Thromboembolic risk management in cancer patients

Introduction

Thromboembolism (TE) in clinical oncology covers the problem of the occurrence of both venous (VTE) and arterial thromboembolic (ATE) events.

The common pathophysiological trigger for ATE and VTE is damage to or dysfunction of endothelium. Whereas many anticancer therapies significantly affect endothelial function, TE may be a clinical manifestation of their off-target toxicity.

Each step of TE risk management, primary and secondary, should be related to the type of cancer disease and the type of anticancer therapy used (Table 1).

Table 1. Risk factors of thromboembolism specific only for cardio-oncology.

* there is no clear confirmation for risk of arterial thromboembolism (ATE) especially myocardial infarction; # there is no clear confirmation for risk of venous thromboembolism (VTE)

The risk associated with cancer disease

Cancer disease (especially metastatic) is a significant risk factor for VTE. The risk of VTE is several times higher in cancer patients in comparison to the general population. The highest relative risk is observed in patients with multiple myeloma, brain and pancreatic cancer; however, the highest absolute number of patients with VTE (venous thrombosis or pulmonary embolism) is observed in lung, colon and prostate cancer [1].

VTE can predict the diagnosis of cancer disease at different stages. Patients with high-grade tumours have higher D-dimer levels (p=0.008), higher leukocyte counts (p=0.001) and lower haemoglobin levels (p=0.008) and may experience VTE events more frequently than those with low-grade tumours (8.2% vs4.0%; log-rank test p=0.037) [2].

The risks associated with cancer treatment

Anticancer therapies, including surgery, hospitalisations and drugs, may be understood as significant risk factors for VTE.Many anticancer drugs can damage the endothelium and increase the risk of VTE. Some chemotherapy regimens and targeted molecules may cause not only venous complications but also arterial events, which seem to be underestimated in daily practice (Table 1).

Primary thromboprophylaxis of VTE

Algorithms of thromboprophylaxis need to be individualised and the expected benefit must always outweigh the risk of bleeding.

Surgery and hospitalisation are such important risk factors for VTE in cancer patients that scientific societies, such as the American Society of Clinical Oncology (ASCO), decided to offer primary thromboprophylaxis [3] for:

• hospitalised patients who have active malignancy and acute medical illness or reduced mobility;
• all patients with malignant disease undergoing major surgical intervention.

Pharmacologic thromboprophylaxis with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH: e.g., enoxaparin 40 mg once daily, dalteparin 5,000 IU once daily) is preferred in surgery.

There are two special populations with a very high risk of VTE-brain tumours and multiple myeloma on specific therapy (Table 1). ASCO has confirmed that patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH (respectively, according to an estimated lower or higher risk of VTE).

Khorana analysed risk associated with other neoplasms and developed a simple predictive model for VTE in outpatients treated with chemotherapy [4]. Characteristics of anticancer drugs have not been included, but the location of the tumour, result of morphology and BMI are scoring:

• points for cancer type defined as below:

• • stomach, pancreas: 2 points
  • lung, lymphoma, gynaecologic, bladder, testicular: 1 point

• and 1 point for each of the following:

• • Pre-chemotherapy platelet count ≥350x10⁹/L
  • Haemoglobin level <10 g/dL and/or use of erythropoiesis-stimulating agents,
  • Pre-chemotherapy leukocyte count >11x10⁹/L
  • BMI ≥35 kg/m²

Khorana et al defined ≥3 points as high risk for VTE and the first studies concerning the effectiveness of LMWH (e.g., dalteparin 5,000 IU daily) included such patients. However, the newest ASCO recommendations defined high-risk outpatients as having a Khorana score ≥2 prior to starting a new systemic chemotherapy regimen and decided that such patients may be offered thromboprophylaxis with apixaban, rivaroxaban, or LMWH, provided there are no significant risk factors for bleeding and no drug interactions. This is a consequence of the publication of two randomised clinical trials which showed a significant 60% reduction in VTE through the use of a direct oral anticoagulant (DOAC), rivaroxaban [5] or apixaban [6] (Table 2).

Table 2. Safety of the use of new oral anticoagulants in the prevention and treatment of VTE in clinical oncology.

*Reduction of dose was possible according to trial protocol; # There was a subgroup of patients with cancer diagnosed within 2 years before the study. VTE: venous thromboembolism

Anticoagulant treatment for VTE

Cancer is a strong risk factor for mortality after VTE. In each VTE case, malignancy progression and poorer response to chemotherapy should be expected. Recurrent VTE could be observed in patients with cancer diagnosed during active anticoagulation. The increased risk of recurrent VTE is greatest in the first few months after malignancy diagnosis but it can persist for many years. The long-term risk of chronic thromboembolic pulmonary hypertension is also real.

There is the real problem of a high prevalence of incidental, asymptomatic pulmonary embolism in oncology. The prognosis of incidental VTE is the same as in symptomatic events, including the risk of recurrent VTE and poor overall survival.

The 2014 European Society of Cardiology (ESC) recommendations for the treatment of VTE in cancer patients allowed the use of LMWH for 3-6 months [7]. Such therapy was uncomfortable and, compared to a vitamin K antagonist (VKA), did not decrease the mortality [8].

The 2019 ESC guidelineshave changed daily practice and new therapeutic options have been proposed for cancer patients [9]:

• LMWH should be considered for the first 6 months over VKAs: e.g., dalteparin (100 IU/kg twice daily or 200 IU/kg once daily), dose reduced by 25% (150 IU/kg once daily) after 30 days of treatment;
• Edoxaban or rivaroxaban should be considered as an alternative to LMWH in patients without gastrointestinal cancer.

Randomised trials have proven that edoxaban and rivaroxaban can be at least as effective as dalteparin [10, 11]. Bleeding observed in cancer patients, especially those with gastrointestinal neoplasms, may be a clinical problem; the limitation of indications is justified (Table 2).

The latest randomised controlled trials, published after the 2019 ESC guidelines, concern the use of apixaban.The Caravaggio study [12] included the largest group of cancer patients and showed that apixaban compared to dalteparin can be able to reduce VTE recurrence (p<0.001 for noninferiority; p=0.09 for superiority) without increased risk of major bleeding even gastrointestinal. The ADAM VTE trial [13] evaluated major bleeding as the primary outcome and showed the most promising safety of apixaban in cardio-oncology.

In patients with active cancer disease (i.e., distant metastases), secondary thromboprophylaxis should be continued beyond 6 months. The DALTECAN study [14] confirmed the validity of this procedure. Although the ASCO suggests that oral anticoagulants should be preferred in this situation, the dosage of DOAC has not yet been defined. We only know that, in the Hokusai study, continuing the same dose of edoxaban until 12 months resulted in additional benefits in preventing VTE recurrence [10].

Understanding of ATE risk

Current epidemiological data show that more and more ATE events such as myocardial infarction and ischaemic stroke can be observed in patients with advanced cancer disease [15]. ATE complications are observed in the same neoplasms as VTE, which confirms the association with the cancer-related increased prothrombotic status. The risk of ATE is significantly increased at the moment of cancer diagnosis (period defined as one month before and one month after). Despite the anticancer treatment used, it remains significant for another year.

Anticancer drugs can directly damage endothelial cells, inhibit their proliferation, reduce the number of endothelial progenitor cells, i.e., they simultaneously damage the endothelium and reduce its renewal and repair capacity [16]. These lead to ATE and VTE. The most surprising results may be observed for vascular endothelial growth factor (VEGF) inhibitors, because these drugs could cause VTE and ATE with at least equal force. Meanwhile, bevacizumab seems to be a strong independent risk factor for the occurrence of ATE but not for VTE [17]. The influence of tyrosine kinase inhibitors with anti-VEGF and anti-BCR-ABL activity on platelet function and endothelial dysfunction is not clearly explained, but it seems to be of key importance in the induction of ATE by these drugs.

The prevention strategy for ATE in oncology should be based on optimal control of the risk factors of atherosclerosis. Statins and aspirin should be used in patients with confirmed atherosclerosis. Percutaneous intervention with stenting can be necessary for most cases presenting as acute coronary syndromes; however, cancer is recognised as an important risk factor for early and late stent thrombosis. Therefore, new generations of drug-eluting stent (DES) should be used, and the duration of dual antiplatelet therapy should be individually defined in relation to bleeding risk.

Special consideration for atrial fibrillation

The CHADS-VASc score and HAS-BLED score have not yet been validated in clinical oncology, so it is not known what the indications for anticoagulation should be in cancer patients with atrial fibrillation (AF) receiving anticancer drugs affecting the endothelial function and modifying the prothrombotic risk. The available data indicate that many patients with AF on current chemotherapy, with a history of bleeding, renal dysfunction, or thrombocytopaenia (induced by cancer disease or anticancer therapy) do not receive anticoagulation even though they have a CHADS-VASc score ≥2 and a HAS-BLED score<3 [18].

LMWH is used as the traditionally preferred alternative, but there is no evidence for its efficacy in stroke prevention. The prevailing opinion is that LMWH should be used as a short-term measure and in selected situations [19]. Anticoagulation with DOAC should be preferred. The available analyses show that anticoagulation with DOAC compared to VKA is more effective in preventing ischaemic or haemorrhagic stroke and systemic embolisms, and safer (less major bleeding, less gastrointestinal or intracranial bleeding) [20].

Conclusion

The degrees of coagulation disorders and endothelial damage as factors induced by both cancer disease and anticancer treatment determine the TE risk. There is a need to protect against all possible vascular complications by using anticoagulation, preferably with oral administration and a suitable safety profile.