First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS Trial

Abstract

See also Rajagopal V, Bhatt DL. Factor Xa inhibitors in acute coronary syndromes: moving from mythology to reality. This issue, pp 436-8.Summary. Background: Unfractionated heparin is widely used in patients with non-ST-elevation acute coronary syndromes but has important limitations. Anticoagulants with predictable kinetics and anticoagulant effects, better efficacy, and greater safety are needed. Objective: To investigate the efficacy and safety of a direct, selective factor Xa inhibitor, DX-9065a (Daiichi Pharmaceuticals LTD, Inc.) compared with heparin, in patients with non-ST-elevation acute coronary syndromes. Patients and methods: Patients (n ¼ 402) from the USA, Canada, and Japan were randomized to blinded, weight-adjusted heparin, low-dose DX-9065a, or high-dose DX-9065a. Results The primary efficacy endpoint of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST-segment monitoring occurred in 33.6%, 34.3%, and 31.3% of patients assigned to heparin, low-dose DX-9065a, and high-dose DX-9065a (P ¼ 0.91 for heparin vs. combined DX-9065a). The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P ¼ 0.125 for heparin vs. high-dose DX-9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients. Higher concentrations of DX-9065a were associated with a lower likelihood of ischemic events (P ¼ 0.03) and a non-significant tendency toward a higher likelihood of major bleeding (P ¼ 0.32). Conclusions: In this small phase II trial, there was a non-significant tendency toward a reduction in ischemic events and bleeding with DX-9065a compared with heparin in patients with acute coronary syndromes. The absence of an effect on ST-monitor ischemia warrants further investigation. These data provide the rationale for adequately powered studies of DX-9065a in acute coronary syndromes or percutaneous intervention.

Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D‐Homophenylalanine Analogues as P3 Residue: Part 2

“…For comparison, we used the fXa inhibitor DX-9065a, which has reached clinical phase II development. [11] However, a drawback observed for these peptidic inhibitors is their fast elimination from the circulation of rats after intravenous inhibitor treatment, although for inhibitors 27, 31, and 34 a slightly improved half-life was found compared to the lead structure 3.…”

First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention

“…Anticoagulants used for PCI increase the risk of bleeding, particularly at femoral access sites. [2][3][4][5][6][7] An unmet need in current practice is an anticoagulant and administration strategy that optimizes efficacy and safety.…”

Novel Anticoagulant Therapy: Principle and Practice

“…DX-9065a was the first of a class of small, synthesized, selective direct FXa inhibitors to undergo phase-II clinical trials in arterial thrombosis (38,39). Efforts to develop orally available selective FXa inhibitors for VTE and prevention of stroke in AF patients are underway (see Table 5.1).…”