Chair UKCPA – HAT and Head of Clinical Pharmacy, University Hospital Southampton
NHS Foundations Trust
Consultant Haematology Pharmacist,
Wirral University Teaching Hospitals NHS Foundation Trust
Oncology Specialist Pharmacist, University Hospital Southampton NHS Foundations Trust
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant cause of death and morbidity in the UK. Between 25,000 and 32,000 deaths per annum are attributed to hospital-acquired VTE. This is more than the total combined deaths per year from breast cancer, AIDS and road traffic accidents and more than 25 times the number who die from MRSA.
Hospital trusts in England are penalised financially if they cannot prove that 90% of adult patients admitted to hospital have had a VTE risk assessment and a bleeding risk assessment. It is assumed that this systematic risk assessment process will result in the appropriate prescribing of thromboprophylaxis, which will substantially reduce VTE-related mortality and death.
Reducing the incidence of hospital-related VTE is the responsibility of the whole multidisciplinary team across both primary and secondary care.
All adults admitted to hospital are at increased risk of developing venous thromboembolism (VTE). Active cancer is an additional causative risk factor and consequently cancer patients are at high risk of developing a VTE. Ensuring appropriate thromboprophylaxis throughout the full period of care of an oncology patient is a real challenge. These patients may be seen on a mainly out-patient basis. They will receive therapy as a standard part of their care that directly influences their risk of developing a clot or increases their risk of bleeding so that the continuation of any pharmacological thromboprophylaxis is no longer recommended. In order to ensure that this group of patients is given the right thromboprophylaxis for the right duration, it is essential that oncology patients are reviewed on a daily basis during an in-patient stay or when clinical parameters change and at every out-patient review.
Three main guidelines are applied to care of oncology patients. Within the UK the National Institute for Health and Clinical Excellence (NICE) has issued guidelines to cover oncology inpatients. Important documents have been developed in the USA by the American Society of Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).
NICE recommends that the majority of patients at risk of VTE should receive mechanical prophylaxis. Mechanical thromboprophylaxis reduces the venous stasis of blood in patients with reduced mobility, which prevents pooling of blood and the propagation of microthrombi. Mechanical thromboprophylaxis is not as effective as pharmacological prophylaxis, but it is not associated with the increased risk of bleeding posed by pharmacological methods.
Antiembolism stockings (AES) are effective if they are an evidence-based brand, and measured and fitted correctly. Patients should be advised to wear stockings continuously during any period of impaired immobility with daily removal for hygiene purposes, to check skin integrity and to exercise feet and toes. Contraindications include conditions associated with poor arterial perfusion, fluid overload, skin disorders and leg deformities. Other mechanical methods include intermittent pneumatic compression devices and foot impulse devices.
Several parenteral anticoagulants are advocated in the NICE guidance:
- unfractionated heparin (UFH)
- low molecular weight heparin (LMWH)
They work by potentiating antihrombin (naturally occuring anticoagulant) and inhibiting the clotting factors thrombin and Factor Xa (fondaparinux only inhibits Factor Xa). UFH is recommended for patients in renal failure (creatinine clearance <15ml/min) as its use is limited by a short half-life, monitoring requirements and risk of heparin-induced thromboctopenia (HIT). For the majority of patients, LMWHs are the agents of choice because of their stable pharmacokinetic profile, reduced monitoring requirements, reduced occurrence of HIT relative to UFH and demonstrated cost effectiveness. In patients with renal failure, a reduced dose should be offered or in severe renal impairment (creatinine clearance <15ml/min) substituted with an UFH. Due to its higher cost, fondaparinux is usually reserved for patients with LMWH-associated HIT. Antiplatelet agents offer inadequate prophylaxis for VTE but form an important part of the bleeding risk assessment.
The association of VTE with underlying malignancy was first reported by Armand Trousseau in 1865 and is supported by the results of a number of more recent studies. Pathophysiological explanations of the aetiology of VTE in cancer include known hypercoagulability (for example pro-coagulants such as tissue factor expressed by cancer cells), vessel wall damage and vessel stasis due to pressure from a tumour. Cancer patients may also undergo prolonged immobilisation, surgical procedures and chemotherapy.
The majority of oncology patients are admitted on a day case basis for chemotherapy. Under the national targets for documented risk assessment, this group of patients is not excluded from the target. Several approaches have been implemented to manage this group: some areas ensure each patient is individually assessed, while in others the medical director has authorised this group as a ‘low risk’ cohort, under Department of Health guidance, so no prophylaxis would be indicated.
Clearly this has the potential for error since certain patients could develop additional risk factors over their period of treatment, such as immobility or dehydration.
The risk factors that need to be taken into account for these patients are: pre-existing risk factors such as a history of VTE, immobility, the type of treatment they are receiving and how it is being administered.
Several chemotherapy treatments increase the risk of DVT. Of particular note are lenalidomide and thalidomide, particularly when used in combination with high-dose dexamethasone, and erythropoietin. A recent meta-analysis of the use of bevacizumab also highlighted increased rates of VTE when this agent is added to chemotherapy regimens.
The use of traditional oral anticoagulants often proves difficult in patients receiving cytotoxic drugs due to known drug interactions. In addition, changes in diet as a result of sickness or changes in taste due to concurrent cytotoxic agents can also result in fluctuations in international normalised ratio. If a patient is already being treated with warfarin, they may be switched to LMWH or UFH, depending on renal function. This should continue for the duration of chemotherapy due to drug interactions, for example 5-fluorouracil and capecitabine increase the INR (the impact of capecitabine may continue for a month after the end of therapy). The chemotherapy prescribed, the need for anticoagulation and cyclical method of administration will need to be taken into account when reviewing the appropriate alternatives.
Other medicines can increase VTE risk and these may or may not be prescribed by an oncologist or haematologist as adjunct or supportive measures. These must also be considered in the risk assessment for VTE risk. Examples include tamoxifen, raloxifene, hormone-replacement therapy, combined oral contraception, nonsteroidal anti-inflammatory drugs, norethisterone or diethylstilboestrol.
Central venous access devices
Many patients treated with intravenous chemotherapy require a ‘central line’ or central venous access device (CVAD), the presence of which has been identified as a major risk factor for upper extremity DVT. The reason for the increased risk may be the result of venous stasis and venous injury after insertion of the CVAD or infections resulting from catheter placement. There are a number of discrepancies between studies of this relationship – which may be due to the recent improvements in catheter materials and design as well as different methods of diagnosing catheter-related DVT, which may be asymptomatic.
NICE guidance suggests that pharmacological or mechanical VTE prophylaxis should not routinely be offered to ambulatory patients with central venous catheters.
In certain situations, both ASCO and NICE advocate extended thromboprophylaxis after discharge. Patients undergoing abdominal surgery for cancers are advised to receive 28 days of pharmacological prophylaxis after abdominal surgery for cancer irrespective of whether the surgery is curative or there is residual tumour. NICE highlights those patients undergoing gynaecological surgery as requiring 28 days of post-operative pharmacological prophylaxis but excludes other abdominal surgery.
Ensuring compliance with this guidance can be challenging. Patients must understand the background for this intervention to ensure that they maintain their treatment for the advised duration. Low molecular weight heparins are the agent of choice as patients or carers can be taught to administer them on discharge. Systems must be in place to ensure effective communication of the treatment plan with the GP and the safe disposal of sharps. Monitoring for heparin-induced thrombocytopenia is required and this may be complicated by chemotherapy’s potential to cause blood dyscrasias.
The new oral anticoagulants may support discharge processes and will certainly offer some flexibility with this patient group when they are available. Apixiban (Bristol-Myers Squibb/Pfizer) is an oral Factor Xa inhibitor and has recently been licensed for elective orthopaedic hip and knee surgery. However, trials are also underway for the use of apixiban (ADOPT) for the prophylaxis of VTE in medical patients.
The MAGELLAN trial of rivaroxiban (Bayer) showed superiority over enoxaparin and placebo in the acutely ill medical population with long-term use (35 ± 4 days) but also showed an increase in bleeding rates in the rivaroxaban arm over enoxaparin plus placebo from day 10 onwards. This trial was presented at the American College of Cardiology congress. Further analysis of the diverse groups within MAGELLAN is required, to allow identification of specific groups who would derive benefit from thromboprophylaxis with rivaroxaban. Other agents are in development but the potential for a licence for this indication is not known.
Prophylaxis in specific populations Solid tumours
Every cancer patient presents their own combination of risk factors for VTE and for bleeding. Therefore, the perceived risk of bleeding needs to be assessed against the stage and type of cancer. Patients with brain, pancreas, stomach, bladder, gynaecological, lung and kidney tumours and metastatic disease are considered to be at increased risk of VTE. The bleeding risk increases with thrombocytopenic episodes during chemotherapy, platelet dysfunction and organ or vascular invasion by tumours.
Cancer patients who are admitted for a medical reason or as part of their oncological treatment should have chemical prophylaxis in the form of LMWH, fondaparinux sodium or UFH (for patients with renal failure) if they have had or are expected to have significantly reduced mobility for three days or more, or are expected to have ongoing reduced mobility relative to their normal state. The risk assessment should be reviewed regularly because the situation can change particularly regarding the risk of bleeding.
The LMWH licences differ. At the time of writing, tinzaparin is licensed only for surgical prophylaxis; enoxaparin is licensed for prophylaxis of bedridden medical patients and dalteparin is licensed for the treatment and extended prophylaxis of patients with solid tumours and symptomatic VTE. The treatment lasts six months in total and the first month is at a higher dose.
The datasheet also lists dose reductions for thrombocytopenia of 50–100 x 10/l. If these products are used outside their licences, written informed consent should be obtained from the patient.
NICE states that the LMWH of choice depends on local practice. There are advantages in patient safety and cost-effective purchasing to having one LMWH for the local health economy and to that end the drugs and therapeutics committee may take responsibility for off-licence use.
Thalidomide and lenalidamide are both used in the treatment of myeloma and as stated earlier they are associated with an increased risk of VTE. Studies differ as to the extent of the problem and how it should be managed but recent guidance advises using LMWH when patients are treated with these agents in combination with dexamethasone or chemotherapy. Patients with myeloma may have fluctuating renal function and plasma viscosity that needs to be taken into account during assessment for prophylaxis and drug selection. More detailed assessment has been suggested for patients with myeloma thus stratifying their risk further and identifying a cohort of patients who may be suitable for aspirin prophylaxis alone.
Recently the Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice concerning both lenalidomide and thalidomide and their link with an increased risk of arterial thromboembolism.
The MHRA advises the use of prophylactic measures for both arterial and venous thrombosis.
The majority of patients with lymphoma will be treated as out-patients. ASCO advises that this patient group does not require routine VTE prophylaxis. Patients with high-grade lymphoma, however, appear to be at higher risk of VTE due to extrinsic vascular compression. When lymphoma patients are treated as in-patients they will undergo routine assessment and appropriate prophylaxis. The NCCN states that if a LMWH is used it should be reviewed if the patient’s platelet count falls below 50 x 10/l, a possible chemotherapy effect. In addition, care needs to be taken if low molecular weight heparins are used in patients undergoing treatment for lymphoma or leukaemia whose chemotherapy may include intrathecal injections. The timing of the last dose of LMWH should be checked before carrying out a lumbar puncture. Many units complete a full clotting screen as part of their pre-intrathecal checks and correct the parameters before proceeding.
Patients with acute promyelocytic leukaemia appear to be at higher risk of VTE than patients with other leukaemias. Leukaemia patients are often hospitalised for long periods of isolation and may have reduced mobility during that time. Leukaemia patients are very likely to suffer from thrombocytopenia due to their chemotherapy treatment and daily monitoring of their platelet count can determine when thromboprophylaxis is appropriate, stopping when platelets fall below 50 x 10/l.
VTE is a common and life-threatening complication for cancer patients with an incidence between 4% and 20%. It is considered one of the leading causes of death in this patient group. Careful assessment for VTE risk of patients with cancer and undergoing chemotherapy treatment is essential along with the use of appropriate prophylactic measures.
As part of the oncology team, pharmacists are well placed to offer advice on appropriate treatment choices and monitoring parameters in this evolving area of cancer care. As our treatment outcomes improve in all areas of oncology, and this patient population grows, increased activity is required to ensure that all measures are taken to prevent avoidable harm to patients.
VTE prophylaxis may be more complex in cancer patients but this should not exclude them from this simple intervention that holds great benefit and prevents morbidity and mortality.
1. Report on the prevention of venous thromboembolism in hospitalised patients. House of Commons Health Committee. www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/99/99.pdf. accessed 24 May 2011.
2. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE. Jan 2010 [AQ3: is this date of access? Also please supply more details so readers can access]
3. American Society of Clinical Oncology Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 25; 34: 5490–5505.
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6. Consensus guidelines for the management of deep venous thrombosis in multiple myeloma. Proceedings of 13th International Myeloma Workshop May 2011. www.myeloma-paris2011.com/files/files/ConsensusPanel1DVTTheFinal.pdf
7. MHRA Drug Safety Update July 2011, 4: A1.