Oral, Direct Factor Xa Inhibitor, BAY 59-7939, Given Once Daily in Patients Undergoing Total Hip Replacement - ODIXa-HIP

Description:

The goal of the trial was to evaluate treatment with rivaroxaban, an oral, direct Factor Xa inhibitor, compared with enoxaparin for prevention of thromboembolic disorders among patients undergoing elective total hip replacement.

Study Design

Study Design:

Patients Enrolled: 873
Mean Follow Up: Up to 60 days
Mean Patient Age: Mean age 65 years
Female: 59

Patient Populations:

Men age ≥18 years and postmenopausal women scheduled for elective, primary total hip replacement surgery

Exclusions:

DVT, PE, myocardial infarction, transient ischemic attack, or ischemic stroke, or intracerebral, intraocular, or gastrointestinal bleeding during prior 6 months; use of medications that might have affected the study outcome (e.g., other anticoagulants, platelet-aggregation inhibitors, or any other drug influencing coagulation); or severe hypertension, severe liver or renal impairment, medical conditions that may interfere with the study, or body weight <45 kg; and abuse of alcohol or drugs

Primary Endpoints:

Composite of any DVT (proximal and/or distal); nonfatal, symptomatic, objectively confirmed PE; and all-cause death

Secondary Endpoints:

1) Major VTE, defined as the composite of the incidence of proximal DVT; symptomatic, objectively confirmed PE; and VTE-related death; 2) symptomatic VTE.

Drug/Procedures Used:

Patients were randomized in a double-blind manner to one of five once daily oral doses of rivaroxaban (5 mg, n = 128; 10 mg, n = 142; 20 mg, n = 139; 30 mg, n = 142; 40 mg, n = 137) or subcutaneous enoxaparin (40 mg, n = 157). Rivaroxaban was given 6-8 hours after surgery and once daily thereafter for 5-9 days; enoxaparin was given the night before surgery, 6-8 hours after wound closure, and once daily thereafter for 5-9 days. Study drug was administered in a double-blind, double-dummy manner.

Principal Findings:

Baseline characteristics were well-balanced among the groups, with a mean duration of surgery of approximately 87 minutes. Twenty-nine percent of randomized patients (255/873) were excluded from the primary efficacy per-protocol analysis, 110 because bilateral venography was not performed and 83 for whom the venograms were inadequate for interpretation.

The primary efficacy composite endpoint of any deep vein thrombosis (DVT), pulmonary embolism (PE), or death occurred in 14.9%, 10.6%, 8.5%, 13.5%, and 6.4% of patients receiving rivaroxaban 5, 10, 20, 30, and 40 mg, respectively, and in 25.2% of patients receiving enoxaparin (p = 0.0852 for trend in dose response). There were no deaths or PEs in the per-protocol population, so all of the events in the composite endpoint were DVTs. Proximal venous thromboembolism (VTE) demonstrated a dose response trend, with rates of 8.5%, 2.7%, 0.9%, 1.9%, and 1.1% for rivaroxaban 5, 10, 20, 30, and 40 mg, respectively, and 2.8% of patients receiving enoxaparin (p = 0.0072 for trend in dose response).

Major postoperative bleeding, the primary safety endpoint, occurred in 2.3%, 0.7%, 4.3%, 4.9%, and 5.1% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban and in 1.9% of the enoxaparin group (p = 0.0391 for trend in dose response). All of the major bleeding episodes were at the surgical site. Minor bleeding events were reported in 3.9%, 3.5%, 4.3%, 5.6%, 10.2%, and 3.8%, respectively. Abnormal liver function tests in the rivaroxaban groups ranged from 3.0% to 6.2% compared with 7.1% with enoxaparin.

Interpretation:

Among patients undergoing elective total hip replacement, treatment with rivaroxaban appeared efficacious for prevention of the endpoint of DVT compared with enoxaparin. A dose-dependent increase in major bleeding was observed with rivaroxaban.

Rivaroxaban, an oral, direct Factor Xa inhibitor, does not require coagulation monitoring and has a relative short half-life of 5-9 hours. Based on the data in the present study and other studies in the orthopedic setting, the larger RECORD trial is underway, evaluating rivaroxaban 10 mg once daily for prevention of DVT and PE in orthopedic surgery. Other studies evaluating this agent in the setting of atrial fibrillation and chronic oral therapy following acute coronary syndrome are also ongoing.

References:

Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006;114:2374-81.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents, Angiography, Nuclear Imaging

Keywords: Arthroplasty, Replacement, Hip, Acute Coronary Syndrome, Morpholines, Pulmonary Embolism, Thiophenes, Venous Thromboembolism, Orthopedics, Liver Function Tests, Half-Life, Enoxaparin, Phlebography, Atrial Fibrillation, Venous Thrombosis, Factor Xa


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