Anticoagulation Guidelines

ANTICOAGULATION GUIDELINES

When using this document please ensure that the version you are using is the most up to date either by checking on the Trust intranet or if the review date has passed, please contact the author.

‘Out of date policy documents must not be relied upon’

Approval Version Issue Date Review Document Author Committee Date Drug & 3 March, March, Dr Joseph Chacko Therapeutics 2010 2012 Consultant Haematologist Committee Hayley Flavell Anticoagulant and Thrombosis Consultant Nurse Jacqui Bowden Clinical Pharmacy Manager D&TC 4 July 2012 July 2014 Kareena Marotta, Jason Mainwaring

Version Control Version Date Author Section Principle Amendment Changes

4 July 2012 Kareena 6.3 Changed Enoxaparin to Dalteparin Marotta, Jason Mainwaring

Anticoagulation Guidelines Version 4 Page 1 of 25 July, 2012 ANTICOAGULATION GUIDELINES Contents

1.0 Introduction

2.0 Contra-indications to anticoagulant therapy

3.0 Indications and duration for anticoagulation 3.1 Indications Table 1 Indications for long term warfarin 3.2 Duration Table 2 Duration of warfarin therapy

4.0 Thrombophilia screening Appendix 7

5.0 Special situations

6.0 Anticoagulant drugs 6.1 Warfarin Monitoring Contra-indications and cautions Initiation of anticoagulation; loading doses Table 3 Standard loading Table 4 Reduced loading Supply of tablets Patient information Anticoagulation Clinic – referral and contact details Appendix 1, 2, 3 6.2 Unfractionated Heparin (UFH) Contra-indications and cautions Monitoring Therapeutic dosing Table 5 Dosing schedule for IV infusion Complications of UFH therapy Appendix 8 6.3 Dalteparin Contra-indications and cautions Monitoring Doses Administration Complications Appendix 8

7.0 Surgical procedures in patients on anticoagulants and bridging anticoagulation Bridging clinic Appendix 5 Appendix 6 Neuraxial (epidural or spinal) anaesthesia and analgesia Dental procedures

8.0 Management of excessive anticoagulation 8.1 Vitamin K1 (phytomenadione) 8.2 Protamine sulphate 8.3 Prothrombin complex concentrate (PCC) 8.4 Fresh Frozen Plasma (FFP) 8.5 Recombinant FVIIa (Novoseven) Table 9 Management of excessive anticoagulation

9.0 Glossary

Anticoagulation Guidelines Version 4 Page 2 of 25 July, 2012 10.0 References

11.0 Appendix 1 Oral, Parenteral Anticoagulation and Intravenous Heparin Prescriptions Appendix 2 Anticoagulation Clinic Referral Form Appendix 3 Anticoagulant Therapy Record and INR Test Request Form Appendix 4 Oral Anticoagulant Therapy; information for patients, alert card and record book Appendix 5 Peri-operative bridging protocol for warfarinised patients Appendix 6 Management of sub-therapeutic INR in patients with mechanical heart valves Appendix 7 Guidelines for thrombophilia testing in the laboratory Appendix 8 Guidelines for monitoring, diagnosing and managing heparin- induced thrombocytopenia (HIT)

Anticoagulation Guidelines Version 4 Page 3 of 25 July, 2012 1.0 Introduction

Anticoagulant drugs are one of the classes of medicines most commonly associated with fatal medication errors.

The National Patient Safety Agency (NPSA) has recommended that all staff who prescribe, adjust the dosage, dispense, prepare, administer, monitor and discharge patients on anticoagulant therapy should have adequate training and have acquired the necessary work competences, as part of safe medication practice. All practitioners should have completed both of the BMJ Learning modules on “Starting and maintaining anticoagulants: how to do it”, and have completed the NPSA competencies before prescribing anticoagulant drugs. Links to the learning modules can be found on the hospital Intranet under e-learning, anticoagulation. http://rbhintranet/elearning/

It is vital that physicians assess the benefits and risks of anticoagulant therapy for individual patients. This assessment should include the cognitive status of the patient, and should clearly establish whether patients understand the potential hazards of anticoagulant therapy, the need for frequent monitoring by blood tests and the various drug and food interactions of oral anticoagulant drugs.

It is also essential that patients and their carers receive adequate verbal and written information about their treatment. This information should be provided before the first dose of anticoagulant is administered, and reinforced at hospital discharge, at the first Anticoagulation Clinic appointment, and when necessary throughout the course of their treatment. When a patient has verbally consented to take the drug as intended, this should be clearly documented in the patient’s health record before anticoagulant therapy is commenced.

See RBCH Anticoagulation Prescriptions (parenteral and oral) for in-patients Appendix 1. Also displayed on the Intranet http://rbhintranet/elearning/ are movies explaining the use of the Oral and Parenteral Anticoagulation Prescriptions and an Anticoagulation Training Workbook for Nurses which includes competences.

This document aims to provide guidelines on prescribing, administration and monitoring of anticoagulant drugs and management of their complications.

For pregnancy see VTE prevention: Guideline for Thromboprophylaxis and Management of VTE in Pregnancy.

2.0 Contra-indications to anticoagulant therapy

 Active bleeding  Acquired bleeding disorders, e.g. acute liver failure  Acute stroke – discuss with Stroke Consultant  Gastro-intestinal bleed during previous 2 weeks  Intracranial bleed during previous 3 months  Head injury in the previous 3 months  Uncontrolled systolic hypertension > 200mmHg  Neurosurgery or spinal surgery in the previous 3 months  Pericarditis or acute bacterial endocarditis  Intra-ocular disease or eye surgery in the previous 3 months  Lumbar puncture, epidural or spinal analgesia during previous 24 hours

Anticoagulation Guidelines Version 4 Page 4 of 25 July, 2012  Recent surgery or organ biopsy with high risk of bleeding (e.g. liver biopsy) – wait for 2 weeks  Untreated inherited bleeding disorders, e.g. haemophilia  Thrombocytopenia <75 x 109/L – discuss with Haematology Consultant  Previous heparin-induced thrombocytopenia (for heparins only)  See additional contra-indications under specific anticoagulant drugs

3.0 Indications and duration for anticoagulation therapy 3.1 Indications  Pulmonary embolism (PE) o See Intranet guidelines for management of PE  Deep vein thrombosis (DVT) o See Intranet guidelines for management of DVT  Venous thrombosis at unusual sites o Cerebral venous sinus thrombosis (CVT) . Start anticoagulation therapy if there is no associated intracranial haemorrhage . Treat for 3 to 6 months or longer depending on underlying risk factors . Discuss with Consultant Neurologist o Venous thrombosis in upper limb . Central venous line (CVL) related  Start anticoagulation with LMWH  Remove line after 24 to 48 hours of anticoagulation  Consider stopping anticoagulation after 3 months . Non-CVL related  Anticoagulation for 6 months – as for proximal DVT o Splanchnic vein thrombosis . Budd-Chiari syndrome . Mesenteric venous thrombosis . Extra hepatic venous thrombosis . Gastroenterology and / or Gastrointestinal Surgery Consultant decision . Discuss thrombosis risk / anticoagulation with Haematology Consultant  Acute coronary syndromes (ACS) o See Intranet guidelines for management of ACS  Atrial fibrillation o Consultant / GP decision o Refer to Anticoagulation Clinic for oral anticoagulation therapy  Mechanical heart valves o Cardiology / Cardiac Surgery Consultant decision o Refer to Anticoagulation Clinic for warfarin maintenance therapy  Acute stroke o Stroke Consultant decision  Peripheral artery disease with limb ischaemia / gangrene o Vascular Surgery Consultant decision

Anticoagulation Guidelines Version 4 Page 5 of 25 July, 2012 3.1 Table 1 Indications for long-term warfarin therapy

Indication Target INR Range Pulmonary embolus 2.5 2.0 – 3.0 Proximal deep vein thrombosis 2.5 2.0 – 3.0 Calf vein thrombus 2.5 2.0 – 3.0 Recurrence of venous thromboembolism when no longer on 2.5 2.0 – 3.0 warfarin therapy Recurrence of venous thromboembolism whilst on warfarin 3.5 3.0 – 4.0 therapy Symptomatic inherited thrombophilia 2.5 2.0 – 3.0 Antiphospholipid syndrome 2.5 2.0 – 3.0 Non-rheumatic atrial fibrillation 2.5 2.0 – 3.0 Atrial fibrillation due to rheumatic heart disease, congential 2.5 2.0 – 3.0 heart disease and thyrotoxicosis Cardioversion 3.0 2.5 – 3.5 Mural thrombus 2.5 2.0 – 3.0 Aortic Mechanical prosthetic heart valve 2.5 or 3.0 2.0 – 3.0 2.5 – 3.5 Mitral Mechanical prosthetic heart valve 2.5 – 3.0 3.0 – 4.0 2.5 – 3.5 Bioprosthetic valve if anticoagulated 2.5 2.0 – 3.0 Aortic Bileaflet 2.5 2.0 – 3.0 Aortic Tilting Disc 3.0 2.5 – 3.5 Mitral Bileaflet 3.0 2.5 – 3.5 Aortic or Mitral Caged Ball 3.5 3.0 – 4.0 Ischaemic stroke without atrial fibrillation Not indicated Retinal vessel occlusion Not indicated Arterial grafts if anticoagulated 2.5 2.0 – 3.0 Peripheral arterial thrombosis Not indicated Coronary artery thrombosis if anticoagulated 2.5 2.0 – 3.0 Coronary artery graft Not indicated Coronary angioplasty and stents Not indicated PNH with platelet count >100 x 109 / L 2.5 2.0 – 3.0

Adapted from British Society of Haematology Guidelines, 132, 277 – 285

Anticoagulation Guidelines Version 4 Page 6 of 25 July, 2012 3.2 Table 2 Duration of anticoagulant therapy

Indication Duration Pulmonary embolus Idiopathic – 6 months Reversible non-recurring transient precipitating cause – 3 months and review* Proximal deep vein thrombosis Idiopathic – 6 months Reversible non-recurrent transient precipitating cause – 3 months and review* Calf vein thrombus Idiopathic – 3 months Reversible non-recurrent transient precipitating cause – 6 weeks Recurrence of venous thromboembolism when Life no longer on warfarin therapy Recurrence of venous thromboembolism whilst Life on warfarin therapy Symptomatic inherited thrombophilia Clinical Review – Haematology Consultant Antiphospholipid syndrome Life Non-rheumatic atrial fibrillation Life Atrial figrillation due to rheumatic heart Life disease, congential heart disease and thyrotoxicosis Cardioversion Clinical Review – Cardiology Consultant Mural thrombus Clinical Review – Cardiology Consultant Aortic Mechanic prosthetic heart valve Life Mitral Mechanical prosthetic heart valve Life Bioprosthetic valve if anticoagulated Life Aortic Bileaflet Life Aortic Tilting Disc Life Mitral Bileaflet Life Aortic or Mitral Caged Ball Life Arterial grafts if anticoagulated Life Coronary artery thrombosis if anticoagulated Life

Adapted from British Society for Haematology Guidelines, 132, 277 – 285

* All patients should be risk-assessed at 3 months. If DVT / PE were provoked by a reversible risk factor and patient has no underlying persistent risk factor for recurrence, treatment can be stopped. All other patients should receive treatment for 6 months unless the risk of bleeding outweighs the risk of thrombosis.

4.0 Thrombophilia screening

Tests for thrombophilia are required only in special clinical circumstances and only at specific time points when anticoagulation treatment can be influenced by the results. See Guidelines for laboratory testing of inherited thrombophilia (Appendix 7) for indications and timing for thrombophilia screening.

Tests are available on request by completing the screening questionnaire. Tests for antiphospholipid syndrome may be requested without the screening questionnaire. The questionnaire is available on the Intranet and through the Coagulation Laboratory.

Anticoagulation Guidelines Version 4 Page 7 of 25 July, 2012 5.0 Special situations

 Intravenous drug users o Consider LMWH therapy for the entire duration of anticoagulation therapy  Active cancer on chemotherapy o Consider LMWH therapy for the entire duration of anticoagulation therapy  Pregnancy o Refer to VTE prevention: Guideline for Thromboprophylaxis and Management of VTE in Pregnancy.

6.0 Anticoagulant drugs

The drugs available for prophylaxis and treatment are : 6.1 Vitamin K antagonist: Warfarin 6.2 Unfractionated Heparin sodium (UFH) 6.3 Low molecular weight heparin (LMWH): Dalteparin

6.1 Warfarin  Warfarin is the most commonly used oral anticoagulant  Warfarin is a vitamin K antagonist. Vitamin K is essential for activation of clotting factors II, VII, IX X and anticoagulant proteins C and S  Warfarin prolongs prothrombin time (PT) and activated partial thromboplastin time (APTT)  Treatment with warfarin has to be monitored with INR (international normalised ratio), INR is prothrombin time (PT) standardised for patients on warfarin  Warfarin can be paradoxically pro-thrombotic in the first 24 hours when loading doses are used. When rapid anticoagulation is required, heparins (UFH or LMWH) should be used as first-line therapy. Warfarin loading should only be commenced in heparinised patients and therapeutic heparin continued for at least 5 days and until INR is therapeutic for 2 consecutive days.  Other vitamin K antagonists, acenocoumarol or phenindione may be used in cases of clear warfarin hypersensitivity. Contact Anticoagulation Clinic (ext. 4778) for advice on dosage adjustment.  Warfarin has a narrow therapeutic window.  Warfarin has major drug interactions (seen BNF Appendix 1) o Use reduced dose warfarin loading schedule (Table 4) to commence oral anticoagulation therapy in patients who are on medications which are known to interact with warfarin o In patients on warfarin therapy, check INR within 4 to 7 days of starting any medication which is known to interact with warfarin  Warfarin has major food interactions

Patients should be informed of risks, precautions and the need for regular INR tests before starting treatment with warfarin. Verbal consent must be recorded in patient’s medical notes and on page 4 of the Oral Anticoagulation Prescription (Appendix 1).

Concurrent anti-platelet therapy will increase the risk of bleeding in warfarinised patients. If patients are already on aspirin, clopidogrel or dipyridamole, check with Cardiology Consultant if anti-platelet therapy can be stopped before commencing warfarin.

Anticoagulation Guidelines Version 4 Page 8 of 25 July, 2012 Contra-indications  Known bleeding disorders, e.g. haemophilia  Thrombocytopenia with platelet count < 75 x 109 / L  Recent cerebral haemorrhage  Hypertension Systolic BP > 230 mmHg + Diastolic BP > 120mm Hg  Severe liver disease with oesophageal varices  Peptic ulcer  Major trauma  Recent eye, brain, spinal cord surgery  Severe kidney disease – CrCl <10mL / min  Pregnancy o Warfarin is teratogenic and is contra-indicated in the first trimester of pregnancy o Women on warfarin therapy should be warned of teratogenicity when planning pregnancy and switched to LMWH for the duration of pregnancy o Seek advice from Cardiology Consultant regarding anticoagulation in pregnant women with metallic heart valves

Cautions  Concomitant use of drugs that increase risk of bleeding (refer to BNF)  Drugs and food interacting with coumarins  Hepatic impairment with prolonged prothrombin time (PT)  Recent surgery  Bacterial endocarditis

Initiation of anticoagulation Check baseline platelet count, INR and LFTs  If baseline INR and / or APTTR > 1.4, exclude clotting factor deficiency.

The dose of warfarin should be taken in the evenings, usually at 6pm

Use standard loading schedule for young fit patients without co-morbidities and requiring rapid oral anticoagulation (Table 3).

Use reduced-intensity loading schedule (Table 4) for the following patients.  Age > 65 years (consider if age > 60 years)  Weight < 50kg  Poor nutritional status  Congestive heart failure or other co-morbidities  Abnormal LFTs  Baseline INR > 1.4  On drugs which enhance warfarin effect

Anticoagulation Guidelines Version 4 Page 9 of 25 July, 2012 Table 3 Standard Warfarin Loading

Day INR Dose Day 1 <1.4 10mg Day 2 <1.8 10mg 1.8 1mg >1.8 Omit dose Day 3 <2.0 10mg 2.0 to 2.5 4mg 2.6 to 3.0 3mg 3.1 to 3.4 2mg 3.5 to 4.0 1mg >4.0 Omit dose Day 4 <1.4 Consult Anticoagulation Clinic Predicted maintenance dose 1.4 8mg 1.5 to 1.7 7mg 1.8 to 2.0 6mg 2.1 to 2.6 5mg 2.7 to 3.0 4mg 3.1 to 3.5 3mg 3.6 to 4.0 2mg >4.0 Omit dose

Modified from British Medical Journal 1988; 297: 1285 – 1288

Table 4 Reduced Warfarin Loading

Day INR Dose Day 1 <1.4 5mg Day 2 <1.8 5mg 1.8 1mg >1.8 Omit dose Day 3 <2.0 5mg 2.0 to 2.5 2mg 2.6 to 3.0 2mg 3.1 to 3.4 1mg 3.5 to 4.0 1mg >4.0 Omit dose Day 4 <1.4 Consult Anticoagulation Clinic Predicted maintenance dose 1.4 4mg 1.5 to 1.7 4mg 1.8 to 2.0 3mg 2.1 to 2.6 3mg 2.7 to 3.0 2mg 3.1 to 3.5 2mg 3.6 to 4.0 1mg >4.0 Omit dose

Modified from Annals of Internal Medicine 2003; 138: 714 - 719

Anticoagulation Guidelines Version 4 Page 10 of 25 July, 2012 Patients with atrial fibrillation do not require rapid anticoagulation and can start warfarin therapy as outpatients without loading doses. The usual starting dose is 1 to 3mg daily. INR is checked 5 to 7 days after starting low dose warfarin.

Supply of warfarin tablets The Pharmacy will supply only warfarin 1mg and 3mg tablets to patients. Supply of 0.5mg and 5mg tablets will be restricted to exceptional circumstances where there is a clear need and there is no risk of confusion between 5mg and 0.5mg tablets.

The National Patient Safety Agency (NPSA) recommends :  Constant daily dosing instead of alternate day dosing  Use the lowest number of tablets possible for daily dosing  Use whole tablets only

Patient Information When starting warfarin the counselling must be documented on page 4 of the Oral Anticoagulation Prescription (Appendix 1).  Doctor to counsel the patient or carer about the first five points on page 4  Doctor and pharmacist to reinforce information with counselling using page 4 during the admission  Nurse to check the patients understanding of information on page 4 at discharge

When counselling patients they should be given each of : (Appendix 4)  Oral Anticoagulant Therapy – Information of Patients (yellow booklet)  Anticoagulation Alert Card  Oral Anticoagulant Therapy – Record Book (small yellow booklet)

The name of the anticoagulant, indication for treatment, therapeutic range (INR), date treatment started and duration of treatment must be recorded in all three of the above.

Anticoagulation Clinic The Anticoagulation Clinic manages all patients on oral anticoagulation therapy.

Patients should be referred to the Anticoagulation Clinic if they require oral anticoagulation therapy after discharge from the hospital.

Complete the Anticoagulation clinic referral form (Appendix 2), fax the completed referral form to 01202 309975 and mail the original form to the Anticoagulation Clinic, Pathology Directorate by internal post. Contact the Clinic by telephone on ext. 4778 / 4781 or by email ([email protected]) to arrange the first appointment with INR test within 2 to 5 days of discharge.

If a patient on warfarin is admitted to hospital for any reason, remember to inform the Anticoagulation Clinic by telephone on ext. 4778 / 4781. If warfarin has to be stopped, document the reason on page 3 of the Oral Anticoagulation Prescription, e.g. “warfarin stopped” or “warfarin on hold, review after surgery”.

When the Anticoagulation Clinic sends dosing information to the patient they will post the BLUE forms, Anticoagulant Therapy Record and INR Test Request Form (Appendix 3). These forms are computer generated and contain the following information:  Patient’s daily dose in mg  Patient’s daily dose in tablet numbers and colour of each tablet  Date of the next blood test  Request form for the next blood test Anticoagulation Guidelines Version 4 Page 11 of 25 July, 2012 When the anticoagulation course has been completed, warfarin can be stopped abruptly, there is no need to taper the dose. If patients were taking aspirin or other anti-platelet drugs before the warfarin course which were stopped, these may need to be restarted if appropriate.

High citrate concentrations will give spuriously high INRs so care must be taken not to underfill sample bottles or to pour two small samples into one bottle to make up the volume.

The Royal Bournemouth Anticoagulation Clinic manages patients for all Bournemouth GP practices with the exception of Denmark Road Medical Centre and Providence Road Surgery. Patients belonging to these practices should be referred directly to the GP surgery. Poole Anticoagulant Service manages patients cared for by Poole, Wimborne, Ferndown and Verwood practices.

Patients not requiring rapid anticoagulation should be referred directly to anticoagulation clinic, where they are counselled and given written information. Thereafter patients are managed by a dose and post service.

6.2 UFH, Unfractionated Heparin

 Indirect inhibitor of coagulation factors IIa (Thrombin) and Xa (Prothrombinase)  Half-life is 45 to 60 minutes after usual intravenous doses

 Contra-indications o Known bleeding disorders, e.g. haemophilia o Thrombocytopenia with platelet count < 75 x 109/L o History of heparin-induced thrombocytopenia (HIT) o Hypersensitivity to heparins o Peptic ulcer o Recent cerebral haemorrhage o Major / life threatening bleeding o Severe hypertension – Systolic BP > 230 mmHg + Diastolic BP > 120mm Hg o Severe liver disease with oesophageal varices o Major trauma o Recent eye, brain, spinal cord surgery o Acute bacterial endocarditis

 Cautions o Concomitant use of drugs that increase bleeding o Liver disease o Recent surgery o Pre-existing diseases or concomitant use of drugs that cause hyperkalaemia o Osteoporosis

 Monitoring (prophylactic doses) o Check baseline platelet count and re-check on days 5 to 7 and days 10 to 14 for outpatients and discharges and days 6 and 14 for inpatients

 Monitoring (treatment doses) o Check baseline FBC and APTT ratio. o Recheck APTT ratio within 6 hours. o Maintain APTT ratio within 1.5 to 2.5 range. o Check platelet count on the 5th day of heparin treatment to exclude heparin-induced thrombocytopenia (HIT), then every 3 to 5 days whilst on UFH for up to 2 weeks

Anticoagulation Guidelines Version 4 Page 12 of 25 July, 2012 o Check platelet count after 24 hours of UFH treatment if patient has been exposed to heparin in the previous 100 days. o Check serum potassium in those at risk of hyperkalaemia o Blood should be taken from the non-infusion arm to check APTT ratio  Prophylactic dosing In patients with CrCl < 20mL/min having prophylaxis for over 10 days: 5000units SC twice daily (using 5000units in 0.2mL ampoule)  Therapeutic dosing; Recommended dose for treatment of venous and arterial thrombosis is heparin 75units/kg (nearest 100 units), maximum dose of 5000 units intravenously followed by continuous intravenous infusion at 18 units/kg/hr and adjusted to maintain APTT ratio between 1.5 to 2.5  Use heparin 1000 units / mL (DO NOT dilute)  Nurses can request APTTR and then adjust the heparin infusion as in Table 5 below  Prescribe on the prescription for intravenous heparin (Appendix 1)

Table 5 Dosing schedule for continuous intravenous infusion of unfractionated heparin

APTTR Adjustment to heparin rate Monitor APTT Ratio (1000units / mL) > 5 Stop for 1 hour then reduce by 0.6mL / hr Inform Dr After 2 hours 4.1 to 5.0 Reduce by 0.4mL / hr After 6 hours 3.1 to 4.0 Reduce by 0.2mL / hr After 6 hours 2.6 to 3.0 Reduce by 0.1mL / hr After 10 hours 1.5 to 2.5 NO CHANGE After 10 hours 1.2 to 1.4 Increase by 0.2mL/hr After 6 hours < 1.2 Increase by 0.4mL / hr After 4 hours Discuss with Dr to consider a bolus.

Modified from British Medical Journal 1988; 297: 1285-1288.

 Complications of UFH therapy o Bleeding is reversed by protamine sulphate: o 1mg of protamine neutralises 100 units of UFH (see 8.2). Consult Haematologist for advice o Osteoporosis is a complication of long-term heparin use only o Hyperkalaemia; The risk appears to increase with duration of therapy, but is usually reversible. Serum potassium should be measured in those at risk eg . Diabetes mellitus . Chronic renal failure . Pre-existing metabolic acidosis . A raised serum potassium

o Heparin-induced thrombocytopenia (HIT) with thromboembolism (HITT) See Guidelines for monitoring, diagnosing and managing heparin-induced thrombocytopenia (HIT) (Appendix 8)

Anticoagulation Guidelines Version 4 Page 13 of 25 July, 2012 6.3 Dalteparin  LMWH mainly inhibit prothrombinase (Factor Xa) and weakly inhibit thrombin (Factor IIa)  Dalteparin is the low molecular weight heparin (LMWH) on the hospital formulary. o Dalteparin only moderately affects the APTT ratio, this should only be measured in suspected overdose and not be monitored routinely. o Anti-Factor Xa level can be used to monitor the anticoagulant effect but has limited predictive value for bleeding complications or antithrombotic efficacy.

 Cautions o Concomitant use of drugs that increase bleeding o Liver disease o Renal impairment o Recent surgery o Pre-existing diseases or concomitant use of drugs that cause hyperkalaemia o Osteoporosis

 Monitoring Routine monitoring of anticoagulant effect is not required except in special circumstances below . Patients having treatment doses for more than 10 days and who have a creatinine clearance between < 30mL/min and 20mL/min . Obesity (BMI > 30kg/m2) . Pregnancy . Those at increased risk of bleeding

Samples for anti-Factor Xa activity are taken 3 to 4 hours after injection to check peak levels, for BD dosing the sample should be taken after the morning dose. Contact haematology medics if 3 to 4 hour post-dalteparin anti-Xa levels are < 1 or > 2units/mL for OD dosing, < 0.5 or > 1units/mL for BD dosing and for all pregnant patients. If the level is within these limits re-check levels within 5 to 7 days.

 Prophylactic dose o In patients with a CrCl ≥ 20mL/min LMWH: Dalteparin 5000units SC daily

o In patients with a CrCl < 20mL/min Up to 10 days - LMWH: Dalteparin 5000units SC OD More than 10 days - Unfractionated Heparin 5000units SC BD

Anticoagulation Guidelines Version 4 Page 14 of 25 July, 2012

 Therapeutic dose Renal function must be checked before prescribing, there have been reports of retroperitoneal bleeds in patients where an excessive dose of dalteparin was administered in renal impairment. Prescribe on the Parenteral Anticoagulation Prescription (Appendix 1). The patient’s creatinine clearance should be calculated using the Creatinine Clearance Calculator on the Intranet under Doctors Information. In obese patients the use of ideal body weight in the creatinine clearance calculation may be considered, this can be calculated using the Ideal Body Weight Calculator on the Intranet under Doctors Information.

The maximum effect of dalteparin is not seen until 1 to 4 hours after administration, for immediate anticoagulant effect prescribe;

IV heparin 5000units bolus followed by

Dalteparin o Venous thromboembolism

Standard dose in patients with CrCl ≥ 30mL/min

Standard dose – 200units/kg SC daily. Single daily dose not exceeding 18000units; see table below for dosing.

Weight (kg) Daily Dose (units) < 46 7500 46 to 56 10000 57 to 68 12500 69 to 82 15000 > 82 18000

In patients at increased risk of bleeding or CrCl < 30mL/min to 20mL/min

Prescribe a dose of 100units/kg SC twice daily and consider referral to the haematology team; see the table below for dosing. In patients with CrCl < 30mL/min to 20mL/min having >10 days treatment monitor anti-Xa levels

Weight (kg) Dose (units) < 46 5000units morning 2500 units evening 46 to 56 5000units BD 57 to 68 7500units morning 5000units evening 69 to 82 7500units BD > 82 10000units morning 7500units evening

In all patients with a CrCl < 20mL/min

Prescribe unfractionated heparin intravenous infusion (see section 6.2).

Anticoagulation Guidelines Version 4 Page 15 of 25 July, 2012

Extended treatment of venous thromboembolism in oncology patients  Month 1 = see above as standard dosing  Months 2 to 6 = 150 units/kg SC daily, using the table below for dosing

Weight (kg) Daily Dose (units) < 57 7500 57 to 68 10000 69 to 82 12500 83 to 98 15000 > 98 18000

 Relevance of continuing treatment beyond 6 months should be evaluated according to individual risk/benefit ratio, particularly taking into account the progression of the cancer  Dose modifications in chemotherapy-induced thrombocytopenia: Platelets 50 to 100 x 109/L - decrease daily dalteparin dose by 2500units until platelets ≥ 100 x 109/L Platelets < 50 x 109/L - discontinue dalteparin until platelets > 50 x 109/L

 Administration Dalteparin should be given subcutaneously (SC), preferably with the patient lying down. Inject into the SC tissue of the anterolateral or posterolateral abdomen, or lateral part of the thigh, alternating from the left to right side. Do not expel the air bubble in the syringe. Vertically introduce the whole length of the needle into the thickness of the skin held between the thumb and forefinger. Hold the skin throughout the duration of the injection. Do not rub the injection site (helps to avoid bruising).

 Overdose o Protamine sulphate only partially reverses the effect of dalteparin so additional measures may be required if bleeding is uncontrollable and life-threatening. o Consult haematologist for advice

 Complications o Bleeding o Osteoporosis is a complication of long-term heparin use only o Hyperkalaemia; The risk appears to increase with duration of therapy, but is usually reversible. Serum potassium should be measured in those at risk eg . Diabetes mellitus . Chronic renal failure . Pre-existing metabolic acidosis . A raised serum potassium o Heparin-induced thrombocytopenia (HIT) with thromboembolism (HITT) See Guidelines for monitoring, diagnosing and managing heparin-induced thrombocytopenia (HIT) Appendix 8

Anticoagulation Guidelines Version 4 Page 16 of 25 July, 2012 7.0 Surgical procedures in patients on anticoagulation

The risk of stopping oral anticoagulation for a procedure has to be assessed by comparing the risk of thrombosis versus the risk of bleeding

 Peri-operative bridging protocol for warfarinised patients – Appendix 5  Management of sub-therapeutic INR in patients with mechanical heart valves – Appendix 6

Bridging Clinic Patients on warfarin should be assessed using the Peri-operative Bridging Protocol for Warfarinised Patients Appendix 5. http://rbhintranet/policies/anticoagulation/bridging_for_warfarin.pdf A peri-operative management plan based on bridging guidelines will be made for each patient. Contact Hayley Flavell, ext. 5862 or Anticoagulation Clinic, ext. 4778 for advice.

Prescribing Guidance

In high risk patients with mechanical valves or AF Prescribe a dose of 100units/kg SC twice daily; see the table below.

Weight (kg) Dose (units) < 50 5000 BD 50 to 69 7500 morning 5000 evening 70 to 79 7500 BD 80 to 89 10000 morning 7500 evening > 89 10000 BD

In moderate risk patients Prescribe a dose of 100units/kg SC once daily; see the table below

Weight (kg) Daily Dose (units) < 46 5000 46 to 56 5000 57 to 68 7500 69 to 82 7500 > 82 10000

Dosing in Renal Impairment  If CrCl ≥ 30mL/min prescribe dalteparin as stated in the tables above  If CrCl <30 to 20mL/min prescribe dalteparin as in the tables above with Anti-Xa monitoring if treatment duration over 10 days; discuss levels with haematology.  If CrCl <20mL/min prescribe unfractionated heparin continuous infusion (see section 6.2).

 Neuraxial (epidural or spinal) anaesthesia and analgesia The following guidelines are based on the ASRA and ESRA guidelines. The Consultant Anaesthetist will decide on the timing of neuraxial blockade. o Avoid neuraxial blockade in patients who are therapeutically anticoagulated. o Neuraxial block should not be performed for 6 hours after administration of IV heparin o IV heparin should not be administered for 1 hour after neuraxial blockade

Anticoagulation Guidelines Version 4 Page 17 of 25 July, 2012 o Neuraxial blocks should not be performed for 12 hours (18 hours if CrCl < 30mL/min) after administration of prophylactic LMWH o Neuraxial blocks should not be performed for 24 hours after administration of therapeutic dalteparin i.e. 200iu/kg per day (36 hours if CrCl < 30mL/min) o Dalteparin should not be administered for 6 hours after a neuraxial block or 24 hours if bloody tap. o Epidural catheters should not be removed within 12 hours after last dose of prophylactic dalteparin. o Dalteparin should not be given until 6 hours removal of epidural catheter. o Avoid concurrent use of epidural analgesia and oral anticoagulant drugs. If this is unavoidable, then ensure INR < 1.5 prior to neuraxial block or removal of epidural catheter. o Bridging anticoagulation will be managed by the Anticoagulation Clinic

 Dental procedures o INR check is not required prior to minor non-invasive procedures o Check INR 3 days prior to invasive dental surgery. o If INR is stable at 2.0 to 4.0, invasive dental procedures may be carried out without discontinuing oral anticoagulants. o Patients requiring single dose antibiotic prophylaxis prior to invasive dental procedures do not require dose reduction or discontinuation of oral anticoagulants. o Post-operatively, tranexamic acid 5% solution can be used as mouthwash four times daily for 2 days, and is available from Pharmacy for topical use. o Do not use NSAID or COX-2 inhibitors for post-operative pain control.

8.0 Management of excessive anticoagulation (see Table 9)

8.1 Vitamin K1 (Phytomenadione) (see Table 9)  Indications: o Bleeding due to vitamin K deficiency o Sustained reversal of warfarin effect  Administration: o 2.5 to 5 mg IV is given if patient has high INR and is bleeding. o 0.5 to 2 mg IV or oral administration of the IV preparation (Konakion-MM) can be given if patient has high INR only, is not bleeding and complete reversal is not required. o Phytomenadione is fat soluble, so in patients with liver dysfunction menadiol the water soluble form of vitamin K should be used for oral administration.  Adverse affects: o Anaphylactoid reactions have been reported.

8.2 Protamine Sulphate  Indicated for reversal of heparin effect although stopping the infusion is usually sufficient. o 1 mg will neutralise 100 units of UFH given within the previous hour o Halve protamine dose if heparin stopped for one hour. o Quarter protamine dose if heparin stopped for two hours. o Neutralisation of LMWH is incomplete o Maximum dose is 50 mg. o Maximum rate of IV injection is 5 mg/min. o Avoid exceeding these doses as excess protamine itself has anticoagulant properties o Monitor APTT ratio o Refer to BNF and SPC of heparin, LMWH and protamine for further details.

Anticoagulation Guidelines Version 4 Page 18 of 25 July, 2012 8.3 Prothrombin complex concentrate (PCC) (see Table 9)  Plasma derived clotting factor concentrate o Contains factors II, Vii, IX, X, protein C, protein S o Contains heparin as an excipient o Octaplex is the PCC available in the Trust  The use of this product must be authorised by a Consultant Haematologist.  Indications: o Emergency reversal of warfarin effect o Life-threatening bleeding in the presence of warfarin o Replacement therapy for factor II, X deficiencies when the specific factor is not available  Dosage for reversal of warfarin effect o See SPC for Octaplex for replacement therapy o Guidelines for Warfarin reversal . Vitamin K should be given concurrently for sustained effect . Discuss with Registrar / Consultant in Haematology . Maximum single dose should be 3,000 units  Initial INR PCC dose required to correct INR to <1.2 2 – 2.5 20 – 30 units / kg 2.6 – 3 30 – 40 units / kg 3 – 3.5 40 – 48 units / kg o PCC is stored in Transfusion Laboratory o Contact the on-call Haematology BMS for PCC o Check pre- and post-INR after PCC administration

 Note : Thrombosis can occur following administration of PCC  Contra-indications o Severe hypersensitivity reactions to plasma proteins o Past history of HIT – within the previous 100 days o DIC  Cautions o Recent MI o Liver disease  Reconstitution o Please read all the instructions and follow them carefully! o During the procedure described below, aseptic technique MUST be maintained! o The product reconstitutes quickly at room temperature o The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discolouration prior to administration. o After reconstitution the solution must be used immediately. o Any unused product or waste material should be disposed of in accordance with local requirements. o Instructions for reconstitution : . If necessary, allow the solvent (water for injection) and the powder in the closed vials to reach the room temperature. This temperature should be maintained during reconstitution. If a water bath is used for warming, care must be taken to avoid water coming into contact with the rubber stoppers or the caps of the vials. The temperatures of the water bath should not exceed 37oC. . Remove the caps from the powder vial and the water vial and clean the rubber stoppers with an alcohol swab. . Remove the protective cover from the short end of the double-ended needle, making sure not to touch the exposed tip of the needle. Then perforate the centre

Anticoagulation Guidelines Version 4 Page 19 of 25 July, 2012 of the water vial rubber stopper with the vertically held needle. In order to withdraw the fluid from the water vial completely, the needle must be introduced into the rubber stopper in such a way that it just penetrates the stopper and is visible in the vial. . Remove the protective cover from the other, long end of the double-ended needle, making sure not to touch the exposed tip of the needle. Hold the water vial upside-down above the upright powder vial and quickly perforate the centre of the powder vial rubber stopper with the needle. The vacuum inside the powder vial draws in the water. . Remove the double-ended needle with the empty water vial from the powder vial, then slowly rotate the powder vial until it is completely dissolved. Octaplex dissolves quickly at room temperature to a colourless to slightly blue solution. If the powder fails to dissolve completely or an aggregate is formed, do not use the preparation.

 Administration o Instructions for injection : . As a precautionary measure, the patients pulse rate should be measured before and during the injection. If a marked increase in the pulse rate occurs the injection speed must be reduced or the administration must be interrupted. . After the powder has been reconstituted in the manner described above, remove the protective cover from the filter needle and perforate the rubber stopper of the powder vial. . Remove the cap of the filter needle and attach a 20mL syringe. . Turn the vial with the attached syringe upside-down and draw up the solution into the syringe. . Disinfect the intended injection site with an alcohol swab. . After removing the filter, inject the solution intravenously at a slow speed: Initially 1mL per minute, not faster than 2 – 3mL per minute. The filter needle is for single use only. Always use a filter needle when drawing up the preparation into a syringe. No blood must flow into the syringe due to the risk of formation of fibrin clots.

8.4 Fresh frozen plasma (FFP)  The use of this product must be authorised by a Consultant Haematologist  Indicated for emergency reversal of warfarin if PCC is contra-indicated  See hospital transfusion policy section 11 for details of administration

8.5 Recombinant FVIIa (Novoseven)  The use of this product must be authorised by a Consultant Haematologist.  Indications o Haemophilia with inhibitors o Acquired haemophilia o Factor VII deficiency  Prior to requesting Novoseven, ensure that local and general haemostatic measures have been implemented. o Platelet count > 50 x 109/L o FFP 15 mL/kg to correct DIC o Cryoprecipitate 1.5 units /10 kg to correct fibrinogen < 1.0 g/L o Correction of acidosis  The product is available through the Transfusion laboratory.  Contra-indications o Allergy to bovine, hamster or mouse proteins

Anticoagulation Guidelines Version 4 Page 20 of 25 July, 2012  Cautions o Recent MI or PCI o Prosthetic heart valves o Recent PE or very high risk for VTE o Recent ischaemic stroke  Side-effects o Thrombosis, e.g. MI and Stroke

Table 9 Management of excessive anticoagulation BCSH recommendations for managing warfarin overdose

TARGET INR 2.5 3.5 Presenting INR Bleeding Intervention 2.0 - 3.0 3.0 - 4.0 Minor/major Investigate for local causes of bleeding 3.1 - 4.5 4.1 - 5.5 None Reduce warfarin dose. Repeat INR in a week. 4.6 - 5.9 5.6 - 5.9 None/minor Omit warfarin for 1 day and reduce dose. Repeat INR within a week 6.0 - 8.0 6.0 - 8.0 None/minor Omit warfarin for 2 to 3 days. Repeat INR on 3rd day. Re-start warfarin when INR < 5.0 at reduced dose. Consider IV vitamin K 2 mg orally (iv preparation)  8.0  8.0 None/minor Omit warfarin for 2 to 3 days. Inject Vitamin K 1 to 2 mg intravenously. Repeat INR daily. Re-start warfarin when INR <5.0 at reduced dose.  8.0  8.0 Major Stop warfarin treatment. Inject PCC and Vitamin K 5 mg intravenously. Infuse FFP 20mL/kg if PCC is contra- indicated. Repeat INR 1 hour after PCC and daily. Review indication for anticoagulation and target INR.

10.0 Glossary

ACS acute coronary syndrome AF atrial fibrillation APTTR activated partial thromboplastin time ratio AVR atrial valve replacement BMI body mass index BMS biomedical scientist CCF congestive cardiac failure DIC disseminated intravascular coagulation DVT deep vein thrombosis FBC full blood count FFP fresh frozen plasma GECS graduated elastic compression stockings GFR glomerular filtration rate HIT heparin induced thrombocytopenia INR International Normalised Ratio IPC intermittent pneumatic compression IV intravenous LFT liver function tests LMWH low molecular weight heparin e.g. dalteparin (Fragmin®) MDRD modification of diet in renal disease MI myocardial infarction MVR mitral valve replacement

Anticoagulation Guidelines Version 4 Page 21 of 25 July, 2012 NSAID non-steroidal anti-inflammatory drug PCI percutaneous coronary intervention PE pulmonary embolus PNH paroxysmal nocturnal haemoglobinuria PCC prothrombin complex concentrate PT prothrombin time SC subcutaneous injection TEDS commonly used brand name for Graduated Elastic Compression Stockings (GECS) U&E urea and electrolytes UFH unfractionated heparin VFP venous foot pump VKA vitamin K antagonist VTE venous thromboembolism

11.0 References

Guidelines on the use and monitoring of heparin. British Committee for Standards in Haematology. July 2005 http://www.bcshguidelines.com/pdf/Heparin_070705.pdf

British National Formulary (BNF: 54) Sept 2007 http://www.bnf.org/bnf/index.htm

Summary of Product Characteristics: Heparin Sodium 1,000units/mL (LEO Laboratories) http://emc.medicines.org.uk/emc/assets/c/html/displayDocPrinterFriendly.asp?documentid=8080 accessed 01 Oct 2007.

Summary of product Characteristics: Dalteparin ‘Fragmin for Surgical and Medical Thromboprophylaxis’ (Pfizer Ltd) http://www.medicines.org.uk/EMC/medicine/9150/SPC/Fragmin+- +Surgical+%26+Medical+Thromboprophylaxis+(2500IU+5000IU+Syringes) accessed 27 Feb 2012.

Summary of Product Characteristics: Dalteparin ‘Fragmin - treatment of VTE’ (Pfizer ltd) http://www.medicines.org.uk/EMC/printfriendlydocument.aspx?documentid=9148&companyid=1 05 accessed 27 Feb 2012.

Summary of Product Characteristics: Protamine Sulphate ‘Prosulf’ (CP Pharmaceuticals) http://emc.medicines.org.uk/emc/assets/c/html/displayDocPrinterFriendly.asp?documentid=1356 7 accessed 01 Oct 2007.

Summary of Product Characteristics: Ocatplex (Octapharma) http://www.medicines.org.uk/EMC/medicine/21897/SPC/octaplex

Oxford Handbook of Clinical Medicine 6th edition. Longmore M, Wilkinson I, Rajagopalan S Oxford University Press

Guidelines on oral anticoagulation (warfarin): third edition - 2005 update. Baglin T, Keeling DM, Watson HG on behalf of the Haemostasis and Thrombosis Task Force for the Committee for Standards in Haematology. British Society of Haematology. Br J Haematol 2005;132:277-85 http://www.bcshguidelines.com/pdf/oralanticoagulation.pdf

Anticoagulation Guidelines Version 4 Page 22 of 25 July, 2012 Guidelines on the use and monitoring of heparin. Baglin T, Barrowcliffe TW, Cohen A, Greaves M for the British Committee for Standards in Haematology. Br J Haematol 2006;133:19-34 http://www.bcshguidelines.com/pdf/Heparin_070705.pdf

Comparison of 10mg and 5mg warfarin initiation nomogram together with LMWH for out-patient treatment of acute venous thromboembolism Ann Intern Med 2003; 138: 714-719

Anticoagulants in venous thromboembolism. BMJ 1988; 297: 1285-1288

Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Holocker et al. Reg Anesth Pain Med 2003 28(3): 172-97.

From bmj learning modules Risk assessment of anticoagulant therapy.

Medication errors: risk assess your dispensing. Cousins DH, Upton DR. Pharmacy in Practice 1998;8:253-256

Medication errors: a national standard for supply of warfarin tablets? Cousins DH, Upton DR. Pharmacy in Practice 1997;7:570

Audit of patients on oral anticoagulants with an INR of eight or above. Murphy PT, Casey MC, Abrams K. Clin Lab Haematol 1998;20:253-257

An audit of warfarin anticoagulation in teaching hospital patients. Sowter J, et al. Pharmaceutical Journal 1997;259;612-613

Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a metaanalysis. Linkins LA, Choe PT, Douketis JD. Ann Intern Med 2003;139:893-900

Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Chest 1998;114:445-69

Guidelines on oral anticoagulation (warfarin): third edition. Baglin T, Rose PE on behalf of the Haemostasis and Thrombosis Task Force for the Committee for Standards in Haematology. British Society of Haematology. Br J Haematol 1998;101(2):374. http://www.bcshguidelines.com/pdf/bjh715.pdf

Problems in General Practice - medication errors. Medical Defence Union. London. 1996

Audit of anticoagulant therapy and acute hospital admissions. Hirri HM, Green PJ. Clin Lab Haematol 2002;24:43-

Anticoagulation Guidelines Version 4 Page 23 of 25 July, 2012 12.0 Appendix 1 Oral and Parenteral Anticoagulation Prescriptions

Appendix 2 Anticoagulation Clinic Referral Form

Appendix 3 Anticoagulant Therapy Record and INR Test Request Form

Appendix 4 Oral Anticoagulant Therapy; information for patients, alert card and record book

Appendix 5 Peri-operative bridging protocol for warfarinised patients

Appendix 6 Management of sub-therapeutic INR in patients with mechanical heart valves

Appendix 7 Guidelines for thrombophilia testing in the laboratory

Appendix 8 Guidelines for monitoring, diagnosing and managing heparin- induced thrombocytopenia (HIT)

Consultation Process

Version Date Author Level of Consultation 4 July 2012 Kareena Marotta & Jason D&TC Mainwaring

Anticoagulation Guidelines Version 4 Page 24 of 25 July, 2012 EQUALITY IMPACT ASSESSMENT – SCREENING FORM

1. Title of document/service for assessment Anticoagulation Guidelines 2. Date of assessment July 2012 3. Date for review July 2014 4. Directorate/Service Trust-wide 5. Approval Committee MGC

Yes/No Rationale 6. Does the document/service affect one group less or more favourably than another on the basis of: No  Race No  Gender (including transgender) No  Religion or belief No  Sexual orientation, to include heterosexual, lesbian, gay and bisexual people No  Age No  Disability – learning disabilities, physical disabilities, sensory impairment and mental health issues No  Marriage and Civil Partnership No  Pregnancy and Maternity 7. Does this document affect an No individual’s human rights? 8. If you have identified potential N/A discrimination, are the exceptions valid, legal and/or justified?

9. If the answers to any of the above questions is ‘yes’ Tick Rationale then: Demonstrate that such a disadvantage or advantage can be justified or is valid

Adjust the policy to remove disadvantage identified or better promote equality

If neither of the above possible, submit to Diversity Committee for review.

10. Screener(s)

Print name: Jacqui Bowden

11. Date Policy approved by July 2012 Committee

12. Upon completion of the screening and approval by Committee, this document should be uploaded to papertrail. Anticoagulation Guidelines Version 4 Page 25 of 25 July, 2012