Correspondence Phosphodiesterase Inhibitors in Chronic Obstructive Pulmonary Disease

Author disclosures are available with the text of this letter at

Yuji Oba, M.D. University of Missouri Columbia, Missouri

To the Editor:

In response to the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for chronic obstructive pulmonary disease (COPD) (1), I believe that the place and role of phosphodiesterase inhibitors (PDEIs) in the current armamentarium of COPD treatments are still at the center of debate. A recent systematic review found that although roflumilast, a selective PDEI, did improve lung function, it did not improve the mortality rate or health-related quality of life over placebo. Roflumilast significantly reduced moderate exacerbations but not severe exacerbations (2). Discontinuation of treatment due to adverse events and overall incidence of adverse events were significantly more common with roflumilast than placebo. In a safety data pool that included a total of 12,054 patients, the incidence of atrial fibrillation was significantly more common with roflumilast than placebo. Suicidality was also more common with roflumilast as compared with placebo (0.08% vs. 0%) (2). It should be noted that an advisory panel of outside experts opposed the Food and Drug Administration’s approval of roflumilast by a 10-to-5 vote. The advisory committee felt that a small improvement in lung function did not outweigh its significant side effects, which primarily consisted of gastrointestinal and psychiatric problems, including suicidal behavior, which led to increased withdrawal from clinical studies. Roflumilast was approved by the Food and Drug Administration after its indication was made more restrictive and a warning about the psychiatric side effects was added to the drug label (2). The recommended dosage of roflumilast is 500 mg once daily, and the cost of 30 days of maintenance treatment, according to the average wholesale price listings, is $207, which is comparable to those of maintenance inhaled therapies. It is very unlikely that roflumilast would be more cost effective than other maintenance inhaled therapies such as a long-acting muscarinic antagonist or a long-acting b-agonist plus inhaled corticosteroid combination, because roflumilast has not been shown to reduce hospitalizations, which are known to have the greatest impact on cost effectiveness in COPD management besides the acquisition costs of medications (3). Theophylline, a nonselective PDEI, can be toxic, and monitoring of drug levels is necessary, but it has been shown to improve respiratory symptoms, gas exchange, lung function, and respiratory muscle function in patients with COPD (4). Theophylline also improves a quality-of-life measure in one study (5), which has not been shown with roflumilast. The use of theophylline was also associated with a reduction in COPD exacerbations in a large observational study (6). In metaanalyses, the improvement in FEV1 was greater with theophylline than with roflumilast (100 vs. 52 ml) (2, 7). The place and role of roflumilast in COPD management are currently unclear. Roflumilast may not be preferred over theophylline for the reasons mentioned above. Postmarketing safety surveillance, an efficacy trial with the background therapy of an inhaled corticosteroid plus long-acting b agonist combination, and a head-to-head trial with theophylline are warranted to further investigate the risk–benefit ratio before its wider use.

References 1. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187:347–365. 2. Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis 2013;7:13–24. 3. Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic evaluation of COPD. Chest 2000;118:1278–1285. 4. Murciano D, Auclair MH, Pariente R, Aubier M. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989;320:1521–1525. 5. Guyatt GH, Townsend M, Pugsley SO, Keller JL, Short HD, Taylor DW, Newhouse MT. Bronchodilators in chronic air-flow limitation. Effects on airway function, exercise capacity, and quality of life. Am Rev Respir Dis 1987;135:1069–1074. 6. Cyr MC, Beauchesne MF, Lemière C, Blais L. Effect of theophylline on the rate of moderate to severe exacerbations among patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol 2008;65:40–50. 7. Ram FS, Jones PW, Castro AA, De Brito JA, Atallah AN, Lacasse Y, Mazzini R, Goldstein R, Cendon S. Oral theophylline for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002;(4):CD003902. Copyright ª 2013 by the American Thoracic Society

GOLD Executive Summary To the Editor:

I read the recent GOLD Executive Summary (1) with misgivings. As someone who trained under Charles Fletcher in the 1950s, I find it a step backward to grade the severity of chronic obstructive pulmonary disease (COPD) solely by the FEV1. COPD consists of two (or more) separate diseases, chronic bronchitis and emphysema. Each of these has its own pathophysiology and therefore management. To lump them together is misleading. The Definition and Overview states that COPD is preventable. This is true, but why not simply say that most is caused by smoking? The Definition and Overview also states that COPD is treatable. Well, perhaps. Chronic bronchitis is, but emphysema is not, except possibly by lung volume reduction surgery or transplantation. Lumping the diseases together under the heading “treatable” is an invitation to the pharmaceutical industry to recommend bronchodilators in every patient with COPD, irrespective of whether they have reversible airway obstruction. This is regrettable. Author disclosures are available with the text of this letter at

John B. West, M.D., Ph.D., D.Sc. University of California, San Diego La Jolla, California Reference 1. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy

Phosphodiesterase inhibitors in chronic obstructive pulmonary disease.

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