John R Manderville , BScPh
Dault and others1 retrospectively examined discharge medications for patients who had been admitted to hospital for acute exacerbation of chronic obstructive pulmonary disease (COPD). Their primary objective was to determine the proportion of admissions for which the combination of long-acting ß 2 agonist, tiotropium, and an inhaled corticosteroid was prescribed. This so-called triple therapy is recommended in the Canadian COPD guidelines for patients with moderate to severe COPD and a history of recurrent exacerbations (one or more exacerbations per year, on average, for 2 consecutive years).2 Presumably, however, some of the patients in the chart review published by Dault and others1 were presenting with their first exacerbation of COPD. Thus, for a significant number of study participants, the prescription of triple therapy might not have been appropriate.
In the Canadian COPD guidelines,2 the use of triple therapy in patients with moderate to severe COPD and a history of recurrent exacerbations is designated as having level 1A evidence. As alluded to by Dault and others,1 the basis for this 1A level of evidence was the Canadian Optimal Therapy of COPD Trial,3 which showed no significant reduction in the proportion of patients experiencing an exacerbation with triple therapy relative to tiotropium monotherapy (the primary end point). As pointed out by Suissa and others,4 the results of the Optimal trial may have been influenced by the withdrawal of inhaled corticosteroids. In other words, patients who were receiving inhaled corticosteroids at the time of randomization and who were assigned to receive placebo would have experienced withdrawal from the regimen of inhaled steroids, with the possibility of a deleterious outcome, as has been demonstrated previously.5,6
Triple therapy is expensive, a factor that should be taken into account during selection of a therapeutic regimen for these patients. It has been my experience that maximal COPD therapy is often routinely prescribed during admission for an acute exacerbation, with little attention paid to the appropriateness of the therapy or the patient’s ability to afford the medication after discharge.
Finally, triple therapy is not without its own inherent risks. For example, analysis of data from the TORCH trial yielded similar values for number needed to treat (in terms of reduction in hospital admissions) and number needed to harm (in terms of cases of pneumonia).7 This potential trade-off might be more favourable for a patient with a significant risk of recurrent exacerbation than for a patient presenting with a first exacerbation and no formal diagnosis of COPD.
1. Dault R, Dubé AI, Blais L, Boileau R, Larrivée P, Dumas ME, et al. Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care centre for exacerbation of their disease. Can J Hosp Pharm. 2012;65(5):373–9.
2. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk DD, Balter M, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update. Can Resp J. 2007;14 Suppl B: 5B–32B.
3. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al.; 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(8):545–55.
4. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Resp J. 2008;31(5):927–33.
5. O’Brien A, Russo-Magno P, Karki A, Hiranniramol S, Hardin M, Kaszuba M, et al. Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction. Am J Respir Crit Care Med. 2001;164(3):365–71.
6. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med. 2002;166(10):1358–63.
7. Graber MA, Dachs R, Darby-Stewart A. Fluticasone or salmeterol alone vs. combination therapy for COPD. Am Fam Physician. 2008;77(5):586–8.
Competing interests: None declared.
Marie-France Beauchesne , PharmD , Robert Boileau , MD
In response to Mr Manderville’s letter, we would like to point out that the recommendation in the Canadian guidelines for chronic obstructive pulmonary disease (COPD) regarding use of the combination of a long-acting anticholinergic, a long-acting ß 2 agonist, and an inhaled corticosteroid (so-called “triple therapy”) is applicable for all levels of exacerbation severity, including mild exacerbations treated at home.1 Our study2 focused on severe COPD exacerbations leading to hospital admission, and the mean number of admissions for an acute exacerbation of COPD in the previous year was about one per patient.
We agree that triple therapy should be prescribed for patients with COPD who are at significant risk of recurrent exacerbation, and we consider that our patients fell into that category, since having one hospital admission for COPD significantly increases the risk of readmission3 and future exacerbation.4 Although the Optimal trial did not show a significant reduction in total COPD exacerbations (i.e., all levels of severity), it did show a significant reduction in the risk of exacerbations leading to hospital admission, as a secondary end point.5 The TORCH trial showed an increase in the absolute number of pneumonia cases among patients receiving inhaled corticosteroid therapy, but there was no associated increase in the risk of mortality, and there was a lower risk of hospitalization in the group treated with long-acting ß 2 agonist and inhaled corticosteroid relative to placebo.6
Finally, we agree that the cost of the medication should be taken into consideration, but overall, the reduction in rate of hospital admission and improvement in quality of life may outweigh this cost.
1. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk DD, Balter M, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease – 2007 update. Can Respir J. 2007;14 Suppl B:5B–32B.
2. Dault R, Dubé AI, Blais L, Boileau R, Larrivée P, Dumas ME, et al. Management of chronic obstructive pulmonary disease in patients admitted to a tertiary care centre for exacerbation of their disease. Can J Hosp Pharm. 2012; 65(5):373–9.
3. Maselli DJ, Müllerova H, Locantore NW, Vestbo J, Hurst JR, Wedzicha JA, et al. Risk factors and mortality associated with hospitalized chronic obstructive pulmonary disease (COPD) exacerbations during the 3-year follow-up in the evaluation of COPD longitudinally to identify predictive surrogate endpoints (ECLIPSE) cohort [abstract]. Am J Respir Crit Care Med. 2011;183:A5374.
4. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, et al.; 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.
5. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al.; 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(8):545–55.
6. Calverley PMA, 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(8):775–89.
Competing interests: Dr. Beauchesne has received grant funding for related work from GlaxoSmithKline, as well as speaker fees from GlaxoSmithKline and AstraZeneca. Dr. Boileau has received grant funding for related work from GlaxoSmithKline; consultancy fees from GlaxoSmithKline, Nycomed, Merck, and Novartis; and speaker fees from GlaxoSmithKline, Boehringer-Ingelheim, and Pfizer.
Canadian Journal of Hospital Pharmacy , VOLUME 66 , NUMBER 1 , January-February 2013