Review Article

Venous Thromboembolism Management and Anticoagulation Opportunities in Cancer Patients

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Abstract

Cancer predisposes to venous thromboembolic complications, especially at the moment of diagnosis, and anticoagulation may be less effective. Additionally, some cancers, especially in the gastrointestinal tract or the genitourinary system, may be associated with an extremely high risk of bleeding. Anticoagulant treatment in venous thromboembolism associated with cancer is characterised by significant differences compared with the general cardiology population. It is necessary to choose the appropriate anticoagulation, either a new non-vitamin K antagonist oral anticoagulant or low-molecular-weight heparin. The efficacy and safety are determined by characteristics of the cancer and anticancer therapy. The duration of anticoagulation determines not only the choice of anticoagulant, but also the dose. There is some evidence to justify the reduction of anticoagulant dosage after 6 months of treatment. In active cancer, it is worth continuing anticoagulation indefinitely, but this does not necessarily mean for the rest of a patient’s life. It is important to repeat an assessment when the risk of bleeding outweighs the benefits.

Keywords

Anticoagulation, cancer, bleeding, cardio-oncology,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/ecr.2025.46

Disclosure: SS has received speaker fees from Pfizer, Novartis, Bayer, BMS, AstraZeneca, AbbVie and Amgen. DMK has served on advisory boards for AstraZeneca, Roche, Merck, MSD, Takeda, Pfizer, Johnson & Johnson, Amgen, Pierre Fabre, Medison, BeOne, Daiichi Sankyo and BMS. All other authors have no conflicts of interest to declare.

Correspondence: Sebastian Szmit, National Research Institute of Oncology, Street: W. K. Roentgen 5, 02-781 Warszawa, Poland. E: s.szmit@gmail.com

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The development of cancer is associated with thromboembolic complications.1,2 Pulmonary embolism or deep vein thrombosis may be the first symptoms of neoplastic disease.3–5 Prothrombotic readiness is highest at the time of diagnosis of malignancy.6,7 Advancement and aggressiveness of cancer may determine a higher prothrombotic risk.8–10 Additionally, some characteristics of cancers and many histopathological or molecular diagnoses of cancers are associated with thromboembolic risk.11 Finally, the type of cancer therapy itself may additionally increase the risk of venous thromboembolism (VTE).12 It has long been known that VTE is associated with higher mortality in all stages of cancer diseases.13 Even among patients under modern cancer therapy, the occurrence of VTE is associated with significantly shorter overall survival.14–16 Therefore, there is an extensive discussion on the principles of primary antithrombotic prophylaxis.17

Predictive models are still under discussion.18 New predictive models were proposed for both primary and secondary prevention in cancer patients.19,20 For primary VTE prevention in patients with cancer, the Khorana score is still the most widespread, but some new algorithms appeared in medical literature and even guidelines.21,22 For secondary prevention, there were some recent developments.23,24 In the case of secondary prophylaxis, anticoagulation is prolonged as long as the cancer disease is considered active.25 However, it can be expected that artificial intelligence methods will provide an opportunity to develop further prediction algorithms and new understanding of the indications for primary and secondary VTE prophylaxis.26

Personalisation of Anticoagulation in Cancer Patients

Apart from the specific prothrombotic readiness associated with cancer and its treatment, another specific feature for this population of patients is a significantly increased risk of bleeding.27 This risk may again be determined by the advancement of the cancer and, more precisely, its location – both the primary and metastatic lesions. The highest risk of bleeding seems to be associated with location in the gastrointestinal tract and the genitourinary system. Another problem increasing the risk of bleeding is the type of cancer treatment, including surgery and all invasive procedures, as well as the toxicity of anticancer pharmacotherapy, such as gastrointestinal, hepatological or nephrological side-effects. A specific risk factor of bleeding is thrombocytopaenia induced by cancer disease or its treatment.28

Thus, similar features of cancer and its treatment determine both the risk of prothrombotic events and the risk of bleeding. They also determine that antithrombotic treatment will require personalisation.29

The European Society of Cardiology guidelines on cardio-oncology published in 2022 indicate two equivalent therapeutic options for the treatment of VTE in cancer patients.30

The first option is the possible choice of oral anticoagulation with drugs that are non-vitamin K antagonists (non-vitamin K antagonist oral anticoagulant; NOAC). In alphabetical order, apixaban, edoxaban and rivaroxaban are listed as anticoagulants with proven use in VTE coexisting with cancer. However, there are contraindications to this group of drugs that should be avoided.

The second option is to choose low-molecular-weight heparin (LMWH) administered subcutaneously and used at the full therapeutic dose if there is no significant thrombocytopaenia (platelet count <50,000/µl).

Both above options have the same class of recommendations and the same level of evidence; that is, because they are based on prospective randomised studies.

In clinical practice, there are situations in which one of these options is more effective or safer for a selected patient (Table 1).

Table 1: Summary of Clinical Situations Indicating the Choice of Better Anticoagulation in Cardio-oncology

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When are Non-vitamin K Antagonist Oral Anticoagulants More Effective?

Before the era of new oral anticoagulants that were non-vitamin K antagonists, LMWH was recommended for VTE treatment in cancer patients.31,32 Dalteparin was considered by many experts to be the dominant standard based on the CLOT study.33 The CLOT trial was more clinically relevant than the enoxaparin trial published at a similar time, and also demonstrated the superiority of LMWH over warfarin.34 The CLOT study lasted 6 months and clearly showed greater efficacy for dalteparin compared with warfarin, whereas the study with enoxaparin versus warfarin lasted only 3 months, and the primary endpoint was to demonstrate superiority through a joint analysis of VTE recurrence and bleeding.

Four randomised studies have confirmed the validity of NOAC use in cancer patients. The two largest studies, Hokusai and Caravaggio, had a non-inferiority design, so the direct conclusion was that the newly evaluated drugs (edoxaban and apixaban, respectively) were non-inferior in efficacy to dalteparin.35,36 It should be remembered that the primary outcome of the Hokusai study was a composite collection of recurrent VTE or major bleeding during the 12 months. The SELECT-D and ADAM-VTE studies were significantly smaller, but designed with randomisation.37,38

One of the conducted meta-analyses confirmed that NOACs may be more effective than dalteparin (RR 0.62; 95% CI [0.43–0.91]).39 This applies primarily to patients with solid tumours (RR 0.68; 95% CI [0.51–0.91]) and, above all, active cancer (RR 0.61; 95% CI [0.44–0.86]). A particular benefit regards patients with incidentally diagnosed pulmonary embolism or deep vein thrombosis (RR 0.45; 95% CI [0.23–0.89]).

A subanalysis of the CARAVAGGIO study with a focus on patients with moderate renal impairment (creatinine clearance 30–59 ml/min) confirmed apixaban may be fourfold more effective than dalteparin in the reduction of the frequency of recurrent VTE (HR 0.27; 95% CI [0.08–0.96]).40

The retrospective cohort study based on electronic health records of 5,100 cancer patients with VTE revealed LMWH and warfarin were less effective in secondary prophylaxis of recurrent VTE.41 NOAC could have a higher efficacy. Patients treated with LMWH had increased risk of major bleeding (HR 2.27; 95% CI [1.62–3.20]) and higher all-cause mortality (HR 1.61; 95% CI [1.15–2.25]) in comparison with NOAC, but it may be an effect of preferring LMWH instead of NOAC in patients with more advanced cancer diseases. The prescription of LMWH was higher in patients with lung (OR 2.07; 95% CI [1.12–3.65]), urological (OR 1.94; 95% CI [1.08–3.49]), gynaecological (OR 4.25; 95% CI [2.31–7.82]) and colorectal (OR 2.26; 95% CI [1.20–4.32]) cancers, where a risk of bleeding can be significantly higher.

The COMMAND VTE Registry-2 included real-world data on clinical outcomes among 5,197 cancer patients treated with NOACs for VTE.42 The frequency of recurrent VTE and the profile of all-cause mortality were similar for the edoxaban, rivaroxaban and apixaban groups. However, the 5-year incidence of major and clinically relevant bleeding was significantly lower in patients receiving rivaroxaban. However, the OSCAR-UK study compared the outcomes of 2,259 patients treated with rivaroxaban and 1,945 patients receiving LMWH, and the weighted risk at 12 months was very similar for VTE patients treated with rivaroxaban and LMWH: efficacy in secondary prophylaxis of VTE (subdistribution HR 0.80; 95% CI [0.37–1.73]), frequency of significant bleedings (subdistribution HR 1.01; 95% CI [0.57–1.81]) and all-cause mortality (subdistribution HR 0.49; 95% CI [0.23–1.06]).43 The results appear to be related to the oncological characteristics of the treated patients.

Three meta-analyses published between 2023 and 2025 confirmed that the use of NOACs in VTE in patients with primary central nervous system tumours is significantly safer compared with LMWH, because it is associated with a significantly lower risk of intracranial haemorrhage.44–46

Does Treatment Duration Matter for Effectiveness?

When choosing anticoagulation treatment, the patient’s preferences should also be considered. This is emphasised by the European Society of Cardiology guidelines on cardio-oncology published in 2022. In oncology, not only cancer therapy effectiveness, but also patient quality of life is becoming increasingly important. Mental health is also understood as one of the favourable outcomes in cardio-oncology.47 It is important to remember that the occurrence of VTE itself negatively impacts the quality of life of cancer patients.48 For many patients, it will become crucial that anticoagulant treatment does not negatively impact their wellbeing. As in the COSIMO study, patients may prefer oral therapy when choosing between a NOAC and LMWH.49

A patient must accept a specific choice of therapy, especially if it includes subcutaneous injections with LMWH. The longer the duration of the anticoagulation, the more probability that a patient may be afraid of receiving injections. Based on the available studies, positive premises can be found regarding the choice of the type of anticoagulation for long-term treatment.

The HOKUSAI study shows that after 3 months of therapy, the efficacy curves separated in favour of edoxaban.50 The CARAVAGGIO study shows that the efficacy curves have already begun to separate in favour of apixaban after 1 month of therapy, exactly when the loading dose of dalteparin was tapered to a maintenance dose. The result was not statistically significant, but the benefit was noticeable.

A recent subanalysis of the CARAVAGGIO trial on the timing of VTE recurrence revealed similar frequencies of recurrent VTE and major bleeding after 7 and 30 days.51 There were six (1%) and 15 (2.6%) VTE recurrent episodes during treatment with apixaban versus five (0.9%) and 20 (3.5%) under dalteparin. Major bleeding occurred in three (0.5%) and nine (1.6%) in the apixaban arm versus five (0.9%) and 11 (1.9%) for dalteparin. This supports the use of apixaban for the initiation of anticoagulant therapy for VTE in cancer patients. However, after 90 days (3 months), the differences between apixaban and dalteparin were: VTE recurrence 27 (4.7%) versus 36 (6.2%), and bleeding 16 (2.8%) versus 17 (2.9%), respectively.

What Dose of Non-vitamin K Antagonist Oral Anticoagulant for Long-term Treatment?

The latest European Society for Medical Oncology guidelines emphasise that duration of anticoagulation in active cancer should be indefinite.52 Full therapeutic doses should be given for periods >6 months.

The validity of prolonged anticoagulation in active cancer was first confirmed by the DALTECAN study.53 Further data were provided by the extension phase of the SELECT-D study with rivaroxaban when it was continued and compared with a placebo.54 Even among cancer patients with low-risk pulmonary embolism, based on the simplified version of the Pulmonary Embolism Severity Index score with 1 point, the 18-month rivaroxaban treatment was more effective than the 6 months of anticoagulation.55 Another study confirmed that prolonged anticoagulation due to VTE beyond 3 months is more effective with apixaban than with LMWH in cancer patients.56

A randomised study showed that 12 months of edoxaban anticoagulation was superior to 3 months in cancer patients with deep vein thrombosis.57 In the next part of this study, the edoxaban dose of 30 mg was compared with the standard dose of 60 mg.58 The validity of 12-month anticoagulation was confirmed for both doses, but only the higher dose; that is, 60 mg during 12-month anticoagulation, resulted in significantly higher rates of bleeding.

Results from one registry study confirm the validity of reducing the anticoagulation dose in long-term treatment.59 The authors observed a low frequency of recurrent VTE, and a decreased rate of bleeding. The beneficial effect was more pronounced in patients with cancer compared with others.

The RENOVE study was not focused solely on cancer patients, but it may be cited as a supporting argument to justify reducing the dose of anticoagulation after 6 months.60 This open-label study included patients with a high risk of VTE recurrence, but most (>60%) had cancer as a predictor of increased risk of VTE recurrence. Subjects were randomly assigned either a reduced dose of apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily), or a full dose of apixaban (5 mg twice daily) or rivaroxaban (20 mg once daily). VTE recurrence was 2.2% in the reduced-dose groups and 1.8% in the full-dose groups (adjusted HR 1.32; 95% CI [0.67–2.60]; absolute difference 0.40%; 95% CI [−1.05, 1.85]; p=0.23 for non-inferiority). The study failed to demonstrate non-inferiority of reduced dose of NOACs. Nevertheless, reducing the dose of anticoagulation resulted in a significant reduction in the risk of major or clinically relevant bleeding (5-year cumulative incidence 9.9% versus 15.2%; adjusted HR 0.61; 95% CI [0.48–0.79]).

The EVE study, although small, was the first in a cancer population to show that reducing the dose of apixaban from the full therapeutic dose of 5 mg twice daily to 2.5 mg twice daily may provide similar anticoagulant efficacy and probably result in a lower risk of bleeding, although the benefit was noticeable only after the next 6 months of anticoagulation.61

The much larger API-CAT study showed a decidedly significant benefit in reducing the risk of bleeding with apixaban if, after at least 6 months of anticoagulation, it is continued at a reduced dose of 2.5 mg twice daily instead of the full therapeutic dose (5 mg twice daily).62 The benefit was very significant during the 12-month study. The study was based on the assumption of non-inferiority for the primary point of observation; that is, the effectiveness of anticoagulation. API-CAT confirmed that the reduced dose of apixaban in prolonged anticoagulation is as effective as the full therapeutic dose. It is worth emphasising that the API-CAT study reflects everyday practice. The majority of patients in the study were patients with breast, lung and colon cancer.

When are Non-vitamin K Antagonist Oral Anticoagulants not the Best?

The previously cited meta-analysis shows that NOACs are not more effective in haematological malignancies.39 Furthermore, there is no greater efficacy of NOACs compared with dalteparin in patients with more advanced cancers expressed as metastatic disease or significantly reduced performance status, defined as an Eastern Cooperative Oncology Group (ECOG) score ≥2.

Another clinical problem is a risk of bleeding observed in patients with haematological malignancies or brain tumours. The retrospective cohort study included 143 patients with active haematological malignancy and newly diagnosed VTE treated with LMWH or NOACs.63 The outcome was very similar regarding a composite endpoint with recurrent VTE, major bleeding or clinically relevant non-major bleeding (24.2% for LMWH versus 18.5% for NOAC; HR 1.51; 95% CI [0.695–3.297]).

Regarding safety in brain tumours, a multicentre, retrospective cohort study was focused on 111 patients with a diagnosis of primary brain tumour or secondary brain metastases who were treated with either NOAC or LMWH due to VTE.64 No significant differences were found between NOAC and LMWH: intracranial haemorrhage 4.3 versus 5.9% (p=0.61), all bleeding events 14.3 versus 27.8% (p=0.10) and recurrent VTE 5.6 versus 6.6% (p=0.96), respectively.

At least two studies have evaluated NOAC and LMWH in patients with primary and secondary brain tumours. In one study, the cumulative incidence of any intracranial haemorrhage was 0% in patients receiving direct oral anticoagulants versus 36.8% in patients treated with LMWH (additionally, a major incidence in 18.2%).65 In patients with brain metastases, there were no differences between direct oral anticoagulants and LMWH regarding intracranial haemorrhage: 27.8 versus 52.9% for all, and 11.1 versus 17.8% for major episodes.

A second study confirmed patients with primary nervous system tumours also benefit significantly more from NOACs.66 In the same study, no significantly greater benefit was demonstrated from the use of NOAC in patients with secondary brain tumours, although the trend of greater benefit was still maintained, and the result probably depends on the nature of the primary tumour that metastasises to the brain.

When to Prefer Low-molecular-weight Heparin?

European Society for Medical Oncology and European Society of Cardiology guidelines suggest when the use of LMWH is preferred. One meta-analysis clearly confirms a trend of increased gastrointestinal bleeding risk for NOACs compared with dalteparin, mainly due to the results of the HOKUSAI and SELECT-D studies.67 The CARAVAGGIO study was the only one that did not confirm increased gastrointestinal bleeding. However, it is important to note the limitations of the CARAVAGGIO study. For example, patients with high-risk gastrointestinal and genitourinary cancers were excluded, which could impact the final results. The latest real-world data confirm a statistically insignificant, but clear trend of increased gastrointestinal bleeding risk in the case of rivaroxaban compared with apixaban.68

Oral anticoagulants may have significant pharmacological interactions with concomitant cancer therapies.69,70 It is reported that the impact of metabolism of coexisting anticancer drugs on the efficacy and safety of apixaban may be minimal, and the risk of bleeding is statistically insignificant.71 Nevertheless, when combining NOAC with antiangiogenic drugs, a higher risk of bleeding may be expected. The risk of bleeding may be lower when LMWH is administered together with vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors. Although the results are, again, not unequivocally statistically significant, the trend is very clear.72

Next, the clinically important problem for anticoagulation is thrombocytopaenia. If the platelet count is <50,000/µl, LMWH should be used at half the therapeutic dose or even at the primary prophylactic dose.73 The authors of the European Hematology Association guidelines proposed such a clinical decision, emphasising that it is based on an individual cohort study, including a low-quality randomised control study. This recommendation was previously proposed by experts from the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on Haemostasis and Malignancy, and the quality of evidence was defined as a moderate consensus among the panel members.74

Bleeding during anticoagulation is a significant clinical problem in cancer patients, because they have specific risk factors. By evaluation of the efficacy and safety of dalteparin or apixaban, the CARAVAGGIO study confirmed the following as independent predictors of major bleeding: ECOG status of 2 (HR 2.31; 95% CI [1.24–4.29]), genitourinary cancer (HR 2.72; 95% CI [1.28–5.77]), upper gastrointestinal cancer (HR 3.17; 95% CI [1.22–8.23]) and non-resected luminal gastrointestinal cancer (HR 2.77; 95% CI [1.38–5.56]).75

A prospective oncology study with apixaban (5 mg twice daily for 6 months, and then 2.5 mg apixaban twice daily for 30 months) identified the following risk factors of clinically relevant bleeding: age >74 years (OR 2.0; 95% CI [1.0–4.1]), BMI <21.7 (OR 2.3; 95% CI [1.1–4.8]) and haemoglobin at baseline <10.5 g/dl for women (OR 2.8; 95% CI [1.1–7.3]) and 11.1 g/dl for men (OR 3.3; 95% CI [1.3–8.4]).76 The authors observed episodes of bleeding mainly during the first 6 months of anticoagulation.

The largest observational, retrospective and multicentre study based on electronic health records of 21,227 patients with active cancer and VTE treated with anticoagulants found some significant predictors of major bleeding: haemoglobin, metastasis, age, platelets, leucocytes and serum creatinine.77

When to Stop Anticoagulation?

Anticoagulation may be less effective in patients with cancer and a lower performance status expressed as ECOG Performance Status Scale 2, compared with patients with a better performance status ECOG equal to 0 or 1.78 It can be assumed that in very advanced cancer, where the end-of-life stage and the toxicity of anticancer treatment overlap, frailty syndrome develops due to the progression of the cancer, and the benefit obtained from anticoagulation may be offset by the frequent occurrence of bleeding. Creating an algorithm for the optimal moment of discontinuation of anticoagulation is the subject, among others, of the SERENITY study.79

There are still some therapeutic uses for vitamin K antagonists (VKA). The first example for VKA preference remains the management of patients with mechanical heart valves.80 Other examples include patients with end-stage renal disease, thrombotic antiphospholipid syndrome, cerebral venous sinus thrombosis and rheumatic atrial fibrillation.81 Such patients may have diagnosed cancer. The discussion about the use of VKA in cardio-oncology is absolutely justified due to an increased real risk of bleeding. Most patients, even with advanced cancer, continue VKA therapy.82 However, the results of one study on the use of VKA indicate a progressive deterioration in the quality of anticoagulation with approaching the end of life.83 Importantly, greater than every third patient required significant changes in VKA dosage in the last quarter of life. A particularly unfavourable picture of treatment control was obtained in the group of cancer patients in whom the decreased quality of anticoagulation control began 6 months before death. Compared with non-oncological patients, patients with cancer showed a higher international normalised ratio variability and more frequent VKA dose adjustments, and required more intensive monitoring.

The development of better standards for personalised selection of anticoagulation, dosage changes during long-term management and even defining the moment of discontinuation of anticoagulation in advanced cancer should be a subject of research by cardio-oncologists in the near future.84–86

Conclusion

The choice of anticoagulants in cardio-oncology must be personalised (Table 1). Just as the appropriate anticancer drug is selected for an individual patient (mainly based on molecular diagnosis), anticoagulation must be personalised. The decision for both drugs will be influenced by the type of cancer diagnosis, its advancement and the treatment methods (previous and current). Of course, searching for the drug that is most effective and safest (with the lowest risk of bleeding) is crucial. In many countries, economic (price of NOAC) and logistical (use of injections) considerations will also determine the choice. However, ultimately, the most important factor is the patient’s willingness to accept a proposed anticoagulant therapy, including its side-effects.

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