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Phase 2 study of TAK-442, an oral factor Xa inhibitor, in patients following acute coronary syndrome

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Issue: 2014: 111/6 (June) pp. 1007–1199
Pages: 1141-1152
Ahead of Print: 2014-03-27

Phase 2 study of TAK-442, an oral factor Xa inhibitor, in patients following acute coronary syndrome

Online Supplementary Material

S. Goldstein (1), E. R. Bates (2), D. L. Bhatt (3), C. Cao (4), D. Holmes (5), S. Kupfer (6), F. Martinez (7), J. Spaeder (4), J. I. Weitz (8), Z. Ye (4), F. Zannad (9), on behalf of the AXIOM investigators

(1) Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan, USA; (2) Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA; (3) VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA; (4) Takeda Global Research & Development, Inc., Statistics, Deerfield, Illinois, USA; (5) Mayo Clinic, Department of Cardiovascular Diseases, Rochester, Minnesota, USA; (6) Takeda Global Research & Development Center, Inc., Clinical Science, Deerfield, Illinois, USA; (7) Cordoba National University, Cordoba, Argentina; (8) McMaster University and Thrombosis & Atherosclerosis Research Institute, Hamilton, Ontario, Canada; (9) Henri Poincaré University of Nancy, Nancy, France


thrombosis, Acute coronary syndrome, Oral factor Xa inhibitors


TAK-442 is an oral direct factor Xa inhibitor. We sought to determine the dose-dependent effect of TAK-442 on major bleeding when added to standard treatment in stabilised patients with acute coronary syndrome (ACS). In this phase II double-blind study, 2,753 ACS patients were randomised to TAK-442 or placebo in addition to usual care using a three-stage adaptive design. Patients were randomised to placebo in all stages, but doses of TAK-442 escalated from 10 mg BID, 20 mg twice-daily (BID), or 40 mg once-daily (QD) in stage 1; to 40 mg BID, 80 mg QD, or 80 mg BID in stage 2; and to 160 mg QD or 120 mg BID in stage 3. Study drug was started 36 hours after emergent treatment of ACS and within seven days of admission, and continued for 24 weeks. The primary endpoint was incidence of TIMI (thrombolysis in myocardial infarction) major bleeding. TIMI major bleeding incidence was low, but higher with the pooled TAK-442 doses than with placebo (17 [0.9%] vs 4 [0.5%]; p=0.47), although the difference was neither significant nor dose-dependent. However, a dose response was evident when using the modified ISTH scale. The incidence of cardiovascular events was similar among TAK-442 dose groups and placebo. When administered over a wide range of doses after an ACS event, TAK-442 treatment did not result in a dose-dependent increase in TIMI major bleeding, but increased bleeding was observed when a more sensitive bleeding scale was used. There was no evidence for efficacy.

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