Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked Venous Thromboembolism

Inclusion Criteria

• Man or woman
• Age ≥ 18 years
• Objectively-confirmed provoked DVT and/or PE
• Treated for at least 3 months with standard therapeutic anticoagulant therapy
• Has not suffered symptomatic recurrence during prior anticoagulant therapy
• Outpatient follow-up at BWH
• AND have at least one of the following persistent provoking VTE risk factors:
• Persistent immobility (defined as paralysis, other inability to ambulate freely, bed-bound, wheelchair-bound)
• Obesity (defined as BMI ≥ 30 kg/m2)
• Heart failure (systolic, diastolic, or combined)
• Chronic lung disease (COPD, asthma, interstitial lung disease)
• Chronic kidney disease (nephrotic/nephritic syndrome, renal dysfunction with creatinine ≤ 2.5 mg/dL)
• Chronic inflammatory/autoimmune disorder (inflammatory arthritis, vasculitis, inflammatory bowel disease, chronic infection)
• Atherosclerotic cardiovascular disease (coronary, cerebrovascular, or peripheral artery disease) (up to 35% in each study group may have atherosclerotic cardiovascular disease as a qualifying persistent risk factor)
• NOTE: Eligible patients will be allowed to have multiple risk factors, and there will not be a limit as to how many of the above risk factors a subject may have. In addition, we will place no limit on the number of patients included with multiple risk factors. A study population with multiple risk factors is highly representative of the provoked VTE population and will provide the greatest generalizability of the study results to real-world clinical practice. Including patients with single and multiple persistent provoking risk factors will also facilitate enrollment. As noted, there is clinical and research equipoise regarding whether patients with a single or multiple persistent provoking VTE risk factors should receive extended duration thromboprophylaxis for secondary prevention.
• Willing to provide written informed consent

Exclusion Criteria

• Women who are pregnant or breastfeeding
• Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control (such as oral contraceptives, other hormonal contraceptives [vaginal products, skin patches, or implanted or injectable products], or mechanical products such as an intrauterine device or barrier methods [diaphragm, condoms, spermicides]) to avoid pregnancy for the entire study
• Active cancer within the past 5 years
• Contraindication to antithrombotic or antiplatelet therapy
• Requirement for ongoing anticoagulant therapy, dual antiplatelet therapy, P2Y12 inhibition, or aspirin at a dose of > 81 mg daily
• Hemoglobin level 2.5 mg/dL, an ALT or AST level > 2 times the upper limit of the normal range, or a total bilirubin level > 1.5 times the upper limit of the normal range
• History of bleeding diathesis or have had recent active bleeding
• Active severe hepatobiliary disease
• More than 6 months that have elapsed without taking an anticoagulant or low-dose aspirin

o NOTE: The risk of recurrent VTE following cessation of anticoagulation rises slowly over the first 3-6 months (26). After this initial period, the cumulative risk of recurrent VTE steepens. Using a limit of no greater than 6 months of interruption in anticoagulation before potential reinitiation of anticoagulation as part of this trial will safely facilitate enrollment as opposed to restricting the population to no greater than 3 months of interruption.

• Known severe thrombophilia (any increased titer antiphospholipid antibody or positive lupus anticoagulant/DRVVT or deficiency of antithrombin, protein C, or protein S) which would indicate long-term full therapeutic anticoagulation with a vitamin K antagonist
• Life expectancy < 12 months or hospice care
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Receiving concurrent non-FDA-approved or investigational agents or