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Senior Academic Half Day 14 th January 2011. Dr Oliver Chapman Consultant Haematologist, UHCW. Summary. Warfarin Heparin LMWH (enoxaparin) Unfractionated Novel anticoagulants Quiz. Rationale. Preventing harm from High Alert Medication- Anticoagulants.

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Senior Academic Half Day14th January 2011

Dr Oliver Chapman

Consultant Haematologist, UHCW

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  • Warfarin

  • Heparin

    • LMWH (enoxaparin)

    • Unfractionated

  • Novel anticoagulants

  • Quiz

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Preventing harm from High Alert Medication- Anticoagulants

The NHS Litigation Authority has reported that medication errors involving anticoagulants fall within the top ten causes of claims against NHS trusts

Anticoagulants are one of the classes of medicines most frequently identified as causing preventable harm and admission to hospital (Pirmohamed M et al. 2004, Howard RL et al. 2007)

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NPSA Risk Assessment

Preventing harm from High Alert Medication- Anticoagulants

  • NPSA risk assessment 2006 found:

    • 120 deaths

    • 480 cases of serious harm

    • anticoagulants the second therapeutic group (after opiates) causing the most deaths and severe harm

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  • CHADS2 score 0 – stroke risk <1%/yr / cancer consider extending treatment duration – INDIVIDUALISED THERAPY (the future?)

    • CHADS2 score 1 – stroke risk 2.5%/year

    • CHADS2 score 2 – stroke risk 4%/yr

    • CHADS2 score 3 – stroke risk 6%/yr

    • CHADS2 score 4 – stroke risk 8%/yr

    • CHADS2 score 6 – stroke risk 18%/yr

    • (cf warfarin fatal bleeding rate approximately 0.6% and 2% life threatening bleeding annually)

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Starting warfarin / cancer consider extending treatment duration – INDIVIDUALISED THERAPY (the future?)

  • 2 regimes based on degree of urgency for therapeutic anticoagulation

    • Rapid anticoagulation in patients requiring heparin ie post thrombosis etc

    • Slow induction of anticoagulation in outpatients not requiring heparin ie prophylaxis eg AF

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Why Warfarin and Heparin Need to overlap When Treating Acute Venous Thromboembolism

  • Pharmacokinetics of warfarin

    • 30 hour T1/2= 5 days to reach steady state

  • Time delay in achieving an antithrombotic effect based on the elimination half-lives of the vitamin K dependent clotting factors

    • (INR≠level of anticoagulation therapy during initiation of warfarin)

  • Protein C

  • Study evidence

    • 20 vs 6.7% incidence rethrombosis (Brandjes DPM, New Engl J Med 1992;327:1485-9)

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Slow induction Venous Thromboembolism

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Warfarin interactions Venous Thromboembolism

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Warfarin Venous Thromboembolism

Refer to elibrary trustwide guidelines “Warfarin Guideline”

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Heparin - uses Venous Thromboembolism

  • Prophylaxis vs. Therapeutic

  • Therapeutic

    • Monitoring mandatory daily APTT-R + regular FBC with UFH/ intravenous heparin

    • Monitoring of LMWH generally not required

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Dosing enoxaparin Venous Thromboembolism

  • Depends on indication (see below)

    • Treatment of VTE / peripheral vascular surgery:

      • Enoxaparin (ie clexane) should be administered subcutaneously as a single daily injection of 1.5 mg/kg (150 IU/kg). Treatment is usually prescribed for at least 5 days and until adequate oral anticoagulation is established.

      • Trust policy is to select the syringe strength which is appropriate to for the patient’s weight as per the following table (colour coded to correspond with the clexane syringe) :

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Dosing enoxaparin Venous Thromboembolism

2 Treatment of unstable angina and non-Q-wave myocardial infarction:

  • Enoxaparin 1 mg/kg bd S/C injection. Treatment with enoxaparin in these patients should be prescribed for a minimum of 2 days and continued until clinical stabilisation. The usual duration of treatment is 2 to 8 days.

    3 Treatment of acute ST-segment elevation myocardial infarction

  • The recommended dose of enoxaparin sodium for patients <75 years is a single IV bolus of 30mg plus a 1mg/kg SC dose followed by 1mg/kg administered SC bd (max 100mg for the first two doses only, followed by 1mg/kg dosing for the remaining doses).

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Dosing enoxaparin Venous Thromboembolism

  • For treatment of acute ST-segment Elevation Myocardial Infarction in elderly patients 75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75mg/kg SC bd (maximum 75mg for the first two doses only, followed by 0.75mg/kg dosing for the remaining doses).

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Dosing enoxaparin Venous Thromboembolism

4 Prevention of extracorporeal thrombus formation during haemodialysis

  • An enoxaparin dose equivalent to 1 mg/kg introduced into the arterial line at the beginning of a dialysis session is usually sufficient for a 4 hour session. If fibrin rings are found, such as after a longer than normal session, a further dose of 0.5 to 1mg/kg may be given. For patients at a high risk of haemorrhage the dose should be reduced to 0.5 mg/kg for double vascular access or 0.75 mg/kg for single vascular access

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Enoxaparin dose adjustments Venous Thromboembolism

Dose adjustments

A dose adjustment is required for patients with severe renal impairment (creatinine clearance < 30 ml/min), according to the following tables, since enoxaparin exposure is significantly increased in this patient population:

Dosage adjustments for therapeutic dosage ranges

Elderly patients

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Dosage adjustments for prophylactic dosage ranges Venous Thromboembolism

Standard dosingSevere renal impairment

40 mg once daily 20 mg once daily

20 mg once daily 20 mg once daily

If treatment with enoxaparin is going to be prolonged eg >2 weeks in patients with renal failure (estimated creatinine clearance <30 ml/min) antiXa activity should be monitored on a single occasion after 7 days treatment (only repeat if significant change in renal function / dose adjustment previously required)

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Anti Xa monitoring Venous Thromboembolism

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Reversal Venous Thromboembolism

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Therapeutic Heparin Venous Thromboembolism

  • LMWH is preferable in most situations

    • At least as effective as UFH in DVT and sub massive PE

    • Lower risk of bleeding (NB UFH often out of therapeutic range)

    • Lower risk of HITT

    • BUT difficulty with reversal – UFH preferred in some situations eg Pregnant patients with mechanical mitral valves who require surgery / patients with very high risk of haemorrhage

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Hirudin (HITTS)

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Prophylaxis (HITTS)

  • In UK VTE causes 25-32,000 deaths / year in hospitalised patients (1)

  • i.e. exceeds deaths from breast cancer, AIDS and traffic accidents combined.

  • i.e. >25x greater than the 955 (2) annual deaths from MRSA

  • Immediate cause of death in 5-10% of all patients who die in hospital (3,4)

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Costs of the problem (HITTS)

  • Estimated NHS costs

    • Hospital based costs £280 million / yr

    • Community based costs £360 million / yr

  • 20% of cost burden attributable to chronic care of post thrombotic syndrome

    • Estimated 25% incidence of chronic leg

      ulcers (5)

    • Chronic pulmonary hypertension

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Venous Thrombo-Embolism (VTE) in hospital inpatients (HITTS)

  • Risk factors

    • Previous VTE

    • Surgery / trauma

    • Increasing age eg >60 years

    • Malignancy

    • Obesity (BMI>30)

    • Sepsis

    • Immobilisation

    • Stroke

    • Cardiac failure

    • Pregnancy, HRT, oral contraceptives

    • Inflammatory bowel disease

    • Nephrotic syndrome

    • Myeloproliferative disorders eg Essential Thrombocythaemia

    • Congenital thrombophilias

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VTE prophylaxis in hospital (HITTS)

  • Mechanical

    • Pneumatic calf compression

    • Compression stockings

  • Pharmacologic

    • Low Molecular Weight Heparin (LMWH)

    • Unfractionated heparin

    • Other anticoagulants

    • Aspirin

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VTE prophylaxis in surgery (HITTS)

  • Meta-analysis (6) of 46 studies


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Why Mothers Die 2000–2002 (HITTS)

  • Thromboembolism remains the leading direct cause of maternal death in UK

  • Substandard care was identified in over 50% of cases

  • The most important aspect of substandard care was the failure to recognise risk factors, and we therefore welcome the publication of the new RCOG guideline, which clearly recommends risk assessment for all pregnant women

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A comparison of the principal randomised trials of thromboprophylaxis in acutely ill MEDICAL patients

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International Guidelines thromboprophylaxis in acutely ill

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Other Key Points of NICE CG 92 thromboprophylaxis in acutely ill

  • Includes day case admissions

  • Excludes minor procedures / investigations which do not cause increased immobility performed under local anaesthetic / sedation eg endoscopy, angiography

  • Offer patients information on VTE and its prevention on admission and include within the discharge plan

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Venous Thromboembolism (VTE) prevention: Background thromboprophylaxis in acutely ill

A number of interrelated measures were introduced 1st April 2010 to ensure a comprehensive National VTE prevention programme for the NHS in England, including:


  • Care Quality Commission / NICE Quality Standards


    VTE prevention is also included in the NHS Standard

    Contract for Acute Services 2010/11

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Prophylaxis Summary thromboprophylaxis in acutely ill

  • Pulmonary embolism is the most common preventable cause of hospital death

  • “ amounts to omission of duty of care and clinical negligence not to provide prophylaxis to the moderate and high risk patients” Autar R, HC99

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Novel Anticoagulants thromboprophylaxis in acutely ill

  • Direct anti Xa inhibitor (oral)

    • Eg rivaroxaban, apixaban, edoxaban

  • Direct Thrombin inhibitor (oral)

    • Eg dabigatran

  • Currently licensed for thrombo-prophylaxis

  • Ongoing phase III trials for therapeutic anticoagulation

  • Fixed dose, no need for monitoring / dose adjustments

  • No reversal agent (t1/2 10-16 hours)

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Case 1 thromboprophylaxis in acutely ill

  • Mrs AB, 59 year old secretary is admitted routinely for cholecystectomy. Metallic Mitral Valve Replacement 5 years before – on warfarin.

  • Warfarin stopped 3 days before admission, INR on admission 1.4.

  • IV heparin infusion started – stopped for 6 hours peri-operatively

  • Cholecystectomy performed following day – uneventful

  • Warfarin restarted day 1 post op, IV heparin continued.

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Case 1 thromboprophylaxis in acutely ill

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Case 1 thromboprophylaxis in acutely ill

  • Day 5 post op deterioration

    • Breathless at rest

    • Hypoxia – Oxygen sats 85% on air

    • Purpura at cannula site

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Case 1 thromboprophylaxis in acutely ill

  • What are the differential diagnoses?

  • What investigations?

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Case 1 : A simple PE? thromboprophylaxis in acutely ill

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HITT Syndrome thromboprophylaxis in acutely ill

  • Deep vein thrombosis,Pulmonary embolism, Myocardial infarction, Occlusion of limb arteries (possibly resulting in amputation), Cerebrovascular accidents (stroke,TIA), Skin necrosis, End-organ damage (e.g., adrenal, bowel, spleen, gallbladder or hepatic infarction; renal failure), Death

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HITT Syndrome thromboprophylaxis in acutely ill

  • ELISA for PF4/heparin Ab (Bristol NBS, via Walsgrave Blood Bank). 93 - 97% sensitive However patients on a course of heparin may develop these Ab without HIT/T (5% on haemodialysis, 10% general surgical, 50% post-CABG). However, negative assay virtually excludes diagnosis

  • Takes 2-3 working days – initially clinical diagnosis

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Case 2 thromboprophylaxis in acutely ill

  • 24 year old woman with x2 previous DVT’s on long term warfarin admitted c/o abdominal discomfort.

  • Routine pregnancy test positive.

  • What are you going to do?

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Case 2 thromboprophylaxis in acutely ill

  • Ascertain likely gestation / liaise with O&G

    • History

    • USS

  • It is estimated that the foetus is 5/40

    • Risk to foetus of warfarin small (peak risk 6-12 weeks)

    • Patient converted to LMWH for remainder of pregnancy

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Case 2 thromboprophylaxis in acutely ill

  • 1 month post delivery the patient presents with acute mid back pain.

    • What investigations?

    • What is the diagnosis?

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Case 2 thromboprophylaxis in acutely ill

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Case 3 thromboprophylaxis in acutely ill

  • You are called urgently to see a 45 year man with a massive haematemesis.

  • On arrival you are told he is on therapeutic heparin – he had a DVT 5 months ago and had been changed from warfarin whilst he was undergoing investigations for abdominal pains.

  • What is your immediate management?

  • Consider UFH vs. LMWH

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Case 3 thromboprophylaxis in acutely ill

  • Resuscitation (call senior colleagues)

    • Wide bore IV access / Fluid replacement whilst X matching blood

    • Check FBC / Coagulation screen / X match etc

  • Stop / Reverse Heparin – protamine

    • UFH

      • Protamine 1mg per 100 units of heparin MAX 50mg (in infusions calculate dose of heparin in preceding 2 hours)

    • LMWH

      • Protamine 1 mg per 1 mg of clexane (Max 50mg)

      • Novoseven – on discussion with haematologist

  • ONLY use novoseven if bleed is life threatening despite above interventions

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Case 4 thromboprophylaxis in acutely ill

  • 76 year man, known atrial fibrillation on warfarin. Attends ED with episode of malaena

  • Outline the management / investigations

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Case 4 thromboprophylaxis in acutely ill

  • IV access

  • FBC / INR / X match / U&E / LFT

  • IV fluids / resuscitation etc

  • INR = 10.0

  • What are you going to do?

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Case 4 thromboprophylaxis in acutely ill

  • Vitamin K

    • 5-10mg stat IV

  • Fresh frozen plasma

    • 10-15 mls / kg if bleed not lifethreatening

  • Prothrombin Complex Concentrate

    • Only if severe haemorrhage / compromise

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Case 5 thromboprophylaxis in acutely ill

  • 32 year old woman presents via A&E with pleuritic chest pain / breathlessness and haemoptysis.

  • Diagnosis of Pulmonary Embolism confirmed with V/Q scanning

  • Treatment – LMWH and commences warfarin 10mg Day1+2.

  • Day 3 INR 2.0 – LMWH stopped and patient discharged on warfarin with anticoagulation clinic appointment 2 days later

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Case 5 thromboprophylaxis in acutely ill

  • Day 4

    • Patient brought into A&E after collapse. Severely unwell. Profoundly hypoxic. Purpuric rash noted (see next slide)

    • Taken to ITU – sedated and ventilated but later dies

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Case 5 thromboprophylaxis in acutely ill

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Case 5 thromboprophylaxis in acutely ill

  • What has happened?

  • How could this have been avoided?

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Summary thromboprophylaxis in acutely ill

  • Warfarin and Heparin are commonly used drugs which you will all encounter.

  • Unless guidelines are followed / care is taken they have adverse safety profiles and life-threatening complications are relatively common.

  • If in doubt….ask a senior colleague