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

• Status: Recruiting
• Trial end date: 2023-06-30
• Target enrollment: 0
• Participant gender: All

Summary

Design: U.S.-based, single-center, randomized placebo-controlled trial.

Brief Treatment Description: Low-intensity apixaban (2.5mg twice daily) for extended-duration secondary prevention of VTE after initial treatment for provoked VTE.

Purpose: To establish the safety and efficacy of low-intensity apixaban versus placebo for extended prevention of recurrence after provoked VTE in patients with at least one persistent provoking factor.

Population: Outpatients with provoked VTE with at least one persistent provoking factor.

Enrollment: 600 subjects

Randomization: 1:1

Clinical Site Locations: 1 center (Brigham and Women's Hospital)

Study Duration: 36 months; enrollment period of up to 20 months with 12-month follow-up.

Primary Safety and Efficacy Outcomes:

Primary Safety Outcome: International Society on Thrombosis and Haemostasis (ISTH) major bleeding at 12 months.

Primary Efficacy Outcome: Symptomatic, recurrent VTE, defined as the composite of deep vein thrombosis and/or pulmonary embolism at 12 months.

Secondary Efficacy Outcome: The composite of death due to cardiovascular cause, nonfatal myocardial infarction, stroke or systemic embolism, critical limb ischemia, or coronary or peripheral ischemia requiring revascularization (major adverse cardiovascular events, including major adverse limb events) at 12 months.

Follow-Up: Follow-up will consist of Electronic Health Record (EHR) review at 12-months from study enrollment.

Interim Analysis: An interim analysis for the primary safety and efficacy outcomes will be performed when 300 subjects have completed 12-month follow-up.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Brigham and Women's Hospital
• Treatments: Apixaban

Criteria

Inclusion Criteria:

• Man or woman

• Age ≥ 18 years

• Objectively-confirmed 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 < 9 mg/dL, a platelet count < 100,000/mm3, a serum creatinine 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 has received an investigational agent within the past 30 days prior to the first dose of study treatment (with the exception of approved medications being used for an approved indication, e.g., investigating a new dosing regimen for an approved indication)

• Any condition, which in the opinion of the investigator, would put the subject at an unacceptable risk from participating in the study

• Any other medical, social, logistical, or psychological reason, which in the opinion of the investigator, would preclude compliance with, or successful completion of, the study protocol