Comparison of Oral Anticoagulants for Extended VEnous Thromboembolism

Determine if apixaban is superior to warfarin in the reduction of clinically relevant bleeding. Determine if rivaroxaban is superior to warfarin in the reduction of clinically relevant bleeding. Determine if apixaban is non-inferior to warfarin in the prevention of recurrent venous thromboembolism. Determine if rivaroxaban is non-inferior to warfarin in the prevention of recurrent venous thromboembolism. An exploratory comparison of apixaban versus rivaroxaban for the prevention of clinically relevant bleeding and recurrent Venous Thromboembolism (VTEs) as a secondary objective.

• Warfarin (Drug): Will be randomized to receive open label warfarin daily to achieve a target INR of 2-3
• Apixaban 2.5 MG (Drug): Will be randomized to receive open label apixaban of 2.5 mg twice daily
• Rivaroxaban 10 MG (Drug): Will be randomized to receive open label rivaroxaban of 10mg daily

Primary outcomes

• Number of Subjects With Clinically Relevant Bleeding Events [Randomization to 12 months]: Primary outcome of Clinically relevant bleeding (composite of major bleeding (MB) and/or clinically relevant non major bleeding (CRNMB))
• Number of Subjects With Recurrent Venous Thromboembolism (VTE) [Randomization to 12 months]: Primary efficacy outcome of recurrent VTE

Other outcomes

• Number of Subjects Experiencing Major Bleeding [Randomization to 12 months]: Major bleeding
• Number of Subjects Experiencing Clinically Relevant Non-major Bleeding [Randomization to 12 months]: Clinically relevant non-major bleeding
• Number of Subjects With Premature Termination of Study Medication [Randomization to 12 months]: Premature termination of study medication
• Number of Subjects Experiencing All-cause Mortality [Randomization to 12 months]: All cause mortality
• Number of Subjects Experiencing Vascular Events (Myocardial Infarction, Ischemic Stroke) [Randomization to 12 months]: MI, ischemic stroke, peripheral arterial embolism

Sex: All, ages: 18 Years to any

3.1 Inclusion Criteria

To be eligible for this trial, patients must meet all of the following criteria:

* Have confirmed acute, symptomatic, first lower extremity proximal DVT and/or PE that is NOT associated with a transient risk factor.
* Have completed an initial treatment course of oral anticoagulant therapy for 3-12 months and have a recommendation from their provider to continue anticoagulation indefinitely.
* Have the capacity to understand and sign an informed consent form.
* Be 18 years of age and older.
* Under the direct care of a healthcare provider for treatment of VTE for the length of time in the study.

3.2 Exclusion Criteria

If a patient meets any of the following criteria, he or she may not be enrolled in the study:

* Creatinine clearance (CrCl) < 30 mL/min as determined by Cockcroft-Gault formula documented within 3 months from date of consent
* Significant liver disease (Child-Pugh B or C)
* Concomitant use of medications that are strong P-glycoprotein or CYP3A4 inducers/inhibitors
* Another indication for chronic therapeutic-dose anticoagulation, such as atrial fibrillation (i.e., rivaroxaban, 10 mg daily, or apixaban, 2.5 mg twice daily, would not be appropriate therapy)
* A clinical indication for a specific anticoagulant regimen (e.g., warfarin with a target INR of 2-3 is recommended for patients with 'triple-positive' antiphospholipid syndrome).
* Life expectancy < 3 months
* Currently pregnant or breast feeding
* Unable / unwilling to pay for one (or more) of the treatment options
* Active Cancer defined as:

Diagnosed with cancer within the past 6 months; or Recurrent, regionally advanced or metastatic disease; Currently receiving treatment or have received any treatment for cancer during the 6 months prior to randomization; or A hematologic malignancy not in complete remission

• Unwilling / unlikely to agree to follow up

Participant flow

Outcome results

• Number of Subjects With Clinically Relevant Bleeding Events (Primary), Count of participants, Participants: Warfarin 0; Apixaban 0; Rivaroxaban 0
• Number of Subjects With Recurrent Venous Thromboembolism (VTE) (Primary), Count of participants, Participants: Warfarin 0; Apixaban 1; Rivaroxaban 0
• Number of Subjects Experiencing Major Bleeding (Other pre specified), Count of participants, Participants: Warfarin 0; Apixaban 0; Rivaroxaban 0
• Number of Subjects Experiencing Clinically Relevant Non-major Bleeding (Other pre specified), Count of participants, Participants: Warfarin 0; Apixaban 0; Rivaroxaban 0
• Number of Subjects With Premature Termination of Study Medication (Other pre specified), Count of participants, Participants: Warfarin 0; Apixaban 0; Rivaroxaban 0
• Number of Subjects Experiencing All-cause Mortality (Other pre specified), Count of participants, Participants: Warfarin 0; Apixaban 0; Rivaroxaban 0
• Number of Subjects Experiencing Vascular Events (Myocardial Infarction, Ischemic Stroke) (Other pre specified), Count of participants, Participants: Warfarin 1; Apixaban 0; Rivaroxaban 0

Adverse events

Time frame: Up to 9 months

• Statistical Analysis Plan (PDF, 2018-07-11)
• Study Protocol (PDF, 2018-09-21)
• Informed Consent Form (PDF, 2018-08-08)

• Thomas Ortel, MD, Principal investigator, Duke University