Researchers who have identified four predictors of clinically relevant bleeding in patients receiving extended anticoagulation with apixaban (Eliquis) for cancer-associated venous thromboembolism (VTE) said their findings might help clinicians to more effectively balance the benefits and risks of extended anticoagulant therapy.
Over a median follow-up of 12.9 months, anaemia or thrombocytopenia was associated with a 93% higher risk of clinically relevant bleeding, while older age, male sex and pulmonary embolism as the initial reason for anticoagulation were linked to increased risks ranging from 38% to 51%, reported Isabelle Mahé, MD, PhD, of Université Paris Cité in France.
Medpage Today reports that three of those factors were associated with a higher risk of major bleeding as well, according to the findings shared at the American Society of Haemotology (ASH) annual meeting and published simultaneously in Lancet Haematology.
“Patients with cancer-associated thrombosis are both at risk of recurrent venous thromboembolism and bleeding during extended anticoagulant,” said Mahé in her ASH poster presentation, noting that identifying high-risk groups could help clinicians balance the benefits and risks of extended anticoagulant therapy.
While several risk factors for clinically relevant bleeding have been consistently identified during the first six months of anticoagulation in this setting – history of bleeding, worse performance status, advanced-stage cancer, and certain tumour types – risks during extended therapy had remained unknown.
The findings presented by Mahé came from a post hoc analysis of the randomised, double-blind API-CAT (Apixaban Cancer Associated Thrombosis) study, the primary analysis of which showed that a lower 2.5-mg dose of apixaban twice daily was non-inferior for subsequent VTE risk to a 5-mg dose twice daily – and safer – during extended anticoagulation for a cancer-related VTE event.
To enrol in the study, patients had to have already taken at least six months of anticoagulation; they then received 12 more months of apixaban at either dose level. During that extended treatment period, VTE occurred in 2.1% of those on the lower dose and 2.8% of those on the higher dose (P=0.001 for non-inferiority). And as hypothesised, the lower apixaban dose was associated with a 25% reduced risk of clinically relevant bleeding (12.1% vs 15.6% with the higher dose, P=0.03).
The trial included 1 766 patients enrolled at 121 hospitals across 11 countries; 56.6% were women and a majority had locally advanced or metastatic cancer. The most common tumour site was gastrointestinal (23.8%, including colorectal cancer in 15.2%), followed by breast cancer (22.7%), gynaecologic cancers (12.1%), and lung cancer (11.3%).
Clinically relevant bleeding occurred in 238 patients (13.9%) during the 12 months of follow-up – least frequently in the breast cancer patients (6.2%) while at a similar range for the other cancer types (15.4-18.5%).
The primary objective of the post hoc analysis was to identify predictors of clinically relevant bleeding during the extended anticoagulation period.
The researchers considered the following factors: age, sex, body mass index, performance status (Eastern Co-operative Oncology Group score of 2 or more), a history of gastrointestinal bleeds, major bleeding in the past month, recent surgery, locally advanced or metastatic cancer, unresected tumours, concomitant antiplatelet therapy, the index VTE event, anaemia/thrombocytopenia (haemoglobin <10 g/dL or platelet count <100,000 cells per μL), and kidney function (creatinine clearance <50 mL/min).
Comparing the baseline characteristics between the group that had clinically relevant bleeding (regardless of treatment assignment) and the group that did not revealed a higher proportion of patients aged 75 and older (36.6% vs 26.7%, respectively), more men (50.4% vs 42.3%), more with anemia/thrombocytopenia (13.9% vs 7.6%), and a higher percentage with pulmonary embolism as their index VTE event (79.4% vs 75.5%).
Predictors with a significant association for clinically relevant bleeding on univariate analysis were then tested in a multivariate analysis, which revealed these four factors associated with increased risk:
• Anaemia/thrombocytopenia: subdistribution hazard ratio (sHR) 1.93 (95% CI 1.27-2.95)
• Age 75 or older: sHR 1.51 (95% CI 1.14-2.02)
• Pulmonary embolism as the index event: sHR 1.47 (95% CI 1.03-2.10)=
• Male sex: sHR 1.38 (95% CI 1.05-1.82)
“Of note, associations were broadly consistent across cancer types, with no evidence of interaction with apixaban dose,” said Mahé.
Major bleeding occurred in 61 patients (3.6% of the full study population), including four that were fatal. The lowest cumulative incidence was in patients with haematologic (1.5%) and breast (1.8%) cancers, reaching as high as 5.6% in those with gastrointestinal cancers.
Anaemia/thrombocytopenia (sHR 4.16, 95% CI 2.29-7.58), age 75 or older (sHR 1.84, 95% CI 1.10-3.08), and male sex (sHR 1.67, 95% CI 1.01-2.76) were also associated with major bleeds.
Study details
Predictors of clinically relevant bleeding during extended anticoagulation for cancer-associated venous thromboembolism (API-CAT): a post-hoc analysis of a randomised, non-inferiority trial
Isabelle Mahé, Céline Chapellee, Charles-Marc Samama et al.
Published in The Lancet on 6 December 2025
Summary
Background
Extended anticoagulation with reduced-dose apixaban was shown to be non-inferior to full-dose apixaban for preventing recurrent venous thromboembolism (VTE) in patients with active cancer and to be associated with fewer clinically relevant bleeding complications in a non-inferiority trial. In this post-hoc analysis, we sought to identify predictors associated with clinically relevant bleeding.
Methods
API-CAT was a randomised, double-blind, non-inferiority trial done in 121 hospitals in 11 countries. Eligible patients were adults older than 18 years, with active cancer diagnosed histologically (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumour, or intra-cerebral metastasis) and acute proximal deep-vein thrombosis or pulmonary embolism, 6 months or more of completed anticoagulation, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were centrally randomly assigned (1:1) to apixaban 5·0 mg or 2·5 mg twice daily orally for 12 months using an interactive web-response system, and stratified by trial centre, index event, and cancer site. The primary endpoint, reported previously, was the centrally adjudicated fatal or non-fatal recurrent venous thromboembolism. The primary objective for this post-hoc analysis was to identify predictors of clinically relevant bleeding during extended therapy in the overall population and to evaluate how these predictors vary according to cancer type. The post hoc-analysis was done in the intention-to-treat population, multivariable competing-risks regression model was built with clinically relevant bleeding as the dependent variable and was adjusted for apixaban dose.
The association between potential predictors and clinically relevant bleeding was expressed as subdistribution hazard ratio (HR) with 95% CIs. Variables with a p value less than 0·05 were considered statistically significant associated with clinically relevant bleeding.
Findings
Between Oct 11, 2018, and Sept 6, 2023, 1766 patients were randomly assigned to the reduced-dose group (n=866) or the full-dose group (n=900). Median follow-up was 12·9 months (IQR 11·8–13·2). 766 (43·4%) of 1766 patients were male and 1000 (56·6%) were female. At 12 months, clinically relevant bleeding occurred in 238 patients. In the overall population, anaemia and/or thrombocytopenia (subdistribution HR 1·93 [95% CI 1·27–2·95]), age 75 years or older (1·51 [1·14–2·02]), pulmonary embolism as the index event (1·47 [1·03–2·10]), and male sex (1·38 [1·05–1·82]) were significantly associated with an increased risk of clinically relevant bleeding. These results are homogeneous across cancer sites, with no evidence of statistically significant interaction between dose regimen and any predictor (all pinteraction>0·30).
Interpretation
During extended treatment for cancer-associated VTE, four predictors of clinically relevant bleeding were identified in the overall population, with no evidence of interaction with the dosing regimen. Although the API-CAT study was not designed to specifically address anticoagulation discontinuation, our findings might help clinicians to more effectively balance the benefits and risks of extended anticoagulant therapy.
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