Felix S.F. Ram, PhD, Clinical Pharmacologist
What are the efficacy and safety of oral phosphodiesterase 4 (PDE4) inhibitors in patients with stable chronic obstructive pulmonary disease (COPD)?
Included studies compared oral PDE4 inhibitors (roflumilast or cilomilast) with placebo in patients > 18 years of age with COPD (FEV1 after bronchodilation < 80% of predicted value, ratio of FEV1 to FVC ≤ 70%). Exclusion criteria included single-dose trials, patients with acute exacerbations, and patients requiring mechanical ventilation. Primary outcomes were lung function (e.g., FEV1) and quality of life (QOL) (St. George's Respiratory Questionnaire [SGRQ] total score, lower scores = better QOL); other outcomes included exacerbations and adverse events.
Cochrane Airways Group Specialized Register, US Food and Drug Administration Web site, and US National Institutes of Health clinical trials registry were searched to August 2010 for randomized controlled trials (RCTs). Reference lists were hand-searched, and authors and drug companies were contacted. 23 RCTs (n = 15 668) met the selection criteria: 9 assessed roflumilast (n = 9211), and 14 assessed cilomilast (n = 6457). 7 roflumilast trials reported adequate allocation concealment, and 6 described method of blinding; no cilomilast trials reported adequate concealment or described method of blinding.
Meta-analysis showed that PDE4 inhibitors improved FEV1 (21 comparisons, n = 14 307, mean difference in change in FEV1 46 mL, 95% CI 39 to 52) and QOL (11 comparisons, n = 7898, mean difference in change in SGRQ total score −1.04, CI −1.66 to −0.41) and reduced exacerbations (Table) compared with placebo. Overall, PDE4 inhibitors increased risk for adverse events, specifically diarrhea, nausea, vomiting, and headache (Table). Drug-specific meta-analyses showed that cilomilast, 15 mg twice daily, increased vomiting (relative risk increase [RRI] 283%, CI 169 to 445), dyspepsia (RRI 197%, CI 121 to 299), and abdominal pain (RRI 86%, CI 50 to 132); roflumilast, 500 µg/d, increased weight loss (RRI 326%, CI 216 to 474).
In patients with stable chronic obstructive pulmonary disease, oral phosphodiesterase 4 inhibitors reduce exacerbations but increase adverse events.
Oral phosphodiesterase 4 (PDE4) inhibitors vs placebo in stable chronic obstructive pulmonary disease (COPD)*
*Abbreviations defined in Glossary. RRR, RRI, NNT, NNH, and CI calculated from data in article using a fixed-effect model.
†Includes acute exacerbations, gastrointestinal symptoms (diarrhea, nausea, vomiting, dyspepsia, abdominal pain, weight loss), influenza-like symptoms, and upper respiratory tract infections.
Felix S.F. Ram. Review: Oral phosphodiesterase 4 inhibitors reduce exacerbations but increase adverse events in COPD. Ann Intern Med. 2011;155:JC3–2. doi: 10.7326/0003-4819-155-6-201109200-02002
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Published: Ann Intern Med. 2011;155(6):JC3-2.
Chronic Obstructive Airway Disease, Pulmonary/Critical Care.
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