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Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis - ODIXa-DVT
Description:
The goal of the trial was to evaluate treatment with rivaroxaban, an oral, direct factor Xa inhibitor, compared with enoxaparin for treatment of proximal deep-vein thrombosis (DVT) among patients with acute symptomatic DVT.
Study Design
Study Design:
Patients Enrolled: 613
Mean Follow Up: 114 days
Mean Patient Age: Mean age, 59 years
Female: 39
Patient Populations:
Symptomatic acute thrombosis of the popliteal or more proximal veins, confirmed by CCUS; age ≥18 years; no symptoms of PE; had not received a VKA; and had received ≤36 hours of treatment with unfractionated heparin or a low molecular weight heparin
Exclusions:
Cerebral ischemia; intracerebral bleeding or gastrointestinal bleeding within the past 6 months; neurosurgery within the past 4 weeks or other surgery within the past 10 days; an active peptic ulcer; a known bleeding disorder; prolonged international normalized ratio (INR) or activated partial thromboplastin time; and a platelet count <100 x 109/L; known brain metastasis; cytotoxic chemotherapy; life expectancy <6 months; body weight <45 kg; severe heart failure; uncontrolled severe hypertension (>200/100 mm Hg); creatinine clearance <30 ml/min or serum creatinine >1.5x the upper limit of normal; impaired liver function (transaminases >2 x ULN); a likelihood of reduced oral drug absorption; child-bearing potential without effective contraception; thrombolytic therapy or treatment with antiplatelet agents, nonsteroidal anti-inflammatory drugs with a half-life of >17 hours, or potent CYP3A4 inhibitors
Primary Endpoints:
• Improvement in thrombotic burden at mean of 21 days without confirmed symptomatic extension or recurrence of DVT, confirmed symptomatic PE, or VTE-related death.
• Improvement in thrombotic burden defined as a ≥4-point reduction in the thrombus score, as measured by CCUS examination.
Secondary Endpoints:
Improvement in thrombus score of ≥4 points as measured by CCUS examination and/or an improved perfusion lung scan on day 21, without deterioration in the other and without symptomatic recurrence of VTE; an improvement in CCUS examination score at 3 months; and the incidence of symptomatic and confirmed PE or DVT (recurrence or extension) during the 3 months of study therapy
Drug/Procedures Used:
Patients were randomized in a double-blind manner to one of four oral doses of rivaroxaban (10 mg BID, n = 119; 20 mg BID, n = 117; 30 mg BID, n = 121; 40 mg once daily, n = 126) or enoxaparin (1 mg/kg) followed by vitamin K antagonist (VKA) (n = 126). Patients underwent complete compression ultrasound (CCUS), which was performed at screening, 21 days, and 84 days.
Principal Findings:
The primary efficacy endpoint of improvement of ≥4 points in thrombus score in the absence of recurrent venous thromboembolism (VTE) and VTE-related death by 21 days occurred in 53.0%, 59.2%, 56.9%, and 43.8% of patients receiving rivaroxaban 10, 20, and 30 mg BID, and 40 mg OD, respectively, and in 45.9% of patients receiving enoxaparin with VKA (p = NS for trend in dose response). At 3 months, the endpoint had occurred in 71.0%, 71.4%, 73.4%, 68.8%, and 71.6%, respectively. Clinical events of VTE-related death, pulmonary embolism (PE), or recurrent DVT occurred in two patients each in the rivaroxaban 10, 20, and 30 mg BID groups, three patients in the 40 mg OD group, and one patient in the enoxaparin with VKA group. All-cause mortality was reported in 2.7% of the rivaroxaban groups and 0.8% of the enoxaparin with VKA group.
Major bleeding occurred in 1.7%, 1.7%, 3.3%, and 1.7% of patients receiving rivaroxaban 10, 20, and 30 mg BID and 40 mg OD, and none of the enoxaparin group (p = NS for trend in dose response). Minor bleeding events were reported in 3.4%, 7.7%, 9.1%, 9.9%, and 6.3%, respectively. There was no dose-response relationship observed in the rivaroxaban groups in abnormal liver function tests, which ranged from 1.9% to 4.3% in the rivaroxaban groups compared with 21.6% in the enoxaparin/VKA group.
Interpretation:
Among patients with acute symptomatic DVT, treatment with rivaroxaban was associated with similar rates of the primary endpoint of improvement of ≥4 points in thrombus score in the absence of recurrent VTE and VTE-related death compared with enoxaparin plus VKA. There was no apparent dose-dependent effect on the primary endpoint or in major bleeding with rivaroxaban.
The novel anticoagulant rivaroxaban, an oral, direct factor Xa inhibitor, does not require coagulation monitoring and has a relative short half-life. In the recent RECORD3 trial, a phase III study of 10 mg of rivaroxaban in patients undergoing total knee replacement surgery, DVT, and major VTE were reduced with rivaroxaban compared with enoxaparin, without an increase in bleeding or adverse events. Other studies evaluating this agent in the setting of atrial fibrillation and acute coronary syndrome are also ongoing. The authors suggest the lack of dose response in the present study may be due to a plateau in the dose range of 20 to 60 mg of rivaroxaban per day. Of note, the primary endpoint in the once daily dose of 40 mg rivaroxaban was somewhat lower than in the twice daily dose groups, suggesting a twice daily dose may be more efficacious for use of rivaroxaban as active therapy, while only a once daily dose may be needed in the prophylactic setting such as the RECORD3 trial.
References:
Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007;116:180-187.
Keywords: Vitamin K, Arthroplasty, Replacement, Knee, Acute Coronary Syndrome, Morpholines, Pulmonary Embolism, Thiophenes, Venous Thromboembolism, Peripheral Vascular Diseases, Liver Function Tests, Half-Life, Enoxaparin, Factor Xa
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