   (2 April 2007)

Author's response to Dr. Brown's letter 29 May 2007
Shawn D. Aaron, MD Ottawa Health Research Institute Send rapid response to journal: Re: Author's response to Dr. Brown's letter saaron{at}ohri.ca Shawn D. Aaron	We thank Dr. Brown for his comments. Dr. Brown is correct in maintaining that many patients randomized into our clinical trial were already taking inhaled corticosteroids (ICS) and/or long-acting beta- agonists (LABAs) at the time of enrollment, and withdrawal effects may have played a role in influencing clinical outcomes. However, the objective of our trial was to determine whether combination treatment with tiotropium plus salmeterol or tiotropium plus fluticasone-salmeterol improved clinical outcomes in adults with moderate and severe COPD. We did not intend to limit the trial to only those patients who were ICS- naive and LABA-naïve as this would have potentially limited the generalizability of the study findings. We agree with Dr. Brown that an interesting additional question would be to determine if these combinations of medications are equally effective in ICS-naive and LABA-naïve patients. However recruitment for this sort of study would likely have to occur in countries where use of long-acting bronchodilator medications is not already common practice for patients with moderate and severe COPD. Conflict of Interest: None declared
Power calculations 29 May 2007
Ejvind Frausing Hansen, MD Send rapid response to journal: Re: Power calculations frausing{at}dadlnet.dk Ejvind Frausing Hansen	I am very confused by the power analysis of this study. The authors state that they have chosen an 18 % absolute reduction in the risk of having at least one exacerabtion as the basis for the power analysis, but the fact is that no previous study on any pharmacological treatment of COPD have demonstrated an effect of that magnitude. It is true that ISOLDE and the study on LABA/ICS combinations have demonstrated a reduction in the exacerbation-rate of 25 %, but this is not the primary outcome in the actual study. The studies that have reported a similar outcome as this study (patients free of exacerbations in the study period) have typically shovn an absolute reduction of around 5 %. The study by Niewoehner on Tiotropium versus placebo showed an absolute risk reduction of 5,7 % (1). The TRISTAN study showed an absolute risk reduction of around 5 % for fluticasone/salmeterol versus placebo, estimated from the Kaplan-Meier plot(2), and the study of the budesonide/formoterol combination versus placebo by Calverley, showed an absolute risk reduction of around 10 % for combination therapy versus placebo, again estimated from the Kaplan-Meier plot (3). As those studys were of active treatment versus placebo, the best guess of an absolute risk reduction for an active treatment on top of other active treatment would be that the effect would be less than 5 %, which is also seen to be the case in this study. 1. Niewoehner DE 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. Calverley P et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361:449-456. 3. Calverley PM et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003; 22: 912-919. Conflict of Interest: None declared
Re: Inhaled Corticosteroid in COPD: safety vs efficacy 15 May 2007
jaspreet Singh, MBBS Send rapid response to journal: Re: Re: Inhaled Corticosteroid in COPD: safety vs efficacy jaspreet{at}gmail.com jaspreet Singh	It seems that industry is dictating its terms and conditions in COPD. As the nature of inflammation in COPD is totally different from that in asthma, then what is the rationale of making the treatments alike?
Possible confounding effect of withdrawal of pre-existing therapy 1 May 2007
Samuel M. Brown, MD Division of Respiratory and Critical Care and Occupational Pulmonary Medicine, University of Utah Send rapid response to journal: Re: Possible confounding effect of withdrawal of pre-existing therapy Samuel.Brown{at}hsc.utah.edu Samuel M. Brown	The authors, commendably, present a study designed to answer a clinically relevant question of whether two expensive therapies are better than one when the individual components appear to be separately efficacious. Unfortunately the authors failed to consider the extent to which clinical practice had already outstripped the evidence. They report that as many as 63.6% of tiotropium-placebo patients (the control group) were taking long-acting beta-agonists (LABAs) usually in combination with inhaled corticosteroids (ICS) at the time of enrollment, and perhaps 25% more were taking ICS without LABAs. In an important sense this control group thus represented a trial of the withdrawal of LABAs and/or ICS, a question which is distinct from the proposed clinical question. The observed 40% dropout rate may well reflect this withdrawal of therapy, as clinical deterioration resulting from withdrawal of therapy has been demonstrated,[1-2] though in the case of the present study spirometric parameters did not clearly worsen. We should not be surprised that sensitivity analysis appears to favor the addition of LABA/ICS therapy to tiotropium, but the extent to which this is confounded by withdrawal effects is uncertain. Though not definitive, an analysis of patients not taking LABA/ICS at baseline could perhaps give a sense for the sample size required to evaluate this effect. Though such a study would be expensive, the clinical question would probably be better answered by enrolling patients at the time that their treating physician would ordinarily consider additional therapy. Unfortunately, the current study was not designed to accurately assess the question posed. [1] Wouters EF, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005 Jun;60(6):480-7. [2]Campbell M, et al. Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med 2005; 99: 1511-1520. Conflict of Interest: None declared
Editor's reply to Dr. Porat 30 April 2007
Harold C. Sox, M.D. Annals of Internal Medicine Send rapid response to journal: Re: Editor's reply to Dr. Porat hsox{at}mail.acponline.org Harold C. Sox	I am replying to Dr. Porat’s letter about editorialists with conflicts of interest related to tiotropium. I commission all of the editorials for Annals, and I try very hard to identify authors who do not have financial relationships that readers might construe as creating a conflict of interest. I ask potential authors, nearly always in writing, to tell me if they have any such financial relationships before they start work on the editorial and warn them I might withdraw the invitation after learning of these relationships (as I have done many times). I raised this issue with the authors of both of the editorials that involved tiotropium, in the earlier case in a telephone conversation and more recently in the letter of invitation to write the editorial. In neither case, did I receive any indication that they had conflicts until we published their disclosure statement. We agree with our correspondent that our readers deserve editorials that they can read without being concerned about the possibility of commercial bias. We do have a policy, and we work hard to enforce the policy, but our procedures failed us in these two instances. We will develop better administrative procedures to assure ourselves that editorialists don’t have conflicts. Harold C. Sox, M.D. Editor Conflict of Interest: None declared
Conflicts of Interest 27 April 2007
Gil Porat, M.D. Colorado Springs Health Partners Send rapid response to journal: Re: Conflicts of Interest poratgil{at}hotmail.com Gil Porat	Annals of Internal Medicine published two editorials regarding tiotropium in the past two years (the first one was 6 September 2005 | Volume 143 Issue 5 | Pages 386-387). Both editorials have been done by physicians that have recieved money and also have grants pending from the pharmaceutical company that sells that drug for well over $100 a month. Both editorials, in my opinion, contain more favorable opinions about the benefits of the drug than the data warrants. Does Annals really think these types of editorials are the best way to analyze studies in which almost all the authors also have been paid consultants for the drug manufacturer? I think you can do better.
Inhaled Corticosteroid in COPD: safety vs efficacy 2 April 2007
Akashdeep Singh, MD, DM Christian Medical College and Hospital Send rapid response to journal: Re: Inhaled Corticosteroid in COPD: safety vs efficacy drsinghakashdeep{at}gmail.com Akashdeep Singh	Chronic obstructive pulmonary disease (COPD) is a disease characterized by progressive and mostly irreversible airflow limitation. While inhaled corticosteroids have a well established role in the treatment of asthma, and have become first-line therapy for patients with persistent disease, their place in the treatment of COPD is less clear. Inhaled corticosteroids are prescribed to as many as 50 percent of patients with stable COPD.1 Airway inflammation in COPD is different from that seen in asthma, characterized by predominant neutrophils and relatively fewer eosinophils, and this inflammatory response is relatively resistant to treatment with corticosteroids. 2 Several trials evaluating the effect of ICS on the outcomes in COPD have found no beneficial effect on disease progression as measured by decline in FEV1.3 A meta-analysis of various trials of ICS in COPD, reported a reduction in exacerbations of COPD with the use of inhaled corticosteroids 4 The recently completed TORCH study 5 which examined the potential benefit of inhaled corticosteroids and long-acting beta-agonists in reducing COPD mortality, reported a 19% three-year rate of pneumonia in patients receiving fluticasone 1000mcg per day, either alone or as part of a combination therapy, corresponding to a significant 1.6-fold increase over placebo. Besides increased risk of pneumonia other adverse systemic effects of the ICS are as follows: hypothalamic-pituitary-adrenal axis suppression, bone mineral density, vertical growth, and ocular toxicity (including subcapsular cataract and glaucoma).6 The adverse effect of inhaled corticosteroids needs to be considered when prescribing these medications to patients with COPD. References 1. Van Andel AE, Reisner C, Menjoge SS, et al.: Analysis of inhaled corticosteroid and oral theophylline use among patients with stable COPD from 1987 to 1995. Chest 1999, 115:703–707. 2. Fabbri LM, Romagnoli M, Corbetta L, et al.: Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003, 167:418–424. 3. Soriano JB, Sin DD, Zhang X, Camp PG, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM, Connett JE, Petersson S, Postma DS, Szafranski W, Vestbo J A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo.Chest. 2007 Mar;131(3):682-9. 4. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;113:59-65. 5. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease. N Engl J Med. 2007 Feb 22;356(8):775-89 6. Irwin RS, Richardson ND. Side effects with inhaled corticosteroids . the physician.s perception. Chest 2006;130(1 Suppl):41S-53S. Conflict of Interest: None declared