Apixaban for Venous Thromboembolism Prophylaxis During Neoadjuvant Therapy in Muscle‑Invasive Bladder Cancer: International Randomized Controlled Trial

The primary objective is to assess the benefits and harms of thromboprophylaxis with apixaban administered during neoadjuvant therapy for muscle‑invasive bladder cancer, in comparison with standard care without anticoagulation, with the aim of determining its impact on venous thromboembolism incidence, overall safety, and efficacy outcomes in patients proceeding to radical cystectomy or chemoradiotherapy.

The trial enrolled 306 adult participants, inclusive of both female and male patients, all aged ≥ 18 years. Eligible individuals were those scheduled to receive neoadjuvant systemic therapy before radical cystectomy or chemoradiotherapy for bladder cancer and were capable of providing written informed consent. No specific dietary, physical activity, or habit restrictions were stipulated for enrollment. Key inclusion criteria focused on age, planned neoadjuvant treatment, and consent capacity, while detailed exclusion criteria were not disclosed. The study population was selected to represent patients at risk for Venous thromboembolism in the context of bladder cancer undergoing planned neoadjuvant therapy.

The study is an international, prospective, randomized, controlled trial comparing oral apixaban 5 mg once daily with no anticoagulation in adult patients undergoing neoadjuvant systemic therapy for muscle‑invasive bladder cancer followed by radical cystectomy or chemoradiotherapy. Eligible participants (≥18 years, planned neoadjuvant therapy, able to give informed consent) undergo a screening visit to confirm inclusion criteria, obtain baseline assessments, and receive randomization. After randomization, participants commence the assigned intervention concurrently with standard neoadjuvant therapy and attend scheduled follow‑up visits at the end of each chemotherapy cycle for safety monitoring, medication adherence checks, and documentation of adverse events. A mandatory contrast‑enhanced CT scan performed after the final neoadjuvant dose and before definitive radical treatment serves as the primary imaging assessment for the composite efficacy and safety endpoints. The end‑of‑study visit occurs six months after randomization, at which time final imaging, collection of secondary outcome data, and evaluation of survival status are performed; long‑term survival follow‑up continues annually up to five years. Participant involvement therefore spans approximately six months for primary outcome assessment, with optional extended follow‑up for survival endpoints. Early termination may occur if the participant withdraws consent, experiences a protocol‑defined major bleeding event, requires therapeutic anticoagulation for another indication, develops a contraindication to study medication, or is lost to follow‑up. The overall trial recruitment period is projected from September 2026 to December 2034, and the primary objective is to assess the incidence of Venous thromboembolism and major bleeding between randomization and the pre‑radical‑treatment CT scan.

The investigational product is APIXABAN, supplied in the pharmaceutical form identified as PHF00099MIG. Each dose contains 5 mg of the active substance apixaban and is administered by oral use. The medication is given once daily throughout the neoadjuvant therapy period, in addition to the prescribed standard‑of‑care regimen.

Patients in the control arm receive standard‑of‑care neoadjuvant therapy without any anticoagulant. Standard neoadjuvant regimens may include gemcitabine‑cisplatin, dose‑dense MVAC, peri‑operative durvalumab combined with gemcitabine‑cisplatin, or enfortumab vedotin plus pembrolizumab, followed by definitive radical cystectomy or chemoradiotherapy as per local practice.

Study medication is dispensed in labeled containers with a predefined treatment calendar. Participants are instructed to take the oral tablet at the same time each day. Compliance is assessed by pill count at each study visit and reinforced through patient diaries and electronic reminders. Adherence to the neoadjuvant chemotherapy schedule is monitored by review of infusion records and imaging reports.

The primary efficacy assessment is the incidence of any objectively confirmed venous thromboembolism, defined as the composite of deep‑vein thrombosis (including distal DVT) and pulmonary embolism. Events are captured from the time of randomisation until the computed tomography (CT) scan performed after the final dose of neoadjuvant therapy and before radical treatment. Confirmation requires detection on the mandatory post‑NAT CT scan or on clinically indicated imaging performed for suspected events.

A secondary efficacy endpoint evaluates the incidence of any objectively confirmed VTE (symptomatic or incidental DVT and/or pulmonary embolism) occurring within six months of randomisation. These events are identified on the same post‑NAT CT scan or on any clinically indicated imaging performed during the six‑month follow‑up period.

Additional tertiary efficacy analyses examine each component of the primary composite endpoint separately (symptomatic VTE, asymptomatic VTE, symptomatic PE, asymptomatic PE, symptomatic DVT, asymptomatic DVT) both within the pre‑radical‑treatment window and over the six‑month follow‑up. The same imaging modalities used for the primary assessment are applied for these component analyses.

All imaging assessments are performed using standard diagnostic CT protocols. Images are reviewed by qualified radiologists blinded to treatment allocation. Data are collected at the defined timepoints (baseline, post‑NAT CT, and any interim clinically indicated scans) and analysed using categorical incidence comparisons between the apixaban and control arms.