Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial

BACKGROUND: Phosphodiesterase-5 (PDE5) inhibitors improve exercise capacity and quality of life in patients with idiopathic pulmonary arterial hypertension. However, whether such beneficial effects take place in selected populations with chronic obstructive pulmonary disease (COPD) remains uncertain. We aimed to assess the effects of tadalafil--a PDE5 inhibitor--on exercise capacity and quality of life in patients with COPD and mild pulmonary hypertension. METHODS: We did a randomised, double-blind, parallel-group, placebo-controlled trial at three centres in Scotland, UK, between Sept 1, 2010, and Sept 1, 2012. Patients with moderate to severe COPD were randomly assigned (1:1), via centralised randomisation with a computer-generated sequence and block sizes of four, to receive daily tadalafil 10 mg or placebo for 12 weeks. Patients, study investigators, outcome assessors, and those administering drugs were masked to group allocation. The primary endpoint was the mean placebo-corrected difference between the baseline and final 6 min walk distance after 12 weeks. We measured change in quality of life at baseline, 8 weeks, and 12 weeks, with standardised questionnaires. Analysis was per protocol and by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01197469. FINDINGS: 120 patients were randomly assigned to receive tadalafil (n=60) or placebo (n=60), of whom 56 (93%) versus 57 (95%) completed the study. At 12 weeks the difference in 6 min walking distance between the tadalafil and placebo groups was 0·5 m (95% CI -11·6 to 12·5; p=0·937). We recorded no statistically significant changes in quality of life (between-group difference on the St George's Respiratory Questionnaire -2·64 95% CI -6·43 to 1·15; Research and Development version 1 short-form-36 4·08 -1·35 to 9·52; Minnesota Living with Heart Failure questionnaire -2·31 -7·06 to 2·45). 19 (32%) of 60 patients in the treatment group had dyspepsia; the severity of dyspepsia ranged from mild to severe, with four (21%) of 19 patients needing a proton-pump inhibitor. Five (8%) of 60 participants had dyspepsia in the placebo group. Headache was noted in 17 (28%) patients in the treatment group versus 5 (8%) in the placebo group, but was mild in all patients. Two (3%) patients in the treatment group had facial flushing, which resulted in one withdrawal. Other withdrawals within the tadalafil group happened after a transient ischaemic attack and two deaths (ruptured abdominal aortic aneurysm and pneumonia). INTERPRETATION: Tadalafil does not improve exercise capacity or quality of life despite exerting pulmonary vasodilation. FUNDING: Chief Scientist Office for Scotland.