Journal
EUROPEAN HEART JOURNAL
Volume 31, Issue 21, Pages 2601-2613Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehq320
Keywords
E5555; Atherothrombosis; Thrombin; PAR-1; Acute coronary syndrome; Coronary artery disease
Categories
Funding
- Eisai
- Eisai Co., Ltd, in Japan
- Eisai Product Creation Systems
- Astra Zeneca
- Bristol-Myers Squibb
- Ethicon
- Heartscape
- Sanofi-aventis
- The Medicines Company
- Pfizer
- Ono
- Otsuka
- Sankyo
- Daiichi
- Takeda
- Asteras
- Kowa
- Ministry of Health, Labour and Welfare (Japan)
- Astellas
- Banyu
- Bayer Yakuhin
- Boehringer Ingelheim
- Chugai
- Daiichi Sankyo
- Dainippon Sumitomo
- Get Bros
- Guidant Japan
- Japan Lifeline
- Kyowa Hakko Kirin
- Mitsubishi Tanabe
- Mochida
- Nihon Kohden
- Nihon Schering
- Novartis
- Pharmacia
- Sanwa Kagaku Kenkyusho
- Schering-Plough
- Sionogi
- Sumitomo
- Tanabe
- Teijin
- Toa Eiyo
- Japan Heart Foundation
- Smoking Research Foundation
- Eli Lilly
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Two multicentre, randomized, double-blind, placebo-controlled Phase II studies assessed the safety and efficacy of the oral protease-activated receptor 1 (PAR-1) antagonist E5555 in addition to standard therapy in Japanese patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD). Patients with ACS (n = 241) or high-risk CAD (n = 263) received E5555 (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). The incidence of TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and combined E5555 (atopaxar) groups (ACS: 6.6% placebo vs. 5.0% E5555; CAD: 1.5% placebo vs. 1.5% E5555). There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg E5555). There was a numerical increase in 'any' TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081). The rate of major cardiovascular adverse events in the combined E5555 group was not different from placebo (ACS: 6.6% placebo vs. 5.0% E5555, P = 0.73; CAD: 4.5% placebo vs. 1.0% E5555, P = 0.066). There was a statistically significant dose-dependent increase in liver function abnormalities and QTcF with E5555. At trough dosing levels in both populations, mean inhibition of platelet aggregation was > 90% with 100 and 200 mg E5555, and 20-60% with 50 mg E5555. E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition. There was a significant dose-dependent increase in liver function abnormalities and QTcF. Although further study is needed, PAR-1 antagonism may have the potential to be a novel pathway for platelet inhibition to add on to the current standard of care therapy.
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