Severe chronic obstructive pulmonary disease is associated with periodic exacerbations of respiratory symptoms that need aggressive treatment and often necessitate hospital admission.1, 2 These exacerbations worsen patient health status, accelerate decline in lung function, and increase mortality.1, 2 The two alternative recommended pharmacological treatments to prevent exacerbations are either an inhaled longacting muscarinic antagonist alone, a fixed combination of an inhaled corticosteroid and longacting β2 agonist, or these two treatments combined.1 These therapies significantly reduce, but do not eliminate, chronic obstructive pulmonary disease exacerbations, especially those necessitating hospital admission, which is problematic for patients at risk of frequent or severe events.3, 4, 5 To increase the doses of longacting bronchodilators6 and inhaled corticosteroids is not a practical option because of the flat dose–response curve and raised risk of side-effects, especially pneumonia with inhaled corticosteroids.7, 8
Alternative approaches to prevent chronic obstructive pulmonary disease exacerbations have been investigated, including long-term macrolide therapy, which is effective but associated with the risks of side-effects and antibiotic resistance;9 statins, which are ineffective;10 and theophylline11 and acetylcysteine,12, 13 which produce inconsistent results. None of these studies have investigated whether or not treatment reduced exacerbations in severe chronic obstructive pulmonary disease not adequately controlled with the best available inhalation therapy with inhaled corticosteroid–longacting β2 agonist combinations or triple longacting muscarinic antagonist–inhaled corticosteroid–longacting β2 agonist therapy.
Research in context
Evidence before this study
We searched Medline for articles published in any language up until Jan 8, 2015, with the search terms “roflumilast” and “chronic obstructive pulmonary disease” but not “asthma” or “randomised trial”. Our final search was done on Jan 8, 2015. We identified 19 articles reporting randomised controlled trials. However, only five trials compared 1-year treatment with roflumilast versus placebo in more than 1000 patients with moderate-to-very-severe chronic obstructive pulmonary disease and included the assessment of lung function, symptoms, quality of life, and exacerbations. These five trials were reported in three original reports. Two replicate positive randomised clinical trials and the pooled analysis of two negative clinical trials showed a significant effect of roflumilast on moderate-to-severe exacerbations and lung function, especially in patients with severe-to-very-severe chronic obstructive pulmonary disease, symptoms of chronic bronchitis, and a risk of exacerbations. However, none of these trials included patients at high risk of exacerbations (>2 per year) while receiving the standard of care, ie inhaled corticosteroid–longacting β2 agonist combinations.
Added value of this study
Our findings show that roflumilast reduces moderate-to-severe exacerbations, especially those that lead to hospital admissions, and improves lung function in patients with severe chronic obstructive pulmonary disease with chronic bronchitis at risk of frequent exacerbations, even those receiving an inhaled corticosteroid–longacting β2 agonist combination or triple therapy with an inhaled corticosteroid–longacting β2 agonist combination plus tiotropium. To identify publications reporting the effects of any other drug in patients with severe to very severe chronic obstructive pulmonary disease, chronic bronchitis, and a high risk of exacerbations while being treated with an inhaled corticosteroid–longacting β2 agonist combination, we also searched Medline using the search terms “cilomilast”, “phosphodiesterase IV inhibitors”, “beclomethasone”, “fluticasone”, “budesonide”, “salmeterol”, “formoterol”, “theophylline”, “aminophylline”, “antibiotics”, “macrolides”, “infliximab”, “benralizumab”, “chronic bronchitis”, “emphysema”, and “randomised trial”. We did not find any studies that had been done in patients with these characteristics.
Implications of all the available evidence
Roflumilast is the only available oral anti-inflammatory drug that provides additional, clinically relevant benefits without unacceptable side-effects. Our findings should help to inform treatment choices for patients with severe to very severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of severe exacerbations even when they are already taking maximum doses of existing inhalation treatments.
Roflumilast is an oral phosphodiesterase-4 inhibitor with anti-inflammatory actions both in vitro and in vivo.14 It consistently improves lung function and reduces the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease, symptoms of chronic bronchitis, and a history of frequent exacerbations.15, 16, 17 The effect on exacerbations is maintained in patients treated with longacting β2 agonists, and is more pronounced in patients with frequent exacerbations.18 However, whether or not roflumilast can effectively reduce exacerbations when patients with chronic obstructive pulmonary disease use inhaled corticosteroid–longacting β2 agonist combinations as their maintenance therapy, which is the regimen recommended at present by evidence-based guidelines,1, 2 is not known.
We postulated that roflumilast would be effective in patients with severe chronic obstructive pulmonary disease who are at risk for exacerbations and whose disease is not adequately controlled with inhaled corticosteroid–longacting β2 agonist combinations or triple longacting muscarinic antagonist–inhaled corticosteroid–longacting β2 agonist therapy. Additionally, we wanted to understand the adverse event profile in this subset of patients to help establish the risk:benefit balance of treatment. To achieve these aims, we undertook the REACT (Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy) study.19