Clinical significance of VTE in cancer

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a significant cause of morbidity and mortality in patients with cancer.1 The presentation, epidemiology and prevalence of VTE varies between cancer and non-cancer patients and the outcome for cancer patients is worse than for non-cancer patients.

Cancer is thought to create a hypercoagulable state where neoplastic cells activate the coagulation cascade through a number of pathways. These include production of procoagulants, release of proinflammatory and proangiogenic cytokines and direct vessel wall damage.(1)

The link between cancer and VTE is well established.(2) There is two-way relationship between cancer and VTE: the risk of VTE is increased fourfold in cancer patients and patients with unprovoked VTE have a higher risk of occult cancer.2,3 Underlying cancer should always be considered in patients presenting with VTE, especially if there is no identifiable risk factor. Cancer is responsible for 18% of all cases of incident VTE.(1) The role of cancer screening in incidental VTE requires further investigation.(2)

The risk of cancer-associated VTE is highly variable owing to the heterogeneity of the disease. A recent meta-analysis quotes the incidence of VTE in cancer patients ranging from 0.5% to 20%.3 Variation in incidence is dependent on many factors including tumour type, stage of disease and the treatment given for cancer. The incidence rate of VTE is highest in the first few months after diagnosis and decreases over time.(2)

Risk factors for developing VTE in cancer patients may be treatment-related, patient-related or disease-related.(4,5) Greater tumour burden, histology and the primary site of the cancer have been identified as risk factors with cancer of the pancreas, lung, brain, ovaries, stomach among some of the sites identified as high risk.(2–4)

Many drugs are associated with increased risk of VTE such as the anti-angiogenesis agents, bevacizumab, lenalidomide and thalidomide.1 Specific chemotherapy agents can increase risk, for example, cisplatin is associated with a higher risk of VTE than oxaliplatin, or drugs may add to the risk when used in combination, for example, doxorubicin or dexamethasone with the immunomodulatory drugs (iMIDs) thalidomide and lenalidomide.(1,2,4)

Hormonal therapy, for example hormone-replacement therapy or anti-oestrogens, such as tamoxifen, and supportive care with erythropoiesis-stimulating agents (EPO) can further add to the risk.(1,2,4)

Other treatment-related factors include transfusion, presence of central venous catheters and radiotherapy.(5) As for patients without cancer, the risk of VTE is higher in cancer patients with coexisting chronic medical illnesses, undergoing major surgery or hospitalisation.

Hospitalised cancer patients, and those undergoing surgery, should receive thromboprophylaxis and, in the case of surgery, extended prophylaxis.(2,4)

The role of thromboprophylaxis in ambulatory outpatients with cancer is less clear and they should not routinely receive pharmacological thromboprophylaxis.(2,4,6) However, certain groups, including patients receiving iMIDs, should be given pharmacological thromboprophylaxis with low-molecular weight heparin (LMWH) or alternatives.(2,4)

Pharmacists should take every opportunity to educate patients about the risk of VTE and the associated signs and symptoms. VTE risk assessment should be a routine part of pre-chemotherapy checks and is a potential area in which pharmacists can develop their role.

The aim of treatment is to prevent fatal pulmonary embolism, reduce the risk of VTE recurrence or VTE complications. Patients with cancer who have established thrombosis are at increased risk of recurrent VTE and of anticoagulant-associated bleeding compared with non-cancer patients.(5)

The use of vitamin K antagonists (VKAs), for example, warfarin or other coumarins, can be particularly complex in cancer patients for a number of reasons.

VKAs are associated with significant drug interactions, including chemotherapy agents (for example, capecitabine) or those commonly used to treat infections in cancer patients (for example, ciprofloxacin, fluconazole). Cancer patients might be older, and have co-morbidities requiring concurrent medications, and could find dose titration potentially confusing.

Poor venous access may result from treatment, thereby making therapeutic drug monitoring more difficult. Invasive procedures, such as line insertion or chemotherapy induced-thrombocytopenia, might necessitate interruption to therapy and the requirement for reversal of the anticoagulant effect.(6) For surgical patients on VKAs, a bridging plan may be necessary.

Malnutrition, gastrointestinal disturbances (for example, disease or chemotherapy-related nausea, vomiting and diarrhoea) and treatment- or disease-related liver impairment can all lead to an unpredictable response to VKAs in cancer patients.

Randomised, controlled studies have compared LMWHs (including dalteparin, enoxaparin and tinzaparin) to VKAs in the long-term treatment of VTE in cancer patients.(7) Of these, the CLOT (Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy) trial, a large study comparing dalteparin with warfarin, demonstrated a statistically significant reduction in VTE recurrence with dalteparin; the number of patients needed to treat was 12 to prevent one episode of recurrent VTE.(8)

There was no difference in the risk of bleeding and mortality with dalteparin compared with warfarin. As the highest risk of recurrence for VTE is in the first month, the dosing schedule for dalteparin in this study was designed to provide intensive anticoagulation initially and reduce the risk of anticoagulant-related bleeding over the long term.(8) Dalteparin is specifically licensed for treating and preventing recurrence of VTE in cancer patients.

A Cochrane meta-analysis published in 2011 showed that compared with warfarin, LMWHs reduce the risk of recurrent VTE when used for the extended treatment of VTE with comparative bleeding and mortality rates.(7)

Key guidelines (from ESMO, ASCO, NCCN and ACCP) recommend LMWHs over VKAs as the preferred agents for long-term treatment of cancer-associated thrombosis.(2,4–6) LMWHs are also recommended as an option for initial therapy in the ESMO and NCCN guidelines and favoured over unfractionated heparin (UFH) by ASCO.(2,4,5)

LMWHs are associated with fewer drug–drug or drug–food interactions than VKAs and are more convenient than UFH as they do not require hospital admission for administration. LMWHs offer greater flexibility than VKAs in terms of onset of action and clearance, and are therefore useful for patients undergoing surgery or other invasive procedures requiring interruption in anticoagulation.(8) LMWHs have more predictable pharmacokinetics and therefore do not generally require the laboratory monitoring associated with VKAs and UFH (with the exception of renal insufficiency; see special groups below). Disadvantages of LMWHs include drug cost and the need for daily subcutaneous administration.

There is a suggestion that heparins may have antineoplastic effects, which could lead to improved survival in cancer patients.(5) Data are inconclusive and insufficient to recommend the use of anticoagulants in cancer patients in the absence of VTE to improve survival.(2,4)

Data regarding duration of therapy for LMWHs are not conclusive, but guidelines recommend a minimum of six months and longer if the stimulus for thrombosis remains, for example, active cancer, ongoing chemotherapy or other risk factors.(2,4)

The role of novel oral anticoagulants (NOACs), such as direct thrombin inhibitors or anti-factor Xa inhibitors, is unclear and the evidence is insufficient to recommend their use for the prevention and treatment of VTE in cancer patients at this time.(4)

Appropriate dosing of treatment dose LMWH in renal impairment represents a challenge. Data are limited in this patient population as many studies excluded patients with creatinine clearance (CrCl) <30ml/min.(6) LWMHs are excreted renally, with clearance of the anti-Xa effect correlating with creatinine clearance (with the exception of tinzaparin).(6,9) Decreased clearance has been associated with increased bleeding risk.(2,4)

Approaches to consider for patients with CrCl <30ml/min include use of UFH/VKAs or anti-Xa monitoring with or without dose reduction.(6) The degree of accumulation, and therefore the magnitude of dose adjustment required, varies between the different LMWH products. Only enoxaparin has specific licensed dosing for renal impairment.

Key guidelines recommend using anti-Xa monitoring if using LMWHs in patients with CrCl < 30ml/min.(2,4,6) For institutions unable to monitor anti-Xa levels, it may be safer to consider treatment with a UFH/VKA.(4,9)

Nutescu et al suggests that dose reduction for tinzaparin and dalteparin when used for prophylaxis is not necessary where treatment duration is for 10 days or less.(9) For cancer patients requiring extended prophylaxis, consideration should be given to monitoring anti-Xa levels.(9) The manufacturers of enoxaparin recommend reducing prophylactic doses in patients with CrCl <30ml/min.

Additional data are required to guide dosing of LMWHs in obesity. As LMWHs are distributed into the intravascular compartment, there is debate as to whether actual or lean body weight should be used.(9) Use of actual body weight could lead to over-anticoagulation; conversely obese patients may be at risk of under-dosing if dose-capping is employed.(4,9)

Nutescu and colleagues recommend using total body weight for dosing obese patients and monitoring anti-Xa levels in patients >190kg.(9)

Monitoring the therapeutic effect of LMWH with anti-Xa has its limitations. Anti-Xa therapeutic ranges need to be established and there is significant variation in reporting between laboratories.(9)

Managing anticoagulation with VKAs in cancer patients can be challenging. LMWHs are associated with a lower risk of VTE recurrence in cancer patients, with no difference in bleeding risk or mortality when compared with warfarin. As with non-cancer patients, further data are required to support the prescribing of LMWHs in renal impairment and obesity.

Pharmacists have an important role to play in ensuring that drugs that contribute to VTE risk are identified in patients’ medication histories and can be considered when assessing risk of thrombosis.

In addition, pharmacists are well placed to educate patients about VTE risk and support the safe management of anticoagulation.

NOACs are of interest, but current evidence is insufficient to support use in cancer patients at this time. Anti-Xa monitoring is important for the safe management of LMWHs in renal impairment and obesity but further

data are required to establish therapeutic levels.