Efficacy and safety of phosphodiesterase 4 inhibitors in patients with asthma: A systematic review and meta‐analysis

Abstract

Phosphodiesterase 4 (PDE4) inhibitors are a novel medication approved for airway inflammatory diseases including chronic obstructive pulmonary disease. Their role and application in asthma are controversial and not defined. A comprehensive search was performed in major databases using the keywords: 'phosphodiesterase 4 inhibitor' or 'roflumilast' and 'asthma'. Placebo-controlled trials reporting lung function, airway hyperresponsiveness by direct challenge, asthma control and exacerbations, and adverse events were included. Random or fixed-effects models were used to calculate odds ratios (OR) and mean differences between the two treatment groups. Statistical analyses were conducted using Mann-Whitney U-tests and Cochrane systematic review software, Review Manager. Seventeen studies were included in the systematic review, of which 14 studies were included in the metaanalysis. Except for significant statistical heterogeneity in pre-and post-challenge predicted percentage of forced expiratory volume in 1 s (FEV 1 %; I 2 = 72%, χ 2 = 3.35, P = 0.06), there was no heterogeneity in outcome measures. Roflumilast (500 μg) significantly improved FEV 1 (mean difference: 0.05, 95% CI: 0.01-0.09, Z = 2.50, P = 0.01), peak expiratory flow, asthma control and exacerbations, but showed variable effects on airway responsiveness to methacholine and a 20% fall in FEV 1 .Of note, PDE4 inhibitors were accompanied with significantly higher adverse events such as headache (OR: 3.99, 95% CI: 1.65-9.66, Z = 3.07, P = 0.002) and nausea (OR: 5.53, 95% CI: 1.38-22.17, Z = 2.41, P = 0.02). In patients with mild asthma, oral PDE4 inhibitors can be considered as an alternative treatment to regular bronchodilators and inhaled controllers.

Management of asthma COPD overlap

“…98e100 In asthma, roflumilast has shown consistent improvements of lung function in a meta-analysis of 14 trials. 101 Moreover, roflumilast is generally well-tolerated in asthma, and the most frequently reported side effects include diarrhea, nausea, and headache. 101,102 No data exist on the effects of roflumilast in ACO patients.…”

“…101 Moreover, roflumilast is generally well-tolerated in asthma, and the most frequently reported side effects include diarrhea, nausea, and headache. 101,102 No data exist on the effects of roflumilast in ACO patients. Interestingly, COPD patients with higher counts of eosinophils had greater reduction in exacerbation rates.…”

Contemporary Concise Review 2018: Asthma and chronic obstructive pulmonary disease

“…Luo et al . performed a systematic review of PDE4 inhibitors in asthma, reporting that 500 mg of roflumilast leads to modest but significant improvements in airway function and asthma control, and reductions in asthma exacerbations . PDE4 inhibitors were mostly well tolerated, with common adverse effects being headache, dizziness and nausea.…”

Classical and Emerging Therapies against Chronic Obstructive Pulmonary Disease

“…The inhibition of PDE-4 increases intracellular cAMP and reduces the activation of inflammatory cells, and PDE-4 inhibitors are a novel medication approved for COPD. [ 24 ] Currently, several selective PDE-4 inhibitors are being developed for the treatment of COPD, such as roflumilast, cilomilast, arofylline, AWD-12-281, and SCH-351591. Roflumilast was associated with a prominent ( P < 0.01) decrease in neutrophil and eosinophil levels and serum levels of pro-inflammatory cytokines.…”