PURPOSE:To investigate the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in the treatment of pulmonary arterial hypertension.
METHODS:In this 16 week, double-blind, placebo-controlled study, 405 patients with idiopathic PAH or PAH associated with connective tissue disease, anorexigen use, HIV, atrial septal defect, or surgical repair of congenital left-to-right shunt were randomized to placebo or tadalafil (2.5, 10, 20 or 40 mg) orally once daily as monotherapy or as add on therapy to bosentan.. Demographics, clinical data, and health related quality of life (HRQoL) data were collected at baseline. Clinical and HRQoL data were again collected at weeks 4, 8, 12 and 16. Cardiopulmonary hemodynamics were conducted in a subset of patients (n=93).
RESULTS:Tadalafil, 40mg, increased 6-minute-walk-distance (6MWD) compared to placebo (+41.1m vs +9.2m) (p<0.001). Changes in WHO functional class and Borg dypsnea score did not differ significantly compared with placebo. Tadalafil 40 mg delayed the time to clinical worsening compared to placebo (p<0.05, relative risk reduction 68% less than placebo). Compared with placebo, improvements were observed in 40 mg tadalafil-treated patients in six of the eight SF-36 domains (p<001), the EuroQol (EQ-5D) US and UK index scores, and for the visual analog scale (VAS) (all p<0.05). Tadalafil 40mg increased cardiac output (0.6 L/min) and reduced pulmonary artery pressures (-4.3mmHg) and pulmonary vascular resistance (-209dyn.s/cm5) compared to baseline (p<0.05). The most common treatment related adverse event reported with tadalafil was headache (32% vs 15% with placebo). Discontinuation due to adverse events was low (tadalafil 11% vs placebo 16%). Of the 405 patients randomized, 189 (47%) were not taking concomitant bosentan. In these patients, tadalafil 40mg increased (p<0.01) 6MWD compared to placebo (+42.2m vs -2.9m).
CONCLUSION:In patients with PAH, tadalafil 40 mg, taken once daily, was well tolerated and significantly improved exercise capacity, quality of life, and delayed time to clinical worsening.
CLINICAL IMPLICATIONS:Treatment with tadalafil may provide an oral once daily therapy to PAH patients that can be combined with bosentan therapy.
DISCLOSURE:Robyn Barst, Consultant fee, speaker bureau, advisory committee, etc. paid consultant for Eli Lilly and Co.; No Product/Research Disclosure Information