Can roflumilast, a phosphodiesterase-4 inhibitor, improve clinical outcomes in patients with moderate-to-severe chronic obstructive pulmonary disease? A meta-analysis

Abstract

Background: Effects of roflumilast on lung function, symptoms, acute exacerbation and adverse events in patients with chronic obstructive pulmonary disease (COPD) are controversial. We aimed to further clarify the efficacy and safety of roflumilast in treatment of moderate-to-severe COPD.

Methods: From 1946 to November 2015, we searched the Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials, ISI Web of Science and American College of Physician using "roflumilast" and "chronic obstructive pulmonary disease" or "COPD". Randomized controlled trials that reported forced expiratory volume in one second (FEV1), forced vital capacity (FVC), transition dyspnea index (TDI), St George's Respiratory Questionnaire (SGRQ), and incidence of COPD exacerbations and adverse events were eligible. We conducted the heterogeneities test and sensitivity analysis, and random-effects or fixed-effects model was applied to calculate risk ratio (RR) and mean difference (MD) for dichotomous and continuous data respectively. Cochrane systematic review software, Review Manager (RevMan), was used to test the hypothesis by Mann-Whitney U-test.

Results: Thirteen trials with a total of 14,563 patients were pooled in our final studies. Except for SGRQ (I (2) = 63 %, χ (2) = 1.71, P = 0.07) and adverse events (I (2) = 94 %, χ (2) = 0.03, P < 0.001), we did not find statistical heterogeneity in outcome measures. The pooled MD of pre- and post-bronchodilator FEV1 was 54.60 (95 % confidence interval (CI) 46.02 ~ 63.18) and 57.86 (95 % CI 49.80 ~ 65.91), and both showed significant improvement in patients with roflumilast (z = 12.47, P <0.001; z = 14.07, P < 0.001), so did in FVC (MD 90.37, 95 % CI 73.95 ~ 106.78, z = 10.79, P < 0.001). Significant alleviation of TDI (MD 0.30, 95 % CI 0.14 ~ 0.46, z = 3.67, P < 0.001) and decrease of acute exacerbation (RR 0.86, 95 % CI 0.81 ~ 0.91, z = 5.54, P < 0.001) were also identified in treatment of roflumilast, but without significant difference in SGRQ (MD -1.30, 95 % CI -3.16 ~ 0.56, z = 1.37, P = 0.17). Moreover, roflumilast significantly increased the incidence of adverse events compared with placebo (RR 1.31, 95 % CI 1.16 ~ 1.47, z = 4.32, P < 0.001).

Conclusions: Roflumilast can be considered as an alternative therapy in selective patients with moderate-to-severe COPD.

Fig. 1

Study flow diagram. ACP, American College of Physician; CENTRAL, Cochrane Central Register of Controlled Trials; COPD, chronic obstructive pulmonary disease; RCT, randomized controlled trial

Fig. 2

Risk of bias summary

Fig. 3

Funnel plot. FEV₁, forced expiratory volume in one second

Fig. 4

Effects of roflumilast vs. placebo on prebronchodilator FEV₁. CI, confidence interval; FEV₁, forced expiratory volume in one second; SD, standard derivation

Fig. 5

Effects of roflumilast vs. placebo on postbronchodilator FEV₁. CI, confidence interval; FEV₁, forced expiratory volume in one second; SD, standard derivation

Fig. 6

Effects of roflumilast vs. placebo on post-bronchodilator FVC, FEV₆ and FEF_25-75. CI, confidence interval; FEF_25-75, forced expiratory flow between 25 and 75 % of the vital capacity; FEV₆, force expiratory volume in six seconds; FVC, forced vital capacity; SD, standard derivation

Fig. 7

Effect of roflumilast vs. placebo on TDI. CI, confidence interval; SD, standard derivation; TDI, transition dyspnea index

Fig. 8

Effect of roflumilast vs. placebo on SGRQ. CI, confidence interval; SD, standard derivation; SGRQ, St George’s Respiratory Questionnaire

Fig. 9

Effect of roflumilast vs. placebo on incidence of COPD exacerbation (number per patient per year). CI, confidence interval; COPD, chronic obstructive pulmonary disease; SD, standard derivation

Fig. 10

Effect of roflumilast vs. placebo on incidence of COPD exacerbation (patients per total). CI, confidence interval; COPD, chronic obstructive pulmonary disease; M.-H., Mantel-Haenszel

Fig. 11

Effect of roflumilast vs. placebo on incidence of adverse events. CI, confidence interval; M.-H., Mantel-Haenszel