Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension; a pilot efficacy trial

Yoshihiro Fukumoto, Norikazu Yamada, Hiromi Matsubara, Minori Mizoguchi, Kazuaki Uchino, Atsushi Yao, Yasuki Kihara, Mitsuhiro Kawano, Hiroshi Watanabe, Yutaka Takeda, Takeshi Adachi, Shinobu Osanai, Nobuhiro Tanabe, Teruo Inoue, Akihiro Kubo, Yuri Ota, Koichiro Fukuda, Takeshi Nakano, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)

Abstract

Background: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. Methods and Results: 23 PAH patients were treated with either placebo (10/2 females/males, 51±16 years, idio-pathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47±14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hy-droxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. Conclusions: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynam-ics in patients with PAH.

Original languageEnglish
Pages (from-to)2619-2625
Number of pages7
JournalCirculation Journal
Volume77
Issue number10
DOIs
Publication statusPublished - 2013

Keywords

  • Pulmonary arterial hypertension
  • Rho-kinase inhibitor
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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