Introduction

Direct oral anticoagulants (DOACs) are recommended as first‑line therapy to prevent thromboembolic complications in patients with atrial fibrillation (AF). One of their advantages is that routine monitoring of their effects is not required. However, certain patient groups may still benefit from such monitoring. For example, in individuals with active cancer, monitoring DOAC plasma concentrations—especially given the increased risk of bleeding—could be crucial.¹ This is because certain chemotherapy drugs are either substrates of P‑glycoprotein (eg, paclitaxel, doxorubicin, tyrosine kinase inhibitors, enzalutamide) or metabolized by CYP3A4 (eg, vinblastine, doxorubicin, tyrosine kinase inhibitors, enzalutamide).² This study aimed to evaluate DOAC activity in a real‑world population of patients undergoing chemotherapy for active cancer.

Patients and methods

This retrospective study included 17 patients from the Outpatient Cardio‑oncology Clinic at the University Clinical Center in Gdansk, Poland, who were treated with chemotherapy for active cancer and were on DOACs. The study measured their plasma trough and peak DOAC concentrations. Plasma peak concentrations were measured 2 hours after drug ingestion. Plasma trough concentrations for apixaban and dabigatran were assessed 12 hours after ingestion, and for rivaroxaban, 24 hours after ingestion. Additional information on reference ranges for individual DOACs is provided in Supplementary material, Table 1. Compliance was assessed based on patient self‑reports collected by attending physicians during visits to the clinic. All patients reported taking DOACs as recommended by their physicians. The analysis included demographic data, comorbidities, and oncologic treatment. The study was conducted between December 1, 2022 and December 31, 2024, and was approved by the Bioethics Committee for Scientific Research at the Medical University of Gdansk (KB/582/2025–2026).

Results

A total of 17 patients at a median (IQR) age of 71 (68–74) years were included in the study; 12 (71%) were men. The study group included individuals with prostate cancer (n = 5; 29.4%), lung cancer (n = 3; 17.6%), breast cancer (n = 2; 11.9%), renal cancer (n = 3; 17.6%), chronic lymphocytic leukemia (n = 3; 17.6%), and 1 case (5.9%) of gastric cancer. Concomitant chronic kidney disease was diagnosed in 3 participants, chronic coronary syndrome in 4, and chronic heart failure in 3. Median estimated glomerular filtration rate (GFR) of the study cohort was 77 (68–86) ml/min/1.73 m², and median body mass index (BMI) was 27 (25–28) kg/m². Except 1 case where the indication for using DOACs was pulmonary embolism, the main reason for administering these drugs was AF. None of the patients were taking any antiplatelet drugs concomitantly.

The most frequently used DOAC was dabigatran (n = 8; 47.1%). In 2 cases, a switch to another DOAC was made: 1 patient was switched from rivaroxaban to apixaban, and another from dabigatran to apixaban. Considering the minimum and maximum DOAC concentrations and the aforementioned conversions, the analysis included 38 measurements of DOAC plasma levels: 16 for dabigatran, 14 for apixaban, and 8 for rivaroxaban. Among the patients on dabigatran, drug levels below the recommended range were observed in 25% of the cases. Similarly, for rivaroxaban, the concentrations below the recommended range were observed in 25% of the cases, and 13% of the measurements exceeded the upper limit of the reference range. For apixaban, all test results fell within the recommended range. In all participants, abnormal DOAC levels were more common at peak concentrations than at troughs (6 vs 1 case). All levels below the reference range were observed in the patients with normal renal function, who received a reduced dose of DOAC (66.7% of the cases). In 1 case, values below the reference range ​​were observed in the case of dabigatran administered at an full dose in a patient with obesity (BMI, 33 kg/m²). Of the individuals with nontherapeutic DOAC plasma concentrations, 66.7% had prostate cancer. Clinical characteristics of the patients included in the study are detailed in Table 1.

Discussion

Based on existing evidence, DOACs show a consistent, predictable association between dosage and clinical outcomes. According to Grześk et al,³ most DOAC activity measurements in the general population fall within the accepted reference values. Our data mainly involved individuals treated with dabigatran (50%), which is significant because of the availability of a drug that reverses its effects—idarucizumab.⁴

However, there are certain groups of patients in whom monitoring plasma DOAC activity should be considered, primarily individuals with considerably impaired renal function, obesity, advanced age, and / or frailty, and those in whom clinically significant drug–drug interactions may occur. We found DOAC activity below or above the reference range in 20.1% of the individuals treated with chemotherapy for oncologic / hematological diseases, which seems to confirm that this population may benefit from this type of monitoring, particularly because such patients are also at an increased risk of bleeding during anticoagulant treatment.¹

Chemotherapeutics that strongly inhibit CYP3A4 and / or P‑glycoprotein can alter DOAC plasma concentrations and lead to clinically significant changes in their anticoagulant effects. Some classes of chemotherapy drugs appear to almost universally interact with CYP3A4, P‑glycoprotein, or both. These include antimitotic microtubule inhibitors (vinca alkaloids and taxanes) and tyrosine kinase inhibitors (except erlotinib, gefitinib, and sorafenib). Conversely, none of the frequently used antimetabolites, platinum‑based agents, intercalating agents, or monoclonal antibodies have significant inhibitory or inducing effects on CYP3A4 or P‑glycoprotein.⁵ In our study, the use of hormone therapy (leuprorelin, triptorelin, enzalutamide, abiraterone) was most often associated with plasma DOAC activity outside the reference range. This is consistent with the literature, which reports that enzalutamide is a strong inhibitor of CYP3A4, whereas abiraterone is a moderate inhibitor of both CYP3A4 and P‑glycoprotein.⁵ Similar data were reported by Sebuhyan et al,⁶ who showed that the use of abiraterone may be associated with increased DOAC activity, and enzalutamide—with decreased DOAC activity. Not only chemotherapy but also many antiseizure medications are metabolized by CYP3A4 and P‑glycoprotein, which also puts this group of patients at a risk of subtherapeutic DOAC activity. As in our study, the lowest risk of subtherapeutic DOAC concentrations in individuals treated with antiseizure medications was observed in those on apixaban.⁷ Besides drug interactions, too low DOAC plasma concentrations observed in our analysis may have resulted from the use of insufficient drug doses relative to renal function (all these patients had eGFR >60 ml/min/1.73 m²), which was most likely due to fear of an increased risk of bleeding in this group. In 1 case, a subtherapeutic DOAC (dabigatran) concentration was observed in a participant with first‑degree obesity, highlighting the role of monitoring DOAC concentrations in this population.⁸

Based on our data, the use of DOACs in cardio‑oncology patients was not associated with frequent bleeding complications—only 1 case required blood transfusion, with both trough and peak plasma levels within normal ranges. This aligns with real‑world evidence reported in the literature, which confirms that a fixed DOAC dose without plasma level monitoring is safe and effective.⁹ This also applies to patients with gastrointestinal cancers, for whom the safety of DOAC use has been verified.¹⁰ There are no large clinical trials examining DOAC concentrations in individuals with hematologic malignancies. Most studies are small observational reports or case series. In 1 of them, the authors indicated that using dabigatran at controlled plasma levels helped prevent stroke in patients with AF treated with ibrutinib.¹¹