Senior Academic Half Senior Academic Half DayDay

1414thth January 2011 January 2011

Dr Oliver ChapmanDr Oliver Chapman

Consultant Haematologist, Consultant Haematologist, UHCWUHCW

SummarySummary

WarfarinWarfarin HeparinHeparin

– LMWH (enoxaparin)LMWH (enoxaparin)– UnfractionatedUnfractionated

Novel anticoagulantsNovel anticoagulants QuizQuiz

RationaleRationale

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

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

Preventing harm from High Alert Medication- Anticoagulants

NPSA Risk AssessmentNPSA Risk Assessment

NPSA risk assessment 2006 found:NPSA risk assessment 2006 found:– 120 deaths120 deaths– 480 cases of serious harm480 cases of serious harm– anticoagulants the second anticoagulants the second

therapeutic group (after opiates) therapeutic group (after opiates) causing the most deaths and causing the most deaths and severe harmsevere harm

Preventing harm from High Alert Medication- Anticoagulants

Haemostasis - Haemostasis - coagulationcoagulation

WarfarinWarfarin

NB If persisting risk NB If persisting risk factor eg paralysis, factor eg paralysis, immobilised limb / immobilised limb / cancer consider cancer consider extending treatment extending treatment duration – duration – INDIVIDUALISED INDIVIDUALISED THERAPY (the future?)THERAPY (the future?)

CHADS2 score 0 – stroke risk <1%/yrCHADS2 score 0 – stroke risk <1%/yrCHADS2 score 1 – stroke risk 2.5%/yearCHADS2 score 1 – stroke risk 2.5%/yearCHADS2 score 2 – stroke risk 4%/yrCHADS2 score 2 – stroke risk 4%/yrCHADS2 score 3 – stroke risk 6%/yrCHADS2 score 3 – stroke risk 6%/yrCHADS2 score 4 – stroke risk 8%/yrCHADS2 score 4 – stroke risk 8%/yrCHADS2 score 6 – stroke risk 18%/yrCHADS2 score 6 – stroke risk 18%/yr

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

Starting warfarinStarting warfarin

2 regimes based on degree of 2 regimes based on degree of urgency for therapeutic urgency for therapeutic anticoagulationanticoagulation

1.1. Rapid anticoagulation in patients Rapid anticoagulation in patients requiring heparin ie post thrombosis requiring heparin ie post thrombosis etcetc

2.2. Slow induction of anticoagulation in Slow induction of anticoagulation in outpatients not requiring heparin ie outpatients not requiring heparin ie prophylaxis eg AFprophylaxis eg AF

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

1. Pharmacokinetics of warfarin 30 hour T1/2= 5 days to reach steady state

2. 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)

3. Protein C4. Study evidence

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

Slow inductionSlow induction

Warfarin interactionsWarfarin interactions

WarfarinWarfarin

Refer to elibrary trustwide guidelines “Warfarin Guideline”

Heparin - usesHeparin - uses

Prophylaxis vs. Prophylaxis vs. TherapeuticTherapeutic TherapeuticTherapeutic

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

– Monitoring of LMWH generally not Monitoring of LMWH generally not requiredrequired

Dosing enoxaparinDosing enoxaparin

Depends on indication (see below) 1. 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) :

Standard VTE dose 1.5 Standard VTE dose 1.5 mg/kg – round to nearest mg/kg – round to nearest syringesyringe

Dosing enoxaparinDosing enoxaparin

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

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

33 Treatment of acute ST-segment elevation Treatment of acute ST-segment elevation

myocardial infarctionmyocardial infarction The recommended dose of enoxaparin sodium for The recommended dose of enoxaparin sodium for

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

Dosing enoxaparinDosing enoxaparin

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

Dosing enoxaparinDosing enoxaparin

44 Prevention of extracorporeal thrombus Prevention of extracorporeal thrombus formation during haemodialysisformation during haemodialysis

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

Dose adjustmentsA 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

Standard dosing Severe renal impairment

1 mg/kg SC twice daily 1 mg/kg SC once daily

1.5 mg/kg SC once daily

1 mg/kg SC once daily

30mg-single IV bolus plus a 1mg/kg SC dose followed by 1mg/kg twice daily.

30mg-single IV bolus plus a 1mg/kg SC dose followed by 1mg/kg once daily.

75years of age (for acute STEMI indication only)

0.75mg/kg SC twice daily without initial bolus.

1mg/kg SC once daily without initial bolus.

Enoxaparin dose Enoxaparin dose adjustmentsadjustments

Dosage adjustments for Dosage adjustments for prophylactic dosage prophylactic dosage rangesrangesStandard dosingStandard dosing Severe renal Severe renal

impairmentimpairment40 mg once daily40 mg once daily 20 mg once daily20 mg once daily

20 mg once daily20 mg once daily 20 mg once daily20 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)

Anti Xa monitoringAnti Xa monitoring

ReversalReversal

Therapeutic HeparinTherapeutic Heparin

LMWH is preferable in most LMWH is preferable in most situationssituations– At least as effective as UFH in DVT and sub At least as effective as UFH in DVT and sub

massive PEmassive PE– Lower risk of bleeding (NB UFH often out of Lower risk of bleeding (NB UFH often out of

therapeutic range)therapeutic range)– Lower risk of HITTLower risk of HITT– BUT difficulty with reversal – UFH preferred in BUT difficulty with reversal – UFH preferred in

some situations eg Pregnant patients with some situations eg Pregnant patients with mechanical mitral valves who require surgery / mechanical mitral valves who require surgery / patients with very high risk of haemorrhagepatients with very high risk of haemorrhage

Heparin induced thrombocytopenia Heparin induced thrombocytopenia and thrombosis syndrome (HITTS)and thrombosis syndrome (HITTS)

HirudinHirudin

ProphylaxisProphylaxis

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

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

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

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

Costs of the problemCosts of the problem

Estimated NHS costsEstimated NHS costs– Hospital based costs £280 million / yrHospital based costs £280 million / yr– Community based costs £360 million / yrCommunity based costs £360 million / yr

20% of cost burden attributable to 20% of cost burden attributable to chronic care of post thrombotic chronic care of post thrombotic syndromesyndrome– Estimated 25% incidence of chronic leg Estimated 25% incidence of chronic leg

ulcers ulcers (5)(5) – Chronic pulmonary hypertensionChronic pulmonary hypertension

Venous Thrombo-Venous Thrombo-Embolism (VTE) in Embolism (VTE) in hospital inpatientshospital inpatients Risk factorsRisk factors

– Previous VTEPrevious VTE– Surgery / traumaSurgery / trauma– Increasing age eg >60 yearsIncreasing age eg >60 years– MalignancyMalignancy– Obesity (BMI>30)Obesity (BMI>30)– SepsisSepsis

– ImmobilisationImmobilisation– StrokeStroke– Cardiac failureCardiac failure– Pregnancy, HRT, oral contraceptivesPregnancy, HRT, oral contraceptives– Inflammatory bowel diseaseInflammatory bowel disease– Nephrotic syndromeNephrotic syndrome– Myeloproliferative disorders eg Essential Myeloproliferative disorders eg Essential

ThrombocythaemiaThrombocythaemia– Congenital thrombophiliasCongenital thrombophilias

VTE prophylaxis in VTE prophylaxis in hospitalhospital MechanicalMechanical

– Pneumatic calf compressionPneumatic calf compression– Compression stockingsCompression stockings

PharmacologicPharmacologic– Low Molecular Weight Heparin (LMWH)Low Molecular Weight Heparin (LMWH)– Unfractionated heparinUnfractionated heparin– Other anticoagulantsOther anticoagulants– AspirinAspirin

VTE prophylaxis in surgery VTE prophylaxis in surgery Meta-analysis Meta-analysis (6)(6) of 46 of 46

studiesstudies

P<0.001

Why Mothers Die 2000–2002Why Mothers Die 2000–2002

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

Substandard care was Substandard care was identified in over 50% of identified in over 50% of casescases

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

A comparison of the principal randomised trials A comparison of the principal randomised trials of thromboprophylaxis in acutely ill of thromboprophylaxis in acutely ill MEDICALMEDICAL patientspatients

International International GuidelinesGuidelines

Other Key Points of Other Key Points of NICE CG 92NICE CG 92 Includes day case admissions Includes day case admissions Excludes minor procedures / Excludes minor procedures /

investigations which do not cause investigations which do not cause increased immobility performed under increased immobility performed under local anaesthetic / sedation eg local anaesthetic / sedation eg endoscopy, angiographyendoscopy, angiography

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

Venous Venous Thromboembolism Thromboembolism (VTE) prevention: (VTE) prevention: BackgroundBackgroundA number of interrelated measures were A number of interrelated measures were

introduced 1introduced 1stst April 2010 to ensure a April 2010 to ensure a comprehensive National VTE prevention comprehensive National VTE prevention programme for the NHS in England, including:programme for the NHS in England, including:

1.1. CQUIN CQUIN

2.2. Care Quality Commission / NICE Quality Care Quality Commission / NICE Quality StandardsStandards

3.3. NHSLANHSLA

VTE prevention is also included in the NHS StandardVTE prevention is also included in the NHS Standard

Contract for Acute Services 2010/11Contract for Acute Services 2010/11

Prophylaxis SummaryProphylaxis Summary

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

““..it amounts to omission of duty of ..it amounts to omission of duty of care and clinical negligence not to care and clinical negligence not to provide prophylaxis to the moderate provide prophylaxis to the moderate and high risk patients” Autar R, HC99and high risk patients” Autar R, HC99

Novel AnticoagulantsNovel Anticoagulants

Direct anti Xa inhibitor (oral)Direct anti Xa inhibitor (oral)– Eg rivaroxaban, apixaban, edoxabanEg rivaroxaban, apixaban, edoxaban

Direct Thrombin inhibitor (oral)Direct Thrombin inhibitor (oral)– Eg dabigatranEg dabigatran

Currently licensed for thrombo-Currently licensed for thrombo-prophylaxisprophylaxis

Ongoing phase III trials for therapeutic Ongoing phase III trials for therapeutic anticoagulationanticoagulation

Fixed dose, no need for monitoring / Fixed dose, no need for monitoring / dose adjustmentsdose adjustments

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

Case 1Case 1

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

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

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

Cholecystectomy performed following day – Cholecystectomy performed following day – uneventfuluneventful

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

Case 1Case 1DayDay HbHb PltsPlts APTR/INRAPTR/INR

00 11.411.4 246246 1.9/1.21.9/1.2

11 9.39.3 126126 2.5/1.12.5/1.1

22 9.19.1 115115 2.0/1.12.0/1.1

33 9.09.0 9999 2.3/1.32.3/1.3

44 9.29.2 8585 1.9/1.41.9/1.4

55 9.39.3 4343 1.7/1.61.7/1.6

Case 1Case 1

Day 5 post op Day 5 post op deteriorationdeterioration– Breathless at restBreathless at rest– Hypoxia – Oxygen Hypoxia – Oxygen

sats 85% on airsats 85% on air– Purpura at Purpura at

cannula sitecannula site

Case 1Case 1

What are the differential What are the differential diagnoses?diagnoses?

What investigations?What investigations?

Case 1 : A simple PE?Case 1 : A simple PE?

HITT SyndromeHITT Syndrome

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

HITT SyndromeHITT Syndrome

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

Takes 2-3 working days – initially clinical Takes 2-3 working days – initially clinical diagnosisdiagnosis

Case 2Case 2

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

Routine pregnancy test positive.Routine pregnancy test positive. What are you going to do?What are you going to do?

Case 2Case 2

Ascertain likely gestation / liaise with Ascertain likely gestation / liaise with O&GO&G– HistoryHistory– USSUSS

It is estimated that the foetus is 5/40It is estimated that the foetus is 5/40– Risk to foetus of warfarin small (peak risk Risk to foetus of warfarin small (peak risk

6-12 weeks)6-12 weeks)– Patient converted to LMWH for remainder Patient converted to LMWH for remainder

of pregnancyof pregnancy

Case 2Case 2

1 month post delivery the patient 1 month post delivery the patient presents with acute mid back presents with acute mid back pain.pain.– What investigations?What investigations?– What is the diagnosis?What is the diagnosis?

Case 2Case 2

Case 3Case 3

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

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

What is your immediate management?What is your immediate management? Consider UFH vs. LMWHConsider UFH vs. LMWH

Case 3Case 3

Resuscitation (call senior colleagues)Resuscitation (call senior colleagues)– Wide bore IV access / Fluid replacement whilst X Wide bore IV access / Fluid replacement whilst X

matching bloodmatching blood– Check FBC / Coagulation screen / X match etcCheck FBC / Coagulation screen / X match etc

Stop / Reverse Heparin – protamineStop / Reverse Heparin – protamine– UFH UFH

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

– LMWH LMWH Protamine 1 mg per 1 mg of clexane (Max 50mg)Protamine 1 mg per 1 mg of clexane (Max 50mg) Novoseven – on discussion with haematologistNovoseven – on discussion with haematologist

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

Case 4Case 4

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

Outline the management / Outline the management / investigationsinvestigations

Case 4Case 4

IV accessIV access FBC / INR / X match / U&E / LFTFBC / INR / X match / U&E / LFT IV fluids / resuscitation etcIV fluids / resuscitation etc

INR = 10.0INR = 10.0 What are you going to do?What are you going to do?

Case 4Case 4

Vitamin KVitamin K– 5-10mg stat IV5-10mg stat IV

Fresh frozen plasmaFresh frozen plasma– 10-15 mls / kg if bleed not 10-15 mls / kg if bleed not

lifethreateninglifethreatening Prothrombin Complex ConcentrateProthrombin Complex Concentrate

– Only if severe haemorrhage / Only if severe haemorrhage / compromisecompromise

Case 5Case 5

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

Diagnosis of Pulmonary Embolism Diagnosis of Pulmonary Embolism confirmed with V/Q scanningconfirmed with V/Q scanning

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

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

Case 5Case 5

Day 4Day 4– Patient brought into A&E after Patient brought into A&E after

collapse. Severely unwell. collapse. Severely unwell. Profoundly hypoxic. Purpuric rash Profoundly hypoxic. Purpuric rash noted (see next slide)noted (see next slide)

– Taken to ITU – sedated and Taken to ITU – sedated and ventilated but later diesventilated but later dies

Case 5Case 5

Case 5Case 5

What has happened?What has happened? How could this have been How could this have been

avoided?avoided?

SummarySummary

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

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

If in doubt….ask a senior colleagueIf in doubt….ask a senior colleague