- Email: [email protected]
Triple therapy vs. dual bronchodilator therapy for chronic obstructive pulmonary disease: Is it worth the cost?
respiratory investigation 53 (2015) 173–175
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Letter to the Editor
Triple therapy vs. dual bronchodilator therapy for chronic obstructive pulmonary disease: Is it worth the cost? To the Editor, Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease, characterized by airflow limitation, for which inhaled bronchodilators and inhaled corticosteroids (ICS) play an essential role in disease control [1]. The long-acting muscarinic antagonist (LAMA) and the long-acting beta agonist (LABA) are regarded as first-line medications for patients with COPD; dual-bronchodilator therapy consisting of LAMA and LABA is believed to be a good treatment option for advanced cases [1]. Current guidelines also recommend a triple therapy for further advanced cases, which adds ICS to dual-bronchodilator therapy, particularly for patients at a high risk for exacerbation [1,2]. Some researchers, however, have strongly opposed the use of ICS in patients with COPD [3]. The merits and demerits of ICS include providing no benefit for all-cause mortality, no reduction in the rate of forced expiratory volume in one second (FEV1) decline, only a slight reduction in exacerbating factors, and an increased risk for the development of pneumonia [4,5]. Recently, Price et al. reported results from an analysis of a real-life prescribing pattern in a UK primary care setting [6]. While the combination of LAMA, LABA, and ICS was prescribed for as many as 23.2% of patients with COPD, the combination of LAMA and LABA was prescribed in only 0.8% of cases [6]. Our increasing concern is whether the therapeutic benefit gained by adding ICS to the dual-bronchodilator therapy actually overcomes the risk of adverse effects and the increased cost of triple therapy [7–10], as the cost of ICS is roughly 1000–4000 Japanese Yen or 10–40 US dollars per month depending on the medication, dosage, and place of prescription. To date, studies that have directly compared the dualbronchodilator therapy and the triple therapy have been limited, both in number and scope [4,5]. In 2011, Karner et al. conducted a meta-analysis to compare the dualbronchodilator therapy and the triple therapy [7], which eventually found and included only a study by Aaron et al.
[8]. Thus, we decided to conduct an updated systematic review and a meta-analysis to compare these two treatments. We searched randomized controlled trials that compared the dual-bronchodilator therapy and the triple therapy, with a follow-up period of more than 1 year. The trials had to evaluate at least one or more of the outcomes concerned (Fig. 1). Among 94 candidate studies found in PubMed, the Cochrane library, and the Web Of Science, we could include only two studies: The Canadian Optimal Therapy of COPD Trial (OPTIMAL trial), and the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management study (WISDOM study) [8,9]. A fixed and a random model was used for an outcome that had an I2o50% or I2 Z50%, respectively. The generic inverse variance method and Parmar's method were used when appropriate. Our analysis found no difference in all-cause mortality, all-cause admission, exacerbation, adverse effect, and serious adverse effect between the dual-bronchodilator arm and the triple therapy arm. The triple therapy was slightly associated with favorable impacts on both the FEV1 and the St. George Respiratory Questionnaire (SGRQ) total score in the two studies, although the observed difference did not reach the minimum clinically important difference in either (i.e., 50 ml for FEV1 and four points for the total SGRQ score [Fig. 1]) [11,12]. Unfortunately, we could not meta-analyze the data for FEV1 and SGRQ due to a deficiency in the data format, and our current meta-analysis was limited by the small number of included studies. In conclusion, the existing head-to-head data are not sufficient to support adding ICS to the dual-bronchodilator therapy for COPD.
Financial statement No support in the form of grants, gifts, equipment, and/or drugs was provided.
http://dx.doi.org/10.1016/j.resinv.2015.01.006 2212-5345/& 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
174
Letter to the Editor / respiratory investigation 53 (2015) 173–175
Fig. 1 – Forrest plots comparing the triple therapy and the dual-bronchodilator therapy for 1 year. Filled circles for FEV1 and SGRQ do not indicate a 95% CI. This figure was made by modifying an originally exported figure by RevMan 5.3 (Cochrane Collaboration, Oxford, UK) as appropriate.
Letter to the Editor / respiratory investigation 53 (2015) 173 –175
Conflict of interest [5]
T. Kaneko received grant and lecture fee from GlaxoSmithKline, Astellas, AstraZeneca, and Boehringer Ingelheim during the last three years. Nobuyuki Horita, MDn, Takeshi Kaneko, MD Department of Pulmonology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan E-mail addresses: [email protected] (N. Horita), [email protected] (T. Kaneko) 30 January 2015
r e f e r e n c e s
[1] Global Initiative for Chronic Obstructive Lung Disease 2014. Global strategy for diagnosis, management, and prevention of COPD. Available from: 〈http://www.goldcopd.org/〉; 2014 [accessed 21.12.14]. [2] COPD guideline for diagnosis and treatment, 4th ed. Tokyo Japan: Japanese Respiratory Society; 2013 (Japanese). [3] Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009;34:13–6. [4] Drummond MB, Dasenbrook EC, Pitz MW, et al. Inhaled corticosteroids in patients with stable chronic obstructive
n
Corresponding author. Tel.: þ81 45 787 2630; fax: þ81 45 786 3444.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
175
pulmonary disease: a systematic review and meta-analysis. J Am Med Assoc 2008;300:2407–16. Yang IA, Clarke MS, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;7:CD002991. Price D, West D, Brusselle G, et al. Management of COPD in the UK primary-care setting: an analysis of real-life prescribing patterns. Int J Chron Obstruct Pulmon Dis 2014;9:889–904. Karner C, Cates CJ. The effect of adding inhaled corticosteroids to tiotropium and long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011;9:CD009039. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasonesalmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146:545–55. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285–94. Najafzadeh M, Marra CA, Sadatsafavi M, et al. Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD. Thorax 2008;63:962–7. American Thoracic Society. Quality of life resource: minimal clinically significant difference. Available from: 〈http://qol. thoracic.org/sections/measurement-properties/minimalclinically-significant-difference.html〉 [accessed 15.01.15]. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J 2002;19(Suppl. 3):S398–404.
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Letter to the Editor
Triple therapy vs. dual bronchodilator therapy for chronic obstructive pulmonary disease: Is it worth the cost? To the Editor, Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease, characterized by airflow limitation, for which inhaled bronchodilators and inhaled corticosteroids (ICS) play an essential role in disease control [1]. The long-acting muscarinic antagonist (LAMA) and the long-acting beta agonist (LABA) are regarded as first-line medications for patients with COPD; dual-bronchodilator therapy consisting of LAMA and LABA is believed to be a good treatment option for advanced cases [1]. Current guidelines also recommend a triple therapy for further advanced cases, which adds ICS to dual-bronchodilator therapy, particularly for patients at a high risk for exacerbation [1,2]. Some researchers, however, have strongly opposed the use of ICS in patients with COPD [3]. The merits and demerits of ICS include providing no benefit for all-cause mortality, no reduction in the rate of forced expiratory volume in one second (FEV1) decline, only a slight reduction in exacerbating factors, and an increased risk for the development of pneumonia [4,5]. Recently, Price et al. reported results from an analysis of a real-life prescribing pattern in a UK primary care setting [6]. While the combination of LAMA, LABA, and ICS was prescribed for as many as 23.2% of patients with COPD, the combination of LAMA and LABA was prescribed in only 0.8% of cases [6]. Our increasing concern is whether the therapeutic benefit gained by adding ICS to the dual-bronchodilator therapy actually overcomes the risk of adverse effects and the increased cost of triple therapy [7–10], as the cost of ICS is roughly 1000–4000 Japanese Yen or 10–40 US dollars per month depending on the medication, dosage, and place of prescription. To date, studies that have directly compared the dualbronchodilator therapy and the triple therapy have been limited, both in number and scope [4,5]. In 2011, Karner et al. conducted a meta-analysis to compare the dualbronchodilator therapy and the triple therapy [7], which eventually found and included only a study by Aaron et al.
[8]. Thus, we decided to conduct an updated systematic review and a meta-analysis to compare these two treatments. We searched randomized controlled trials that compared the dual-bronchodilator therapy and the triple therapy, with a follow-up period of more than 1 year. The trials had to evaluate at least one or more of the outcomes concerned (Fig. 1). Among 94 candidate studies found in PubMed, the Cochrane library, and the Web Of Science, we could include only two studies: The Canadian Optimal Therapy of COPD Trial (OPTIMAL trial), and the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management study (WISDOM study) [8,9]. A fixed and a random model was used for an outcome that had an I2o50% or I2 Z50%, respectively. The generic inverse variance method and Parmar's method were used when appropriate. Our analysis found no difference in all-cause mortality, all-cause admission, exacerbation, adverse effect, and serious adverse effect between the dual-bronchodilator arm and the triple therapy arm. The triple therapy was slightly associated with favorable impacts on both the FEV1 and the St. George Respiratory Questionnaire (SGRQ) total score in the two studies, although the observed difference did not reach the minimum clinically important difference in either (i.e., 50 ml for FEV1 and four points for the total SGRQ score [Fig. 1]) [11,12]. Unfortunately, we could not meta-analyze the data for FEV1 and SGRQ due to a deficiency in the data format, and our current meta-analysis was limited by the small number of included studies. In conclusion, the existing head-to-head data are not sufficient to support adding ICS to the dual-bronchodilator therapy for COPD.
Financial statement No support in the form of grants, gifts, equipment, and/or drugs was provided.
http://dx.doi.org/10.1016/j.resinv.2015.01.006 2212-5345/& 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
174
Letter to the Editor / respiratory investigation 53 (2015) 173–175
Fig. 1 – Forrest plots comparing the triple therapy and the dual-bronchodilator therapy for 1 year. Filled circles for FEV1 and SGRQ do not indicate a 95% CI. This figure was made by modifying an originally exported figure by RevMan 5.3 (Cochrane Collaboration, Oxford, UK) as appropriate.
Letter to the Editor / respiratory investigation 53 (2015) 173 –175
Conflict of interest [5]
T. Kaneko received grant and lecture fee from GlaxoSmithKline, Astellas, AstraZeneca, and Boehringer Ingelheim during the last three years. Nobuyuki Horita, MDn, Takeshi Kaneko, MD Department of Pulmonology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan E-mail addresses: [email protected] (N. Horita), [email protected] (T. Kaneko) 30 January 2015
r e f e r e n c e s
[1] Global Initiative for Chronic Obstructive Lung Disease 2014. Global strategy for diagnosis, management, and prevention of COPD. Available from: 〈http://www.goldcopd.org/〉; 2014 [accessed 21.12.14]. [2] COPD guideline for diagnosis and treatment, 4th ed. Tokyo Japan: Japanese Respiratory Society; 2013 (Japanese). [3] Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009;34:13–6. [4] Drummond MB, Dasenbrook EC, Pitz MW, et al. Inhaled corticosteroids in patients with stable chronic obstructive
n
Corresponding author. Tel.: þ81 45 787 2630; fax: þ81 45 786 3444.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
175
pulmonary disease: a systematic review and meta-analysis. J Am Med Assoc 2008;300:2407–16. Yang IA, Clarke MS, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;7:CD002991. Price D, West D, Brusselle G, et al. Management of COPD in the UK primary-care setting: an analysis of real-life prescribing patterns. Int J Chron Obstruct Pulmon Dis 2014;9:889–904. Karner C, Cates CJ. The effect of adding inhaled corticosteroids to tiotropium and long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011;9:CD009039. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasonesalmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146:545–55. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285–94. Najafzadeh M, Marra CA, Sadatsafavi M, et al. Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD. Thorax 2008;63:962–7. American Thoracic Society. Quality of life resource: minimal clinically significant difference. Available from: 〈http://qol. thoracic.org/sections/measurement-properties/minimalclinically-significant-difference.html〉 [accessed 15.01.15]. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J 2002;19(Suppl. 3):S398–404.