darexaban and Stroke

Anticoagulant therapy, known as warfarin, has been underused despite its marked benefit from embolic prevention. The intricate maintenance has made physicians constrained the use of warfarin for the many decades. Facing the 21(st) century, several new anticoagulants which inhibit single coagulant factor, such as activated factor X (Xa) or activated factor II (thrombin), has been developed. We now have selective thrombin inhibitor, dabigatran, already rolled out in clinical practice around the world. Among these drugs, four new Xa inhibitors are in final developing stage. This article reviewed the current status of new Xa inhibitors. Rivaroxaban leads the other Xa inhibitors in distribution. The phase III clinical study called ROCKET AF study had been completed and recently published. Statistical non-inferiority was clearly established compared to regular warfarin therapy. The Japanese rolled J-ROCKET AF study with 1,000 patients and the usage of reduced dose of rivaroxaban has made a similar outcome and safety end points compared to the initial ROCKET AF study. ARISTOTLE study, a phase III clinical study of apixaban has also been finished this year and will be presented soon. A phase III study of using edoxaban, a Japanese manufactured Xa inhibitor, named ENGAGE AF-TIMI 48 will be completed by next year. Darexaban, another Japan-made Xa inhibitor is in its preparation of phase III trial following favorable results of its late phase II study (OPAL-2). Having every trial with its favorable outcome, multiple alternatives of Xa inhibitors will be out in practice in no distant future. In addition, we must be aware to have a deliberate evaluation for each result, even pharmacological profiles of each Xa inhibitors with a 12 hour half-life period shows similarity, the difference in twice-daily dosing with once a day, or the difference in severity of patients' atrial fibrillation risk factor each trial contains might affect the results of phase III trials.

Topics: Anticoagulants; Atrial Fibrillation; Azepines; Benzamides; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes

Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa.. To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF).. In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability.. A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity.. In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Azepines; Benzamides; Biomarkers; Double-Blind Method; Down-Regulation; Drug Administration Schedule; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Male; Middle Aged; Risk Factors; Stroke; Time Factors; Treatment Outcome; Warfarin

To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS).. In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia.. Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13-4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose-response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity.. Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT00994292.

Topics: Acute Coronary Syndrome; Administration, Oral; Azepines; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Risk Factors; Secondary Prevention; Stroke; Thromboembolism; Treatment Outcome