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      Potential treatment benefits and safety of roflumilast in COPD: a systematic review and meta-analysis

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          Current evidence suggests that roflumilast is efficacious in treating COPD, especially in preventing the acute exacerbation of COPD.


          This study was designed to evaluate the clinical effects and safety of roflumilast in the treatment of stable COPD using randomized clinical trial (RCT) data.


          A MEDLINE, EMBASE, and Cochrane Controlled Trials Register search was carried out. RCTs reporting the treatment effects of roflumilast in COPD were identified. Relevant data were extracted and a meta-analysis was performed.


          A total of nine articles and 13 RCT studies were identified. Overall, 29.1% of the subjects in the roflumilast group showed evidence of exacerbation. The corresponding figure was 32.2% in the placebo group. According to pooled analysis, the use of roflumilast reduced COPD exacerbations in comparison to placebo (odds ratio [OR] =0.82, 95% confidence interval [CI] =0.75–0.9). The quality of life and spirometry were improved. For patients receiving baseline pre-bronchodilators, their average forced expiratory volume in the first second showed evidence of change when they took roflumilast (64.88 mL; 95% CI =54.09–75.66). Those who took placebo showed no evidence of change. Similar result was observed in patients receiving baseline (54.49 mL; 95% CI =44.04–64.94). As for the safety of roflumilast treatment, the overall cumulative incidence of adverse drug reaction was 54.2% in the roflumilast group and 48.2% in the placebo group (OR =1.36, 95% CI =1.13–1.65). The adverse effects included diarrhea, headache, nausea, weight loss, and insomnia.


          The efficacy of roflumilast in the prevention of acute exacerbation of COPD is obvious. Roflumilast is proved to be able to improve spirometry of COPD patients. The adverse drug reaction did not increase significantly in the roflumilast group compared with the control group. COPD patients can benefit from roflumilast therapy. However, our results are limited by the cohort design of the selected studies and the degree of heterogeneity among them; hence, more randomized trials are needed to further support this conclusion.

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          Roflumilast--an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial.

          Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD. This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting. 1411 patients with COPD were randomly assigned roflumilast 250 microg (n=576), roflumilast 500 microg (n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat. 1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the roflumilast 250 microg group, and 124 (22%) from the roflumilast 500 microg group. Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 microg (by 74 mL [SD 18]) and roflumilast 500 microg (by 97 mL [18]) compared with placebo (p<0.0001). Improvement in health-related quality of life was greater with roflumilast 250 microg (-3.4 units [0.6]) and roflumilast 500 microg (-3.5 units [0.6]) than with placebo (-1.8 units [0.8]), although the differences between treatment groups were not significant. The mean numbers of exacerbations per patient were 1.13 (2.37), 1.03 (2.33), and 0.75 (1.89) with placebo, roflumilast 250 microg, and roflumilast 500 microg, respectively. Most adverse events were mild to moderate in intensity and resolved during the study. Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.
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            Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD

            Background As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further. Methods The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset. Results The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%). Conclusions This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment. Trials registration identifiers: NCT00076089 and NCT00430729.
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              Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease.

              The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown. To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD. We conducted a randomized, placebo-controlled, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 microg roflumilast and 753 receiving placebo once daily. We recorded post-bronchodilator FEV1, exacerbation rate, St. George's Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks (p=0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p=0.024). The St. George's Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration. In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                30 June 2016
                : 11
                : 1477-1483
                [1 ]Department of Respiration, Tianjin Hospital of ITCWM (Tianjin Nankai Hospital)
                [2 ]Department of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China
                Author notes
                Correspondence: Lianfang Yuan, Department of Respiration, Tianjin Hospital of ITCWM (Tianjin Nankai Hospital), No 6, Changjiang Road, Nankai District, Tianjin 300100, People’s Republic of China, Email alane527@
                © 2016 Yuan et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.


                Respiratory medicine

                meta-analysis, copd, roflumilast, efficacy, spirometry, adverse drug reaction


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