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

Chronic obstructive pulmonary disease (COPD), a common disease with a prevalence reported to be 7.8 to 19.7 %, is characterized by persistent and progressive airflow limitation as well as frequent exacerbations [1, 2]. Global Burden of Disease (GBD) Study projected that COPD will become the third leading cause of death worldwide by 2020, and it was estimated as the direct underlying cause of 7.8 % of all deaths and 27 % of deaths related with smoking [3, 4].

Acute exacerbation of COPD is defined as respiratory symptoms deterioration and medication alteration, and it has been demonstrated to be associated with detriment of quality of life, decline of lung function and increase of mortality [1, 5‐7]. Hurst and his colleagues analyzed 2138 patients with COPD, and they found a trend of more exacerbations as the severity of COPD increased, that was 22, 33 and 47 % in stage 2 (moderate), stage 3 (severe) and stage 4 (very severe), respectively [8]. Therefore, effective treatment and management in patients with moderate-to-severe COPD is paramount to decrease exacerbations, and improve lung function, quality of life and clinical outcomes.

Phosphodiesterase-4 (PDE4) is a vital enzyme in the metabolism of cyclic adenosine monophosphate (cAMP) and inhibition of PDE4 can inactivate immune and inflammatory cells via increase cAMP [9]. It is recommended by the Global Initiative for Chronic Obstructive Lung Disease (GLOD) guideline that a combination of PDE4 inhibitor and long-acting bronchodilator can be considered as an alternative treatment in patients with severe COPD due to the effective improvement of lung functions [1]. Roflumilast is a novel selective inhibitor of PDE4, which functions mainly by its active metabolite, roflumilast N-oxide, via the conversion by cytochrome P450 (CYP) 3A4 and 1A2 isozymes [10]. Rabe and his colleagues conducted a randomized controlled trial (RCT) in 1157 patients with moderate-to-severe COPD, and they found that roflumilast could significantly improve post-bronchodilator forced expiratory volume in one second (FEV₁) (0.097 ± 0.018, P < 0.0001) and post-bronchodilator forced vital capacity (FVC) (0.114 ± 0.031, P = 0.0002), and decrease incidence of acute exacerbations (28 % vs. 35 %, P = 0.0114) compared with placebo [11], which were further demonstrated by a subsequent meta-analysis of seven trials with 9675 patients but without improving health-related quality of life by St George’s Respiratory Questionnaire (SGRQ) (mean difference (MD) −0.70, 95 % confidence interval (CI) −2.65 ~ 1.26, P = 0.49) or decreasing mortality rate (risk ratio (RR) 0.90, 95 % CI 0.63 ~ 1.29, P = 0.56) [12].

However, Fabbri and his colleagues randomly assigned 743 patients with moderate-to-severe COPD into roflumilast plus tiotropium and tiotropium groups and they reported a significant improvement in Shortness of Breath Questionnaire (SOBQ) (MD −2.6, 95 % CI −4.5 ~ −0.8, P = 0.0051) in roflumilast plus tiotropium [13]. Moreover, a recent placebo-controlled randomized study, which investigated the additional treatment of roflumilast in moderate-to-severe COPD with chronic bronchitis, did not reveal any significant changes in lung function, quality of life, or exercise tolerance between rolumilast and placebo [14]. Therefore, the accurate roles of roflumilast in the treatment of patients with COPD still remain controversial.

In this study, we conducted a meta-analysis of all published RCTs with the aim of updating and further clarifying the efficacy and safety of roflumilast in patients with COPD.

Our study protocol was approved by the Institutional Ethical Committee for Clinical and Biomedical Research of West China Hospital (Sichuan, China), so did in each enrolled trial by the corresponding institutional review board. All participants provided written informed consent.

Initially 120 records were identified, of which 118 were extracted from electronic databases and 2 were extracted from reference lists review. (Fig. 1) By screening the titles and abstracts, 99 studies were discarded for duplication (n = 52), not RCTs (n = 40), patients without COPD (n = 6), and intervention treatment without roflumilast (n = 1). We searched the full-text articles for the remaining 21 studies, and eventually 13 trials [11, 13, 14, 16‐25] were enrolled in our final analysis due to 5 studies not reporting eligible outcomes and 3 studies being retrospective studies.

In our meta-analysis, we found that roflumilast could significantly improve lung functions, including pre- and post-bronchodilator FEV₁, FVC, FEV₆ and FEF_25-75, alleviate dyspnea symptoms (TDI), and decrease incidence of acute exacerbation, but could not improve quality of life (SGRQ) or decrease early acute exacerbation onset, even with a significant increase of risk of adverse events.

Persistent airflow limitation is the hallmark of COPD, which is also used to evaluate the severity and treatment responses by GOLD guideline [1]. FEV₁ is the most common spirometric parameter to assess airflow limitation, and the post-bronchodilator FEV₁ independently divided patients with COPD into 4 stages of severity, and classified them into 4 groups with symptoms and acute exacerbations. Therefore, FEV₁ improvement is usually rendered as an important factor to identify the treatment efficacy of a new drug for COPD. Previous meta-analyses have reported that roflumilast significantly improved lung function through pre-bronchodilator FEV₁ compared with placebo, but they did not evaluate the post-bronchodilator FEV₁ nor consider the onset time of roflumilast in improving FEV₁ [12, 26, 27]. Our study not only confirmed the effect of roflumilast on improving both pre- and post-bronchodilator FEV₁, post-bronchodilator FEV₆ and FEF_25-75, but also further demonstrated that roflumilast could improve FEV₁ as early as 12 weeks and the improvement effect lasted for as long as 52 weeks afterward, which we think has important clinical insights because it can facilitate physicians to set up the optimal follow-up plan and determine the administration duration.

It is well known that FVC is a volumetric parameter, which represents lung volume change and is rarely used to assess treatment responses in patients with COPD. Recent years, however, Tashkin and his colleagues conducted a cohort study of 5,756 patients with moderate-to-severe COPD to examine acute bronchodilator responsiveness patterns in theses patients, and they found that mean improvements from baseline were 229 ml in FEV₁ and 407 ml in FVC, and approximately 49 % of patients with very severe COPD showed a volume response rather than a flow response to the bronchodilators [28], which also revealed the potential value of FVC alteration in evaluating treatment responses in patients with severe airflow limitation and failed to exhibit the requisite threshold increase in FEV₁. In our study, 6 studies reported the change of FVC from baseline and the final pooled analysis resulted in greater improvement of FVC in patients with roflumilast than placebo. However, we could not compare the mean change of FVC and FEV₁ or analyze the proportion of patients who responded to FVC and FEV₁ due to the insufficient data reported. Therefore, future studies focusing on these issues were warranted.

Chronic and progressive dyspnea is one of the typical symptoms in patients with COPD, and is a major cause of disability and impaired quality of life [1]. In our pooled meta-analysis, we found a significant improvement of TDI but without decreasing SGRQ scores in patients with roflumilast compared with placebo. That is, roflumilast could relieve the symptom of dyspnea, but could not attenuate other symptoms including but not limited to cough, sputum, activity endurance, and daily life. As we know, TDI is an evaluative instrument to measure breathlessness related to activities of daily living, and a large of RCTs have demonstrated reliability and accuracy in the characteristics of TDI [29]; while SGRQ is a widely used questionnaire with documented comprehensive measures, and it is recommended that regular treatment for symptoms should be considered if a COPD patient with a symptom score equivalent to SGRQ score ≥ 25 [30‐32]. Thus, the different outcomes in the effects of roflumilast on TDI and SGRQ may due to the different content and aspects in each scoring system. However, interpretation of our results should be cautious because of the potential heterogeneity in SGRQ, and the difference of corresponding parts about dyspnea in SGRQ still remains unknown.

COPD exacerbation is an acute event, which can lead to the decline of lung functions and even be fatal to patients [1]. The three meta-analyses mentioned previously also demonstrated the significant decrease of acute exacerbation rate in treatment with roflumilast, but they again did not take the different time points into account when evaluated the effect of roflumilast on affecting incidence of acute exacerbation [12, 26, 27]. Our study illustrated that although roflumilast could significantly reduce the incidence of acute exacerbation, but we did not find such an effect before 24 weeks. Therefore, the improvement of lung function may be earlier than decrease of acute exacerbation, and a minimal treatment duration of 24 weeks might be optimal to achieve improvement of both lung functions and acute exacerbation, which was also explained by a recent RCT with negative effects in FEV₁ and acute exacerbation due to limited follow-up [14]. Nevertheless, we should notice the limited studies with relatively small samples and the various conditions conducted in different studies with different lengths, and further studies in evaluating acute exacerbation in 12 weeks are needed before a precise conclusion can be drawn.

It has long been recognized that weight loss, malnutrition and skeletal muscle dysfunction are common comorbidities in patients with COPD especially in later stage [33]. Based on the presently available studies, the mostly reported adverse events are diarrhea and weight loss. Our meta-analysis indeed showed a significant increase of adverse event in patients with roflumilast, which further demonstrated the conclusions by Yan and Chong [12, 27], but went contrary to the findings of Oba [26]. However, Rabe and his colleagues also perceived that most adverse events (>90 %) resolved or relieved during the course of the study [11]. Meanwhile, in our study, we also found that the incidence of adverse events between roflumilast and placebo was similar in 52 weeks even though the P value was on the borderline. As a result, administration of roflumilast should be cautious with consideration of the treatment benefits and detriments in patients with COPD comorbidities.

Limitations for our meta-analysis are as follows: First, the baseline demographics of patients and extent of airflow limitation in COPD were not identical among the enrolled trials, which may lead to selection biases. Second, potential heterogeneities existed in some outcomes such as post-bronchodilator FEV₆, SGRQ and incidence of adverse events, which may cause potential confusions to our results and conclusions. Third, the number of studies and patients for pre- and post-FEV₁ varied in different follow-up groups, especially in 12 weeks, which may also result in inaccurate conclusions. Finally, subgroup analysis of FVC by follow-up time points and comparison of improvement degrees and proportions between FVC and FEV₁ could not be achieved due to limited data and studies.

Roflumilast can be considered as an alternative therapy in selective patients with moderate-to-severe COPD due to the effect of lung function improvement, dyspnea alleviation and acute exacerbation decrease but increase of risk of adverse events. More large studies are needed, particularly with different follow-up and treatment duration, to further determine the role of roflumilast, including cost-effectiveness and time-to-survive, in patients with moderate-to-severe COPD.