Outcomes of extended reduced‐dose apixaban versus full‐dose apixaban in cancer‐associated venous thromboembolism

Venous thromboembolism (VTE) is one of the important causes of morbidity and mortality among patients with active malignancy. Current guidelines from the American Society of Clinical Oncology (ASCO) suggest extended anticoagulation for patients with active cancer and established VTE to prevent recurrent VTE.1 Although the Apixaban Cancer Associated Thrombosis (API-CAT) trial showed that reduced-dose apixaban was noninferior to full-dose apixaban for extended anticoagulation beyond 6 months of full-dose anticoagulation,2 the real-world evidence to guide optimal dosing strategies in this patient population remains scarce. Our study sought to measure the real-world outcomes between reduced- and full-dose apixaban for extended anticoagulation in patients with cancer-associated VTE. We utilized TriNetX to perform this retrospective cohort study. TriNetX is a global federated health research network that provides access to electronic medical records from approximately 132 million patients, primarily in the United States. Adult patients (≥18 years) with lung, colorectal, breast or prostate cancer who were receiving cancer-directed therapy (chemotherapy, radiation therapy, targeted therapy or hormonal therapy) and had a concurrent diagnosis of VTE between 1 January 2015 and 1 January 2024 were identified using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes (Table S1). Patients were divided into two groups: patients who received apixaban 2.5 mg twice daily (BID) and patients who received apixaban 5 mg BID after an initial 6 months of full-dose anticoagulation. We performed propensity score matching (PSM) (1:1) using nearest neighbour matching with a 0.1 pooled standard deviation calliper. Standardized mean difference (SMD) was used in PSM to measure the covariate balance, with SMD <0.1 indicating adequate balance between two groups. Study outcomes included 1-year rates of recurrent VTE, gastrointestinal (GI) bleeding, all-cause hospitalization and mortality. The 1-year rates refer to the cumulative incidence of different outcomes during the 1-year period beginning at the start of follow-up. The start of follow-up was defined as the time when patients entered the analysis after completing an initial 6 months of full-dose apixaban and another 6 months of either reduced-dose or full-dose apixaban. We performed statistical analyses on the TriNetX platform, with significance set at p < 0.05 (two-sided). TriNetX calculates hazard ratios (HRs) and cumulative incidences (CIs) using R survival package version 3.2-3 with the proportional hazard assumption tested using Schoenfeld residuals. This study did not require institutional review board review or informed consent due to the use of de-identified data. Our study identified 54 936 patients with lung, colorectal, breast and prostate cancer who were receiving cancer treatment, including 1393 patients who received reduced-dose apixaban and 53 543 who received full-dose apixaban. In the reduced-dose group, 38.9% had breast cancer, 30.4% lung cancer, 30.3% prostate cancer and 23.4% colorectal cancer, whereas in the full-dose group, 30.9% had breast cancer, 32.9% lung cancer, 23.0% prostate cancer and 29.3% colorectal cancer. Percentages exceed 100% because some patients had multiple cancer diagnoses. Table 1 shows the baseline characteristics of patients with active cancer receiving reduced-dose and full-dose apixaban before and after PSM. After PSM, there were 1393 patients in the reduced-dose group (mean age 72.9 ± 11.5 years; 53.2% female; 74.6% White, 15.3% African American, 1.4% Asians) and 1393 patients in the full-dose group (mean age 72.7 ± 10.9 years of age; 53.6% female; 74.4% White, 16.2% African American, 1.4% Asians). Reduced-dose apixaban was associated with lower risk of recurrent VTE (27.5% vs. 51.50%; HR: 0.42; 95% confidence interval CI: 0.37–0.47, p = 0.01). Table S2 shows the percentages of different VTE events. Reduced-dose therapy was also associated with a lower risk of GI bleeding (5.5% vs. 8.3%; HR: 0.68; 95% CI: 0.51–0.91, p = 0.01) and all-cause hospitalization (55.8% vs. 66.8%; HR: 0.75; 95% CI: 0.68–0.82, p < 0.01). There was no significant difference observed in all-cause mortality between these two treatment groups (21.4% vs. 22.7%; HR: 0.98; 95% CI: 0.84–1.15; p = 0.80). Kaplan–Meier curves for outcomes measured are shown in Figure S1. Our study showed that reduced-dose therapy was not associated with a higher risk of recurrent VTE compared to full-dose therapy among patients with active cancer. Current guidelines from the American Society of Hematology recommend that either reduced-dose or full-dose apixaban may be used in secondary prevention of recurrent VTE. In a meta-analysis of five randomized controlled trials involving 8781 patients, Ibrahim et al. compared reduced-dose versus full-dose direct oral anticoagulants (DOACs) for extended VTE treatment and found no statistically significant difference in recurrent VTE risk among patients with active cancer (risk ratio RR 0.98; 95% CI, 0.58–1.66).3 Our finding further supports that reduced-dose apixaban may offer comparable efficacy to full-dose therapy for patients with active cancer. These findings additionally suggest that dosing strategy may not be the primary determinant of VTE recurrence in patients with cancer receiving apixaban and that individualized risk assessments should play a central role in informing anticoagulation strategies. Our study also found that patients with active cancer who were treated with reduced-dose apixaban had a lower risk of GI bleeding compared to those receiving the full dose. This is consistent with the findings demonstrated in the API-CAT trial, which showed a significantly lower risk of GI bleeding in the reduced-dose group, approximately half of the full-dose group (1.4% vs. 2.9%).2 Additionally, Ibrahim et al. demonstrated that reduced-dose DOACs were associated with significantly lower clinically relevant bleeding (RR 0.75; 95% CI, 0.61–0.93) compared with full-dose DOACs among patients with active cancer.3 Our findings support the role of dose optimization in balancing efficacy and safety, particularly in the cancer population. In this real-world analysis of patients with cancer-associated VTE receiving extended anticoagulation, reduced-dose apixaban was not associated with an increased risk of recurrent VTE and was associated with a lower risk of GI bleeding and all-cause hospitalization compared to full-dose apixaban. These results suggest that reduced-dose apixaban may provide a favourable balance of efficacy and safety during the extended treatment phase in this population. There were several limitations of our study. Its retrospective design limited our ability to account for undocumented interruptions in anticoagulation therapy, antiplatelet therapy and medication non-adherence. In addition, indication bias may have influenced treatment selection, as physicians may have prescribed reduced-dose apixaban to patients perceived to have a lower risk of recurrent VTE and higher bleeding risk. Although propensity score matching was used, residual confounding from unmeasured factors cannot be completely excluded. Furthermore, certain high-risk patient subgroups, such as patients with obesity, were underrepresented in our cohort, which may limit the generalizability of our findings. Aravinthan Vignarajah: Methodology; data curation; investigation; formal analysis. Michael Maroules: Writing – review and editing. Gunwant Guron: Writing – review and editing. Jia Yi Tan: Conceptualization; supervision; project administration; writing – original draft. Lay She Ng: Data curation; formal analysis; methodology; investigation. Yong Hao Yeo: Methodology; data curation; investigation. Jacob Cogan: Writing – review and editing. Robert Kratzke: Writing – review and editing. A portion of this work was presented in abstract form at the American Society of Hematology Annual Meeting, 2025. The full study has not been published elsewhere. This research received no specific grant from funding agencies in the public, commercial or not-for-profit sectors. The authors have no conflicts of interest to disclose. This research study was conducted retrospectively from data obtained from TriNetx. It does not require institutional review approval as the population data are de-identified. The population data on TriNetx are de-identified. The data that support the findings of this study are available from the TriNetx. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.