Blood clots, also known as venous thromboembolism (VTE), are a common and serious complication for people with cancer. They can lead to pain, hospitalizations, delayed cancer treatment, and even death. Although national guidelines recommend using blood thinners (anticoagulants) to prevent clots in cancer patients who are at higher risk, these medications are not commonly prescribed due to concerns about bleeding and inconvenience.

This study will test different ways of using a commonly prescribed blood thinner called apixaban (brand name Eliquis) to see if it can safely and effectively reduce the risk of blood clots and death in cancer patients who are at moderate risk for VTE. The study focuses on people who have a "Khorana score" of 2, which puts them at intermediate risk for developing blood clots.

The study will include approximately 996 participants with solid tumors or lymphoma who are starting or recently started cancer-directed therapy. Participants will be randomly assigned to one of three groups:

Group 1: Apixaban 2.5 mg twice a day (standard prophylactic dose)

Group 2: Apixaban 5 mg once a day (an alternative, more convenient dose)

Group 3: No anticoagulant (standard care)

Participants will take the assigned treatment (if applicable) for 6 months. Researchers will monitor whether participants develop blood clots, experience serious bleeding events, or die from any cause during the study period.

By comparing these three groups, the researchers hope to learn whether a once-daily dose of apixaban can work as well as the standard twice-daily dose, and whether either dosing strategy is better than no anticoagulation at all. If successful, the study may help increase the safe use of VTE prevention in cancer patients and improve overall outcomes, especially in patients at intermediate risk.

This is a pragmatic trial, meaning it is designed to fit into real-world clinical practice with minimal extra procedures. The study drug is not provided by the sponsor and will be prescribed and filled through usual care channels. Participants and their doctors will decide whether to continue the medication after the study ends.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in ambulatory patients with cancer, particularly within the first several months after initiating cancer-directed therapy (CDT). The Khorana Risk Score (KRS) is a validated tool used to identify cancer patients at increased risk of VTE. While patients with a KRS ≥ 2 are eligible for VTE prophylaxis under current clinical guidelines, there remains a major gap between these recommendations and clinical practice. Implementation of prophylaxis is low due to concerns about bleeding, uncertainty regarding net clinical benefit, and challenges with medication adherence-particularly with twice-daily dosing regimens.

Apixaban, a direct oral anticoagulant (DOAC), is FDA-approved and supported by NCCN and ASH guidelines for VTE prevention in high-risk ambulatory cancer patients. The AVERT trial demonstrated that apixaban 2.5 mg twice daily significantly reduced VTE events in cancer patients with a KRS ≥ 2 but increased the risk of major bleeding. However, this dosing strategy remains underutilized. The possibility of once-daily dosing with apixaban, which could improve adherence and acceptance among patients and physicians, has not been adequately studied in this population.

This single-center, phase III, open-label, pragmatic randomized clinical trial will evaluate two dosing strategies of apixaban for VTE prevention in cancer outpatients with a KRS of 2. A total of 996 participants will be randomized 1:1:1 to receive:

Arm 1: Apixaban 2.5 mg twice daily

Arm 2: Apixaban 5 mg once daily

Arm 3: No anticoagulant prophylaxis (standard care)

The primary objective is to compare the incidence of VTE across these arms over a 6-month treatment period. Secondary objectives include comparisons of all-cause mortality and rates of clinically significant bleeding events (CTCAE grade ≥ 3).

Participants must have a solid tumor or lymphoma and be initiating or recently initiated on CDT. Those with recent VTE, active anticoagulation for another indication, hematologic malignancies (e.g., acute leukemia, myeloma), or high bleeding risk are excluded.

Randomization occurs after eligibility is confirmed via chart review and informed consent is obtained. In line with a pragmatic trial design, there are no mandated study visits beyond a brief 2-month patient-reported outcomes (PRO) check-in. All other data, including VTE events, mortality, bleeding, and adherence, are captured via electronic health record abstraction and PRO questionnaires.

Drug is not provided as part of the study; apixaban will be prescribed as part of usual clinical care and filled through the participant's pharmacy. Participants who are unable to obtain the drug due to insurance or financial barriers will still be followed in their assigned study arm per intent-to-treat principles.

The study will use a formal interim analysis following the O'Brien and Fleming approach, with stopping rules for futility and efficacy. Final analyses will compare VTE incidence and other endpoints using chi-square tests and Kaplan-Meier survival analysis, as appropriate.

This trial is designed to generate real-world evidence to inform anticoagulant prescribing practices in cancer outpatients at intermediate risk for VTE. Results may support broader, more personalized adoption of thromboprophylaxis strategies that balance effectiveness, safety, and feasibility.

Inclusion Criteria:

• Age ≥ 18 years
• Diagnosed with an active solid tumor or lymphoma
• Starting a new systemic cancer treatment or changing cancer treatment
• Khorana Risk Score of 2 (calculated based on lab and clinical data at treatment initiation)
• Not currently receiving therapeutic anticoagulation
• Able to provide informed consent

Exclusion Criteria:

• Active bleeding or high risk of bleeding (e.g., recent major surgery, CNS tumors with hemorrhagic risk)
• Known contraindication to apixaban (e.g., allergy, severe liver disease, dual strong CYP3A4 and P-gp inhibitors)
• Current therapeutic-dose anticoagulation for VTE or atrial fibrillation
• Platelet count < 50,000/µL
• Creatinine clearance < 25 mL/min
• Life expectancy < 3 months
• Pregnant or breastfeeding
• Inability to comply with study procedures

Anonymized patient related data will be incorporated into publications and will be made available to other investigators at reasonable request.