This multicenter, retrospective, observational study included patients over the age of 18, diagnosed hematologic malignancy according to the World Health Organization criteria [10], received a hematopoietic stem cell transplant (autologous-HCT (auto-HCT) or allogeneic-HCT (allo-HCT), diagnosed with VTE 100 days prior to or 100 days post-HCT (since the risk for adverse bleeding events and recurrent VTE tend to be highest in the first 3 months after the first VTE occurrence), and received at least one month of a DOAC for treatment of their VTE. The intention for requiring at least one month of DOAC therapy was to ensure better correlates with clinical findings and accurately reflect the patient population. If an outcome event was noted, confirmation of DOAC use at the time of event was conducted. VTE types included in this study were deep venous thromboembolism (DVT) (including peripherally inserted central catheter (PICC)-associated VTE) and pulmonary embolism (PE) [10]. Patients were excluded if they had a solid tumor malignancy without hematologic malignancy, received non-FDA approved dosing of a DOAC for VTE treatment (Table 4), and if they were not monitored by their provider at least monthly at any of the participating institutions during the study period. Patients in this study received their HCT from one of three participating National Cancer Institute (NCI)-designated Comprehensive Cancer Centers in California: University of California, Davis Health (UCDH) Comprehensive Cancer Center, University of California, San Diego (UCSD) Moores Cancer Center, and University of California, San Francisco (UCSF) Hellen Diller Comprehensive Cancer Center. The study period spanned approximately nine years: from July 1, 2012 to May 18, 2021 and patients were monitored for six months after date of DOAC initiation. Drug interactions were captured for patients who were on a concomitant P-glycoprotein (p-gp)/strong cytochrome P450 3A4 (CYP3A4) inhibitor (i.e., posaconazole, voriconazole, clarithromycin), as well as whether the DOAC was appropriately adjusted (Table 5) or withheld based on manufacturer recommendations when co-administered with P-gp and/or strong CYP3A4 inhibitors [11,12,13,14]. Clinical review was conducted by clinical pharmacists at each of the three participating institutions using the electronic medical record system. All clinical notes by physicians, nurses, and pharmacists documented during the study period and pertinent laboratory values were utilized to inform the outcomes studied.

The primary safety endpoint was any episode of major bleeding. Major bleeding was defined according to International Society on Thrombosis and Haemostasias (ISTH) criteria and modeled after previous studies: overt bleeding plus a hemoglobin decrease of ≥ 2 g/dL or transfusion of ≥ 2 units of packed red blood cells; bleeding in a critical site (intracranial, intraspinal/epidural, intraocular, retroperitoneal, pericardial, intraarticular, intramuscular with compartment syndrome), or fatal bleeding [15]. Secondary outcomes included any episode of clinically relevant non-major bleeding (CRNMB) or minor bleeding per ISTH criteria and VTE recurrence. Clinically relevant non-major bleeding (CRNMB) was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, an unscheduled contact with the health care team, or temporary anticoagulant cessation. Minor bleeding was defined as overt bleeding not meeting criteria for major bleeding or CRNMB. All outcome measures were recorded within 6 months of the date of DOAC initiation in each patient.

Patient demographic and clinical characteristics assessed include sex, stem cell transplant type (auto-HCT or allo-HCT), stem cell source (peripheral blood, cord blood, or bone marrow), age at time of transplant, race, type of malignancy, indication for anticoagulation (VTE, PE, or line-associated VTE), platelets at baseline and at the time of the bleeding event, HAS-BLED score, and creatinine clearance (CrCl) at baseline prior to DOAC initiation. Other patient data collected at baseline include presence of drug-drug interactions at time of DOAC initiation and time from DOAC initiation to bleed. Drug metabolism interactions documented included strong CYP3A4/P-glycoprotein inducers (i.e., carbamazepine, phenobarbital, phenytoin, rifampin, or St John’s wort) and strong CYP3A4/P-glycoprotein inhibitors (defined as use of HIV protease inhibitors, posaconazole, clarithromycin, telithromycin, nefazodone, amiodarone, diltiazem, dronedarone, or verapamil) [11,12,13,14]. Select medications that may increase risk of VTE (i.e. bevacizumab, erythropoietin, estrogens, progestins, lenalidomide, pomalidomide, thalidomide, and tamoxifen) in this patient population were also assessed [17]. Concomitant antiplatelet therapy (aspirin, clopidogrel, ticagrelor, and prasugrel), which may increase bleeding risk, were also documented.

Patient characteristics and outcome measurements were reported using descriptive statistics as frequencies and percentages.