Supra-Regional Audit Anticoagulation in Palliative Care 4 th March 2010 Dr Helen Emms Dr Carolyn Watt Denise Farrance Dr Richard Latten Dr Leslie Johnny
Overview Review of current standard & guidelines Helen Emms Summary of coagulation & anti-coagulants Carolyn Watt Literature review Leslie Johnny Audit Data Richard Latten Proposed updates to standards & guidelines Helen Emms
Review of current standards & guidelines Dr Helen Emms Consultant in Palliative Medicine St John s Hospice Wirral
Guidelines General management of suspected Deep Venous Thrombosis (DVT) / Pulmonary Embolism (PE) Decisions surrounding the use of anticoagulation in patients with advanced cancer should be discussed with a senior physician. Figure 3.1 illustrates some general guidelines regarding the investigation and management of thromboembolic disease. [Level 4]
Aims and duration of anticoagulation Table 3.1 illustrates: The suggested duration of treatment for patients on warfarin and LMWH, and The target INR for patients on warfarin. [Level 4] Oral anticoagulation may be stopped abruptly when the duration of therapy is completed. [Level 2] Advice on the management of bleeding and /or high INR is given in Table 3.2. [Level 3]
Low Molecular Weight Heparin (LMWH) In some patients LMWH may be a better choice for patients than warfarin. Possible clinical indications for use of LMWH include: Treatment of thromboembolic disease e.g. DVT / PE whilst warfarin therapy is being initiated. Heparin treatment is usually temporary and is stopped when adequate anticoagulation with warfarin is achieved i.e. INR >2. [Level 4] Long term treatment of thromboembolic disease where warfarin therapy is not appropriate e.g. liver disease, unstable INR, difficult venepuncture (see Figure 3.1). [Level 4] Extension of the thrombus despite the use of warfarin. [Level 1+]
Low Molecular Weight Heparin (LMWH) - continued Prophylaxis of DVT in appropriate patients e.g. first five months of treatment with thalidomide in patients with additional thrombotic risk factors; 15 in patients taking diethylstilboestrol there is a significant increase in the risk of deep vein thrombosis and decisions should be made on an individual patient basis. Daily injections are more acceptable to patients than anti-embolic stockings. [Level 2++] There are a number of Low Molecular Weight Heparins available. They include Dalteparin, Enoxaparin and Tinzaparin. Choice will vary according to local policies. They are all given using a once-daily administration schedule via the subcutaneous route. There may be clinical situations where a split twice-daily dose schedule gives better symptom control. [Level 4]
Low Molecular Weight Heparin (LMWH) - continued Renal function should be checked prior to, and during treatment with LMWH. Renal impairment may require dose adjustment. [Level 4] All LMWH treatment doses are calculated according to the weight of the patient. Table 3.3 gives the dosing schedule for dalteparin. Other drug doses are available in the BNF. [Level 3] The recommended prophylactic dose of dalteparin is 5000 units daily via the subcutaneous route. [Level 3] Contraindications to treatment with LMWH are listed in Table 3.4. [Level 3]
Table 3.3
Table 3.4
Low Molecular Weight Heparin (LMWH) - continued The risk of heparin-induced thrombocytopenia is low with LMWH but may occur after 5-10 days. Platelet counts should be measured just before commencing treatment with heparin. Regular monitoring of the platelet count is recommended if it is given for longer than 4 days. If there is a 50% reduction of the platelet count, heparin should be stopped. [Level 4] Inhibition of aldosterone secretion by heparin can result in hyperkalaemia. Patients with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with the duration of therapy. Plasma potassium concentration should be measured in patients at risk of hyperkalaemia before starting LMWH. It should then be monitored at regular intervals, especially if the heparin is to be continued for longer than 7 days. [Level 3]
Low Molecular Weight Heparin (LMWH) - continued For patients requiring long-term therapy with LMWH, monitoring anti-factor Xa activity levels may be advisable and it is best to seek advice from the local haematologist. This especially applies especially to patients who are under or over-weight, those with renal impairment and those at risk of bleeding. [Level 4] Treatment should be kept under regular review as continuation of LMWH may not be appropriate in certain circumstances e.g. if the patient is in the dying phase. [Level 4]
Standards 1. The following information should be documented in the case notes: [Grade D] All patients on anticoagulation - Indication for anticoagulation Patients commencing warfarin - Target INR Patients commencing on LMWH - Weight (kg) - Intended duration of treatment - Daily warfarin dose and INR when checked (inpatients) - Renal function - Platelet count
2. The full blood count, urea and electrolytes should be checked as follows: [Grade C] - Prior to commencing treatment with LMWH. - Seven days after starting treatment with LMWH. - Every 4 weeks during treatment with LMWH (if appropriate) 3. All patients receiving anticoagulation should be issued with the standard anticoagulation booklet. [Grade D] 4. For patients on warfarin, clinician responsibility for both INR monitoring and patient follow-up should be clearly documented in the case notes and the patient-held anticoagulation booklet. [Grade D]
Summary of coagulation & anticoagulants Dr C.S.Watt Consultant in Palliative Medicine St John s Hospice, Lancaster
Coagulation - how it happens Anti-coagulant Drugs - how they affect the process Anti-Coagulant Drugs of coagulation - how they affect the process of coagulation
Injury to blood vessel Coagulation a) vascular constriction b) exposed collagen + von Willebrands factor affect platelets Aggregation adherence to surface LOOSE PLATELET PLUG c) COAGULATION CASCADE
Coagulation Cascade Intrinsic Pathway Surface Collagen XII XIIa Prekallekrein HMW Kininogen Extrinsic Pathway Tissue Factor XI Ca HMWK XIa Ca VII VIIa Ca Phospholipids IX IXa Ca VIII VIIIa PL V Va X Prothrombin II Ca PL Xa Thrombin IIa Fibrinogen I Fibrin Ia Forms Mesh CLOT XIIa
Coagulation Coagulation Cascade Intrinsic and Extrinsic Pathway Common Pathway to produce Prothombinase Prothombinase converts Prothombin Thrombin Thrombin converts Fibrinogen Fibrin Fibrin forms x-linked mesh to stabilise platelet plug and form CLOT
Anticoagulant Action XII XIIa VIIa and Tissue Factor XI Xla Antithrombin Protein C Protein S Thrombomodulin ---- = Inhibitory Effect IX IXa X Xa VIII VIIIa Prothrombin Thrombin V Va Fibrinogen Fibrin
Anticoagulants Coumarin Anticoagulant Warfarin Mode of Action:» Antagonising the effect of vitamin K» Vitamin K is required in the synthesis of coagulation factors, II, VII, IX, X and many cofactors including protein C, protein S and thrombomodulin» (vitamin K dependent carboxylation)
Anticoagulants Unfractionated Heparin Mode of Action:» Binds to anti-thrombin» inhibitory effect on factors IIa, IXa, Xa, XIa, XIIa» Tissue Factor Pathway Inhibitor» Inhibits thrombin induced activation of platelets and factors V, VIII» Affects platelet aggregation Low Molecular Weight Heparin -Enoxaparin, Tinzaparin, Dalteparin Mode of Action:» Inactivates factor Xa» Tissue Factor Pathway Inhibitor
Anticoagulants Fondaparinux Sodium Mode of Action:» Inhibits Factor Xa
New oral anticoagulants Rivaroxaban - Factor Xa inhibitor Dabigatran - Direct thrombin inhibitor Marketing authorisation for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery Fixed daily oral dosing without monitoring Recent DTB review of dabigatran (Pradaxa ) and rivaroxaban (Xarelto ) concluded: until more robust clinical efficacy and safety data are available for both drugs, it is advisable to use a more established alternative where possible.
New oral anticoagulants Apixaban (seeking European regulatory approval 2010) Oral Factor Xa inhibitor to prevent and treat venous thromboembolism in patients who have had orthopaedic surgery
References Oxford Handbook of Clinical Medicine 5 th Edition Longmore et al O.U.P. ISBN : 0-19-262988-3 Pg 650 Principles of Anatomy and Physiology 2003 Tortora and Grabowski. John Wiley and Sons Inc. USA ISBN : 0-471-41501-4 Oxford Textbook of Medicine IV Edition 2003 Warrell et al O.U.P. ISBN : 0-19-852789-6 Vol 3 Pg 733-739 British National Formulary vol58. ISBN; 978 0 85369 848 7. Pg 125-133 Hirsh J. et al. Heparin and Low-Molecular-Weight Heparin Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest 119:64S-94S,2001 (suppl 1)
Literature Review Dr Leslie Johnny Speciality Registrar in Palliative Medicine St John s Hospice, Wirral
General Principles Thromboembolic events are among the leading causes of death in cancer patients Frequently asymptomatic Up to 15% of patients with cancer are thought to develop symptomatic VTE
General Principles VTE common among malignant brain tumours, adenocarcinoma of ovary, pancreas, colon, stomach, lung, prostate and kidney. Direct alterations to the coagulation pathway can cause a hypercoagulable state. Specific risk estimates of VTE by cancer type, stage and treatment are largely unknown (Geerts et al) Further increases in risk can be caused by a whole range of factors many of which are common in palliative care patients.
General Principles 500 000 patients currently prescribed oral anticoagulant drugs. Warfarin is the most frequently prescribed Most commonly associated with medication errors in primary and secondary care. Most common drugs involved in errors resulting in claims against NHS Trusts. NPSA recommendations in March 2007
Studies showing cancer link to PE The Olmsted County analysis by Silverstein et al The Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study Sallah et al Ambrus et al
Choice of anticoagulation Recurrent VTE occurs in 27% of patients despite a therapeutic INR Current recommendations support use of Low Molecular Weight Heparin as first line for initial and long term management of cancer associated thrombosis Lee -Treatment of Venous Thromboembolism in cancer patients -2009
Warfarin Vs Heparin CLOT study LMWH vs. Oral Anticoagulant Therapy by Lee et al Primary Outcome- Recurrent VTE Secondary Outcome Clinical Bleeding, Death
Warfarin is generally inferior to therapeutic LMWH for treatment of VTE in patients with cancer (grade A, level Ib) BJH Meyer et al showed that an initial treatment with full-dose enoxaparin, followed by a half dose, significantly reduces the haemorrhagic risk compared with oral anticoagulants without influencing the risk of recurrence.
LMWH vs Unfractionated Heparin (UFH) LMWH is likely to be superior to UFH in the initial treatment of VTE in patients with cancer. Need for more trials to better address this research question in cancer patients. Cochrane Review in 2007 (LMWH)
Survival Benefit Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. Survival benefit of heparin in cancer patients (Hypothesis Direct effect on tumour and excess thrombin production) Patients with small cell lung cancer Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy.
Venous Thromboembolism Prophylaxis
Surgical Prophylaxis evidence Bergqvist et al. & Rasmussen et al. Dalteparin good VTE prophylactic effect No increased risk bleeding for cancer patients Two agents have shown efficacy and safety for VTE prophylaxis in cancer patients under a certain set of clinical conditions: dalteparin and enoxaparin for abdominal or pelvic surgery for malignancy
Prophylaxis in Medical patients Three major studies: PREVENT- Dalteparin (14% had cancer) ARTEMIS-Fondaparinux (5% had cancer) MEDENOX- Enoxoparin (5% had cancer)
Mismetti and colleagues Meta-analysis (2000) Seven trials comparing a prophylactic heparin treatment to a control in medical patients. Four studies evaluated UFH Three studies evaluated a LMWH A significant decrease in DVT and in clinical PE were observed with heparins as compared to control (risk reductions of 56% and 58% respectively, p 0.001 in both cases), without significant difference in the incidence of major bleeding or deaths
There is no data available on the numbers of cancer patients needed to treat to prevent one VTE. The appropriateness of generalising these studies to palliative care patients is uncertain. There are no studies to date examining the efficacy of using thrombo prophylaxis within this group.
Comparisons among anticoagulant agents ENOXACAN study Enoxaparin is as safe and effective as UFH in preventing VTE in major elective surgery for abdominal or pelvic malignancy. McLeod Both heparin and enoxaparin provide highly safe and effective prophylaxis in colorectal cancer surgery patients. Among LMWH products, the current literature does not indicate that any single LMWH has been shown as superior to any other
ACCP guidelines from 2005 The guidelines have provided 1A evidence-based recommendations therapy for LMWH or UFH in only high-risk patients, with cancer patients undergoing surgery considered to be most significant. Hospitalized cancer patients have also been considered to be at high risk of DVT,and 1A recommendations include prophylaxis with LMWH (dalteparin or enoxaparin) or low-dose UFH 3 times daily
ACCP guidelines from 2005 In the event that there is a contraindication to pharmacological thromboprophylaxis, consider non-pharmacological treatments. Non-pharmacological strategies include graduated compression stockings, intermittent pneumatic compression, leg elevation and early mobilization.
Mechanical prophylaxis No randomized clinical trials have evaluated mechanical methods of prophylaxis in general medical patients. These measures should be considered as alternative methods when contraindications to anticoagulants exist (Geerts et al 2004)
Nice Guidance on Mechanical Prophylaxis Mechanical methods have been proven to be effective in surgical patients and do not to add the risk of bleeding. Large study in stroke patients did not show any beneficial effect of stockings in stroke patients but did show an increase in skin complications associated with their use
Gap between theory and practise Heterogeneity of clinical studies, selected populations, concern about bleeding, and the lack of a clear clinical benefit are some of the reasons Only few trials were conducted using symptomatic VTE and/or mortality as the primary end point. Asymptomatic DVT, however, were the great majority of events detected during the studies
Patients Attitudes (Qualitative study) Low molecular weight heparin is acceptable to inpatients with advanced cancer receiving palliative care and has a positive impact on overall quality of life. Antiembolic stockings are an unacceptable intervention in this patient group. Guidelines on thromboprophylaxis are urgently needed for palliative care inpatient units and hospices. S I R Noble, senior lecturer in palliative medicine,1 A Nelson, palliative care research coordinator,2 C Turner, specialist registrar,3 and I G Finlay, professor of palliative medicine4
NICE guidance 2010 Decisions should be made on an individual basis with consideration of risk and burden of treatment. On initiation of therapy, a clinical plan should be made to review the appropriateness of treatment if there is felt to be a sufficient potential benefit from treatment. The treatment choice is LMWH in a once daily dose. There is a lack of evidence to support long term primary prophylaxis in patients with cancer.
Using antiplatelet therapy as a convenient prophylactic two for one. Not recommended because the protective effective of aspirin against VTE is insufficient Consider offering temporary inferior vena caval filters to patients who are at very high risk of VTE (such as patients with a previous VTE event or an active malignancy) and for whom mechanical and pharmacological VTE prophylaxis are contraindicated.
Calvary, Bethlehem Guidance Thrombopropylaxis should be considered in previously ambulatory patients, admitted to the inpatient facility with acute change in their condition and mobility. This may include infection, hypercalcemia, recent spinal cord compression, post operative or recent functional decline with restorative care as the goal. Need to take account of the patient s prognosis and the potential effect on quality of life to avoid inappropriate treatment.
Pan Birmingham Cancer Network As a part of the holistic assessment all patients should have their risk of VTE assessed to decide whether they may benefit from anticoagulation with LMWH, to reduce the risk of symptomatic and life limiting VTE. These guidelines are aimed at palliative patients admitted to a hospice or hospital
Consideration of primary prophylaxis in palliative care patients for VTE should keep at its centre the focus of high quality symptom control At present there are insufficient studies to support treating all cancer inpatients with primary prophylaxis for VTE
Proposed updates to standards & guidelines Dr Helen Emms Consultant in Palliative Medicine St John s Hospice Wirral
Overview of proposed changes General Principles Some information previously in guidelines moved to general principles section Guidelines Split into 2 sections 1. Venous Thrombo-Embolism Prophylaxis 2. Therapeutic anticoagulation Standards 2 potential new standards
Explanation of colours Red = proposed new or changed text Green = no change in wording but altered position Strikethrough = proposed text moved or removed
Moved to General Principles It is important for the clinician to decide whether anticoagulation is appropriate on an individual patient basis. Decisions surrounding the use of anticoagulation in patients with advanced cancer should be discussed with a senior physician. Prophylactic and therapeutic anticoagulation should be kept under regular review as continuation may not be appropriate in certain circumstances e.g. if the patient is in the dying phase.
Moved to General Principles Poor INR control may subject the patient to an increased risk of bleeding without adequately treating the venous thrombosis. Low Molecular Weight Heparin (LMWH) is an alternative to warfarin in palliative care patients and can be used for prophylaxis of venous thromboembolism (VTE) in high-risk patients.
Moved to General Principles There are a number of Low Molecular Weight Heparins available. They include Dalteparin, Enoxaparin and Tinzaparin. Choice will vary according to local policies/formulary. They are all given using a once-daily administration schedule via the subcutaneous route. There may be clinical situations (e.g. Acute Coronary Syndromes) where a split twice-daily dose schedule gives better symptom control. The risk of heparin-induced thrombocytopenia is low with LMWH but may occur after 5-10 days. Platelet counts should be measured just before commencing treatment with heparin. Regular monitoring of the platelet count is recommended if it is given for longer than 4 days. If there is a 50% reduction of the platelet count, heparin should be stopped.
Moved to General Principles Renal function should be checked prior to, and during treatment with LMWH. Renal impairment may require dose adjustment. Inhibition of aldosterone secretion by heparin can result in hyperkalaemia. Patients with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with the duration of therapy. Plasma potassium concentration should be measured in patients at risk of hyperkalaemia before starting LMWH. It should then be monitored at regular intervals, especially if the heparin is to be continued for longer than 7 days.
Moved to General Principles Contraindications to treatment with LMWH are listed in Table 3.4. Table 3.4 Contraindications when considering the use of treatment with LMWH Acute bacterial endocarditis Haemophilia and other haemorrhagic disorders History of heparin-induced thrombocytopenia Known hypersensitivity to heparin or LMWH After major trauma Peptic ulcer Recent cerebral haemorrhage Recent injury or surgery to central nervous system / eyes/ ears Severe hypertension Severe liver disease (including oesophageal varices) Spinal or epidural anaesthesia Thrombocytopenia
Guidelines Venous Thrombo-Embolism (VTE) prophylaxis The appropriateness of VTE prophylaxis for palliative care patients should be made on an individual patient basis, including consideration of the stage of the patient s illness. [Level 4] Palliative care patients in the dying phase of their illness (e.g. supported by an end-of-life care pathway) should not be routinely given pharmacological or mechanical VTE prophylaxis. [Level 4]
Qualitative research has shown the acceptability of VTE prophylaxis with LMWH to patients and a desire to be involved in the decision making process. The views of the patient, their families, carers and the multi-disciplinary team looking after the patient should be taken into account when making decisions regarding the provision of VTE prophylaxis. [Level 4] The potential benefit of reducing VTE events should be balanced with the potential harms of bleeding and the qualitative aspects of receiving VTE prophylaxis. Assess all patients for risk of bleeding before offering pharmacological VTE prophylaxis. [Level 4]
For patients in whom pharmacological prophylaxis is contraindicated, consider whether mechanical VTE prophylaxis is appropriate. Potential options include: antiembolism stockings, foot impulse devices and intermittent pneumatic compression devices. [Level 4] The National Institute for Heath and Clinical Excellence (NICE) gives guidance regarding the assessment and provision of VTE prophylaxis for patients admitted to hospital. (http://www.nice.org.uk/nicemedia/pdf/cg92fullguideline.pdf) Aspects are summarised in figures 1-4 below: All decisions regarding the provision of VTE prophylaxis should be reviewed at regular intervals. [Level 4]
Guidelines General management of suspected Deep Venous Thrombosis (DVT) / Pulmonary Embolism (PE) Figure 3.1 illustrates some general guidelines regarding the investigation and management of thrombo-embolic disease. [Level 4]
Aims, duration and choice of therapeutic anticoagulation In some patients LMWH may be a better choice for patients than warfarin. Possible clinical indications for use of LMWH include: Treatment of thromboembolic disease e.g. DVT / PE whilst warfarin therapy is being initiated. Heparin treatment is usually temporary and is stopped when adequate anticoagulation with warfarin is achieved i.e. INR >2. 13 [Level 4] Long term treatment of thromboembolic disease where warfarin therapy is not appropriate e.g. liver disease, unstable INR, difficult venepuncture (see Figure 3.1). 5 [Level 4] Extension of the thrombus despite the use of warfarin. [Level 1+]
All LMWH treatment doses are calculated according to the weight of the patient. Drug doses are available in the BNF. [Level 3] For patients requiring long-term therapy with LMWH, monitoring anti-factor Xa activity levels may be advisable and it is best to seek advice from the local haematologist. This especially applies especially to patients who are under or over-weight, those with renal impairment and those at risk of bleeding. [Level 4]
Table 3.1 illustrates: The suggested duration of treatment for patients on warfarin and LMWH, and The target INR for patients on warfarin. [Level 4] Anticoagulation may be stopped abruptly when the duration of therapy is completed. [Level 2]
Advice on the management of bleeding and /or high INR Guidelines are given in Table 3.2. [Level 3] If the INR is outside the target range, check for bleeding, haematuria or significant bruising. [Level 3]
Standards 1. The following information should be documented in the case notes: [Grade D] All patients on anticoagulation - Indication for anticoagulation Patients commencing warfarin - Target INR Patients commencing on LMWH - Weight (kg) - Intended duration of treatment - Daily warfarin dose and INR when checked (inpatients) - Renal function - Platelet count
2. The full blood count, urea and electrolytes should be checked as follows: [Grade C] - Prior to commencing treatment with LMWH. - Seven days after starting treatment with LMWH. - Every 4 weeks during treatment with LMWH (if appropriate) 3. If there is a 50% reduction of the platelet count, heparin should be stopped. [Grade D] 4. All patients receiving anticoagulation should be issued with the standard anticoagulation booklet. [Grade D] 5. For patients on warfarin, clinician responsibility for both INR monitoring and patient follow-up should be clearly documented in the case notes and the patient-held anticoagulation booklet. [Grade D]
6. The need for VTE prophylaxis should be considered in all patients and the decision, with reasoning, documented in the case notes. [Grade D]