Antiplatelets and Antiplatelets and

AnticoagulantsAnticoagulants

Julian HolmesJulian Holmes

H+T specialist pharmacistH+T specialist pharmacist

NUHNUH

Clinical updateClinical update

•• IntroductionIntroduction

•• NUH anticoagulation serviceNUH anticoagulation service

•• AntiplateletsAntiplatelets

•• Anticoagulants Anticoagulants –– warfarin, LMWHwarfarin, LMWH

•• New anticoagulantsNew anticoagulants

IntroductionIntroduction

•• Anticoagulants consistently associated Anticoagulants consistently associated with serious adverse incidents in primary with serious adverse incidents in primary and secondary care (at least 600 between and secondary care (at least 600 between 19901990--2002)2002)

•• Warfarin and NSAIDWarfarin and NSAID’’s among most s among most frequent drug related reason for hospital frequent drug related reason for hospital admissionsadmissions

•• Due to this Due to this –– BCSH/ACCP guidelines and BCSH/ACCP guidelines and NPSA alertsNPSA alerts

NUH anticoagulation serviceNUH anticoagulation service

•• Fully merged service across both sites dosing ~6800 patientsFully merged service across both sites dosing ~6800 patients

•• Morning clinics (20Morning clinics (20--100+ patients) at QMC site Mon100+ patients) at QMC site Mon--Fri with Fri with capillary samplingcapillary sampling

•• GP remote dosing in pm (300GP remote dosing in pm (300--800+ samples) 800+ samples) –– Most Nottingham Most Nottingham GPGP’’s do nots do not dose patientsdose patients

•• Monday early morning clinicsMonday early morning clinics

•• Self testing patientsSelf testing patients

•• Dosing for Dosing for SAFESAFE discharge on both sites discharge on both sites –– cut off times due to GP cut off times due to GP work in pmwork in pm

•• Helpline Helpline –– 9194413 9194413

•• PGDPGD’’s for warfarin, enoxaparin, vitamin ks for warfarin, enoxaparin, vitamin k

•• Out patient DVT service run with NEMSOut patient DVT service run with NEMS

•• KPI for waiting times, discharges etcKPI for waiting times, discharges etc

AntiplateletsAntiplatelets

•• Arterial thrombi platelet rich so use antiplateletsArterial thrombi platelet rich so use antiplatelets

•• Agents disrupt platelet activation via inhibition of Agents disrupt platelet activation via inhibition of

agonists and adhesion/aggregationagonists and adhesion/aggregation

•• Aspirin Aspirin –– irreversibly inhibits COXirreversibly inhibits COX--1 and block 1 and block

formation of platelet agonist thromboxane formation of platelet agonist thromboxane ––

effect last platelet lifetime (~10/7)effect last platelet lifetime (~10/7)

AntiplateletsAntiplatelets

•• Dipyridamole increases platelet Dipyridamole increases platelet

aggregation inhibitor cAMPaggregation inhibitor cAMP

•• Thienopyridine drugs (clopidogrel and Thienopyridine drugs (clopidogrel and

prasugrel) reduce platelet activation by prasugrel) reduce platelet activation by

nonnon--competitively and irreversibly blocking competitively and irreversibly blocking

the binding of ADP to P2Ythe binding of ADP to P2Y12 12 receptors on receptors on

platelet membraneplatelet membrane

AntiplateletsAntiplatelets

•• Clopidogrel is transformed by CYP450 Clopidogrel is transformed by CYP450 enzymes to active metabolite which enzymes to active metabolite which results in variability in effectresults in variability in effect

•• Prasugrel more potent inhibitor and less Prasugrel more potent inhibitor and less affected by CYP450 variationaffected by CYP450 variation

•• Ticagrelor is direct reversible P2YTicagrelor is direct reversible P2Y1212

antagonist and does not require hepatic antagonist and does not require hepatic activationactivation

Antiplatelets usesAntiplatelets uses

•• Not used in primary prevention of cardiovascular eventsNot used in primary prevention of cardiovascular events

•• MI/unstable anginaMI/unstable angina –– aspirin long term and P2Yaspirin long term and P2Y1212

blocker for 12 months (STEMI at least 4 weeks dual blocker for 12 months (STEMI at least 4 weeks dual therapy but PCI preferred treatment), if aspirin C/I therapy but PCI preferred treatment), if aspirin C/I monotherapy with P2Ymonotherapy with P2Y1212 blockerblocker

•• PCIPCI –– bare metal stents aspirin long term clopidogrel for bare metal stents aspirin long term clopidogrel for at least 28 days at least 28 days –– drug eluting stents aspirin long term drug eluting stents aspirin long term clopidogrel for at least 12 months, if aspirin C/I clopidogrel for at least 12 months, if aspirin C/I monotherapy with P2Ymonotherapy with P2Y1212 blockerblocker

•• Stable angina/CADStable angina/CAD –– aspirin long term, if aspirin C/I aspirin long term, if aspirin C/I monotherapy with P2Ymonotherapy with P2Y1212 blockerblocker

Antiplatelets usesAntiplatelets uses

•• Ischaemic strokeIschaemic stroke (not AF related)(not AF related) ––

•• long term clopidogrel long term clopidogrel

•• if clopidogrel plus PPI not tolerated if clopidogrel plus PPI not tolerated dipyridamole and aspirin alternativedipyridamole and aspirin alternative

•• if clopidogrel and dipyridamole not if clopidogrel and dipyridamole not tolerated or C/I use aspirin alone tolerated or C/I use aspirin alone

•• If clopidogrel and aspirin not tolerated or If clopidogrel and aspirin not tolerated or C/I use dipyridamoleC/I use dipyridamole

Antiplatelet usesAntiplatelet uses

•• Peripheral arterial disease and Peripheral arterial disease and

multivascular diseasemultivascular disease –– clopidogrel clopidogrel

long termlong term

•• TIATIA -- dipyridamole and aspirin long term dipyridamole and aspirin long term

–– if aspirin not tolerated or C/I if aspirin not tolerated or C/I

dipyridamole alonedipyridamole alone

Antiplatets and anticoagulantsAntiplatets and anticoagulants

•• Therapy can be combined e.g. aspirin and Therapy can be combined e.g. aspirin and

warfarin for AF in pts with ACSwarfarin for AF in pts with ACS

•• 55--10% of pts with a stent have an indication for 10% of pts with a stent have an indication for

anticoagulationanticoagulation

•• Triple therapy in some pts Triple therapy in some pts –– usually used for usually used for

shortest possible time then to dual therapyshortest possible time then to dual therapy

•• If pts have stable CAD and on warfarin usually If pts have stable CAD and on warfarin usually

no antiplatelet therapy necessaryno antiplatelet therapy necessary

Counselling pointsCounselling points

•• Reason for therapyReason for therapy

•• Missed dosesMissed doses

•• Side effectsSide effects

•• Peri operative issuesPeri operative issues

•• Duration of therapyDuration of therapy

AnticoagulantsAnticoagulants

• The cost of blood clots in the UK:

• DVT leads to 66,000 hospitalisations each year

• 15,000 deaths due to PE each year

• VTE costs the NHS £8781 per 100 patients

• The cost of each stroke patient admitted to hospital is approx £2,000

• The major burden of stroke is chronic disability, it accounts for around 6% of total NHS and social services expenditure - £2.3 billion per year

Clotting cascadeClotting cascade

WarfarinWarfarin

•• Competitively antagonises the effect of vitamin K Competitively antagonises the effect of vitamin K which is essential for the synthesis of clotting which is essential for the synthesis of clotting factors II, VII, IX and X (and the natural factors II, VII, IX and X (and the natural anticoagulants protein C and S). anticoagulants protein C and S).

•• The clotting factor levels are reduced at rates The clotting factor levels are reduced at rates proportional to their halfproportional to their half--liveslives

•• Monitored by the prothrombin time (INR) , this Monitored by the prothrombin time (INR) , this is prolonged by deficiencies of factors V, VII, X, is prolonged by deficiencies of factors V, VII, X, II and low fibrinogen, it reflects alterations in II and low fibrinogen, it reflects alterations in the extrinsic and common pathwaysthe extrinsic and common pathways

•• Alternatives phenindione and acenocoumarolAlternatives phenindione and acenocoumarol

Relationship Between INR and Relationship Between INR and

Efficacy/SafetyEfficacy/Safety

•• LowLow--intensity treatment:intensity treatment:

–– Efficacy rapidly diminishes below INR 2.0Efficacy rapidly diminishes below INR 2.0

–– No efficacy below INR 1.5No efficacy below INR 1.5

•• HighHigh--intensity treatment:intensity treatment:

–– Safety compromised above INR 4 (risk of Safety compromised above INR 4 (risk of

bleeds increases significantly at INR>5)bleeds increases significantly at INR>5)

Relative Contraindications to Relative Contraindications to

Warfarin TherapyWarfarin Therapy

•• Pregnancy (teratogenic use LMWH)Pregnancy (teratogenic use LMWH)

•• Situations where the risk of hemorrhage is Situations where the risk of hemorrhage is

greater than the potential clinical benefits greater than the potential clinical benefits

of therapyof therapy

–– Uncontrolled alcohol/drug abuseUncontrolled alcohol/drug abuse

–– Unsupervised dementia/psychosisUnsupervised dementia/psychosis

Warfarin: Major Adverse Warfarin: Major Adverse

EffectEffect——HemorrhageHemorrhage

•• Factors that may influence bleeding risk:Factors that may influence bleeding risk:

–– Intensity of anticoagulationIntensity of anticoagulation

–– Concomitant clinical disordersConcomitant clinical disorders

–– Concomitant use of other medicationsConcomitant use of other medications

–– Quality of managementQuality of management

Warfarin: Current Warfarin: Current

Indications/IntensityIndications/Intensity

IndicationIndication INR rangeINR range

Prophylaxis of venous thrombosis (highProphylaxis of venous thrombosis (high--risk surgery)risk surgery) 22--33

Treatment of venous thrombosisTreatment of venous thrombosis

Treatment of PETreatment of PE

Prevention of systemic embolism (arterial)Prevention of systemic embolism (arterial)

Tissue heart valvesTissue heart valves

AMI (to prevent systemic embolism)AMI (to prevent systemic embolism)

Valvular heart diseaseValvular heart disease

Atrial fibrillationAtrial fibrillation

Bileaflet mechanical valve in aortic positionBileaflet mechanical valve in aortic position

Mechanical prosthetic valves (high risk)Mechanical prosthetic valves (high risk) 2.52.5––3.53.5

Certain patients with thrombosis and the antiphospholipid syndroCertain patients with thrombosis and the antiphospholipid syndromeme

Recurrent thrombosis and older prosthetic valvesRecurrent thrombosis and older prosthetic valves 33--44

Reversal of anticoagulantsReversal of anticoagulants

•• Warfarin use vitamin K and concentrated Warfarin use vitamin K and concentrated

clotting factors if needed (octaplex or clotting factors if needed (octaplex or

rVIIa)rVIIa)

•• UFH reverse with protamineUFH reverse with protamine

•• LMWH can be partially reversed with LMWH can be partially reversed with

protamineprotamine

Duration of therapy and Duration of therapy and

thrombophilia screeningthrombophilia screening

•• 3 months 3 months –– DVT below knee, provoked DVT/PEDVT below knee, provoked DVT/PE

•• 3 months 3 months –– above knee DVT unprovoked, PE above knee DVT unprovoked, PE

unprovoked (but follow up with resp and ?long unprovoked (but follow up with resp and ?long

term)term)

•• Long term Long term –– heart valves, recurrent VTE, heart valves, recurrent VTE,

inherited clotting disorders, AFinherited clotting disorders, AF

•• NUH follow up unprovoked events if <50, VTE at NUH follow up unprovoked events if <50, VTE at

unusual sites and if strong family historyunusual sites and if strong family history

Drug interactions with warfarinDrug interactions with warfarin

•• These can broadly be divided into 2 mechanisms These can broadly be divided into 2 mechanisms ––pharmacokinetic and pharmacodynamicpharmacokinetic and pharmacodynamic

•• PHARMACOKINETIC interactions affect the processes by PHARMACOKINETIC interactions affect the processes by which drugs are: absorbed, distributed, metabolised and which drugs are: absorbed, distributed, metabolised and excreted (does not usually effect warfarin)excreted (does not usually effect warfarin)

•• PHARMACODYNAMIC interactions occur when the the PHARMACODYNAMIC interactions occur when the the effects of one drug are changed by the presence of effects of one drug are changed by the presence of another drug at its site of actionanother drug at its site of action

•• Can be additive e.g. antihypertensivesCan be additive e.g. antihypertensives

•• Can be antagonistic e.g. warfarin and vitamin KCan be antagonistic e.g. warfarin and vitamin K

Absorption interactions with Absorption interactions with

warfarinwarfarin

•• Can effect rate or total amount of absorptionCan effect rate or total amount of absorption

•• Colestyramine binds to warfarin and reduces its Colestyramine binds to warfarin and reduces its

absorptionabsorption

•• May also reduce vitamin K absorptionMay also reduce vitamin K absorption

•• Need to separate dosages by at least 2 hoursNeed to separate dosages by at least 2 hours

•• Sucralfate may also bind to and reduce warfarin Sucralfate may also bind to and reduce warfarin

absorptionabsorption

Distribution interactions with Distribution interactions with

warfarinwarfarin

•• Warfarin very highly plasma protein boundWarfarin very highly plasma protein bound

•• Interaction usually due to displacement of Interaction usually due to displacement of warfarin from protein binding sites in warfarin from protein binding sites in plasmaplasma

•• Increases the amount of free warfarin Increases the amount of free warfarin which is then exposed to metabolismwhich is then exposed to metabolism

•• Effect usually transient and not thought to Effect usually transient and not thought to play a major role in interactionsplay a major role in interactions

Metabolism interactions with Metabolism interactions with

warfarinwarfarin

•• Most drugs are altered to make them more Most drugs are altered to make them more

water soluble and thus more easily excretedwater soluble and thus more easily excreted

•• This mostly occurs in the liver by enzymes This mostly occurs in the liver by enzymes

known as cytochrome P450 systemknown as cytochrome P450 system

•• Interactions between drugs can result in:Interactions between drugs can result in:

1.1.Increased metabolism (via enzyme induction)Increased metabolism (via enzyme induction)

2.2.Decreased metabolism (via enzyme inhibition)Decreased metabolism (via enzyme inhibition)

Cytochrome (CYP) P450 and Cytochrome (CYP) P450 and

warfarin (1)warfarin (1)

•• There are many subtypes of cytochrome There are many subtypes of cytochrome

enzymesenzymes

•• Warfarin is a mixture of 2 isomers Warfarin is a mixture of 2 isomers –– R and SR and S

•• SS--warfarin is the more potent (by 4 fold) warfarin is the more potent (by 4 fold)

anticoagulant and is metabolised by CYP2C9anticoagulant and is metabolised by CYP2C9

•• RR--warfarin is metabolised by CYP1A2, CYP2C19 warfarin is metabolised by CYP1A2, CYP2C19

and CYP3A4and CYP3A4

CYP450 and warfarin (2)CYP450 and warfarin (2)

•• Can possibly predict warfarin interactions from Can possibly predict warfarin interactions from knowing which other drugs affect the same knowing which other drugs affect the same cytochrome enzymescytochrome enzymes

•• Patients may show considerable variation in their Patients may show considerable variation in their CYP450 ability and response to inhibitors or CYP450 ability and response to inhibitors or inducers (depends on dose of inducer/inhibitor inducers (depends on dose of inducer/inhibitor and warfarin, genetics, age and hepatic disease)and warfarin, genetics, age and hepatic disease)

•• Accurate prediction of interactions can be Accurate prediction of interactions can be difficult and problems usually arise when drugs difficult and problems usually arise when drugs are added or withdrawn to patients stabilised on are added or withdrawn to patients stabilised on warfainwarfain

Enzyme induction interactions (1)Enzyme induction interactions (1)

•• These drugs increase metabolism of warfarin by These drugs increase metabolism of warfarin by inducing the synthesis of new liver enzymes and inducing the synthesis of new liver enzymes and thus lowering INRthus lowering INR

•• Initial effect within first 2 days, maximal effect Initial effect within first 2 days, maximal effect after ~ 1 week (may take several weeks to fully after ~ 1 week (may take several weeks to fully develop) develop) –– onset depends on half life of drug onset depends on half life of drug (e.g. rifampicin onset more rapid than (e.g. rifampicin onset more rapid than phenobarbitone)phenobarbitone)

•• Dissipation of effect gradual Dissipation of effect gradual –– again depends on again depends on half life of inducer and decay of enzymatic half life of inducer and decay of enzymatic activityactivity

Enzyme induction interactions (2)Enzyme induction interactions (2)

•• May need to raise warfarin dose while May need to raise warfarin dose while

patient taking inducerpatient taking inducer

•• Examples include: alcohol (chronic), Examples include: alcohol (chronic),

barbiturates, carbamazepine, griseofulvin, barbiturates, carbamazepine, griseofulvin,

nevirapine, phenytoin, rifampicin (potent nevirapine, phenytoin, rifampicin (potent

inducer), tobacco smoke inducer), tobacco smoke

Enzyme inhibition interactions (1)Enzyme inhibition interactions (1)

•• These drugs reduce warfarin metabolism These drugs reduce warfarin metabolism by inhibiting liver enzymes and increasing by inhibiting liver enzymes and increasing INRINR

•• Initial effect rapid (within 1Initial effect rapid (within 1--3 days)3 days)

•• Dissipation of effect more rapid than Dissipation of effect more rapid than inductioninduction

•• May need to reduce warfarin dose whilst May need to reduce warfarin dose whilst patient taking inhibitor drugpatient taking inhibitor drug

Enzyme inhibition interactions (2)Enzyme inhibition interactions (2)

•• Numerous drugs act as inhibitors and may raise INRNumerous drugs act as inhibitors and may raise INR

•• Inhibitors of SInhibitors of S-- warfarin include: amiodarone, cimetidine, warfarin include: amiodarone, cimetidine, coco--trimoxazole, disulfiram (may chelate metal ions trimoxazole, disulfiram (may chelate metal ions necessary for production of active thrombin), necessary for production of active thrombin), fluvoxamine, metronidazole, phenylbutazone, zafirlukastfluvoxamine, metronidazole, phenylbutazone, zafirlukast

•• Inhibitors of RInhibitors of R--warfarin include: clarithromycin, warfarin include: clarithromycin, ciprofloxacin, danazol, erythromycin, fluconazole, ciprofloxacin, danazol, erythromycin, fluconazole, fluoxetine, itraconazole, ketoconazole, miconazole, fluoxetine, itraconazole, ketoconazole, miconazole, norfloxacin, omeprazole, zileutonnorfloxacin, omeprazole, zileuton

Enzyme inhibition interactions (3)Enzyme inhibition interactions (3)

•• Other CYP 450 inhibitors that can affect Other CYP 450 inhibitors that can affect

warfarin include: allopurinol, warfarin include: allopurinol,

azapropazone, dextropropoxyphene, azapropazone, dextropropoxyphene,

fibrates (can also increase affinity of the fibrates (can also increase affinity of the

anticoagulant for its receptor) and anticoagulant for its receptor) and

propafenonepropafenone

Other mechanisms (1)Other mechanisms (1)

•• Tamoxifen may compete with warfarin for Tamoxifen may compete with warfarin for

metabolism by CYP system metabolism by CYP system –– can raise INRcan raise INR

•• Thyroid/Antithyroid drugs Thyroid/Antithyroid drugs –– hypothyroid hypothyroid

catabolism of clotting factors low and if started catabolism of clotting factors low and if started

on thyroid replacement will need less warfarin. on thyroid replacement will need less warfarin.

Hyperthyroid increased catabolism and if started Hyperthyroid increased catabolism and if started

on antithyroid drug need more warfarin on antithyroid drug need more warfarin

Other mechanisms (2)Other mechanisms (2)

•• High dose corticosteroids may increase the High dose corticosteroids may increase the

coaguability of the bloodcoaguability of the blood

•• Oral contraceptives may increase plasma Oral contraceptives may increase plasma

levels of factor X and fibrinogen and levels of factor X and fibrinogen and

reduce antithrombin III levelsreduce antithrombin III levels

•• Flutamide, anabolic steroids and paracetamol Flutamide, anabolic steroids and paracetamol

(higher dose and prolonged use) may increase (higher dose and prolonged use) may increase

INR by largely unknown mechanismsINR by largely unknown mechanisms

•• Cytotoxic drugs may decrease INR Cytotoxic drugs may decrease INR

(azathioprine) or increase INR (fluorouracil) (azathioprine) or increase INR (fluorouracil)

again by largely unknown mechanismsagain by largely unknown mechanisms

Unknown mechanismsUnknown mechanisms

Warfarin interactions with Warfarin interactions with

herbal medicinesherbal medicines

•• Perception of being Perception of being ‘‘safesafe’’ but still potential for but still potential for

interaction with warfarininteraction with warfarin

•• Possibly similar mechanisms as for conventional Possibly similar mechanisms as for conventional

medicines, but information on products limitedmedicines, but information on products limited

•• ReportedReported and and theoreticaltheoretical interactionsinteractions

•• Difficult to predict outcome as levels of active Difficult to predict outcome as levels of active

ingredients vary between herbal preparations for ingredients vary between herbal preparations for

same productsame product

Reported interactions (1)Reported interactions (1)

•• Liver enzyme induction Liver enzyme induction –– St. Johns Wort, St. Johns Wort, avocado (also may impair warfarin absorption)avocado (also may impair warfarin absorption)

•• Liver enzyme inhibition Liver enzyme inhibition –– cranberry juice, lycium, cranberry juice, lycium, grapefruit juicegrapefruit juice

•• AntiAnti--platelet actions platelet actions –– danshen (plus danshen (plus antithrombin III action and reduced elimination antithrombin III action and reduced elimination of warfarin), panax ginseng, garlic, gingko of warfarin), panax ginseng, garlic, gingko biloba, boldobiloba, boldo

•• Contains coumarin derivatives Contains coumarin derivatives –– dong quai (plus dong quai (plus inhibits platelet activation), PCinhibits platelet activation), PC--SPES, fenugreek, SPES, fenugreek, sweet woodruff, tonka, sweet woodruff, tonka,

Reported interactions (2)Reported interactions (2)

•• Increased vitamin K content Increased vitamin K content –– green green vegetables etcvegetables etc

•• Vitamin K like action Vitamin K like action –– coco--enzyme Q10enzyme Q10

•• Increased vitamin K synthesis and Increased vitamin K synthesis and absorption absorption –– NattoNatto

•• Unknown mechanism but increased INR Unknown mechanism but increased INR ––devildevil’’s claw, glucosamine, papain, mango s claw, glucosamine, papain, mango fruitfruit

Theoretical interactions (1)Theoretical interactions (1)

•• Antiplatelet Antiplatelet –– arnica, clove (eugenol), cod liver arnica, clove (eugenol), cod liver

oil (DHA and EPA) and other fish oils, dandelion oil (DHA and EPA) and other fish oils, dandelion

root, feverfew, flaxseed oils, tumericroot, feverfew, flaxseed oils, tumeric

•• Contains coumarin derivatives Contains coumarin derivatives –– alfalfa, anise, alfalfa, anise,

capsicum, chamomile, ginseng (Siberian), horse capsicum, chamomile, ginseng (Siberian), horse

chestnut, horseradish, liquorice root, nettle, chestnut, horseradish, liquorice root, nettle,

parsley, rueparsley, rue

•• Liver enzyme inhibitors Liver enzyme inhibitors –– echinacea, ipriflavone, echinacea, ipriflavone,

milk thistlemilk thistle

Theoretical interactions (2)Theoretical interactions (2)

•• Contains salicylates Contains salicylates –– black haw, German black haw, German

sarsaparilla, meadowsweet, poplar, willow sarsaparilla, meadowsweet, poplar, willow

barkbark

•• Miscellaneous Miscellaneous –– chondroitin (anticoagulant chondroitin (anticoagulant

or antithrombotic) and evening primrose or antithrombotic) and evening primrose

oil (anticoagulant)oil (anticoagulant)

Which drugs are common Which drugs are common ‘‘culpritsculprits’’??

•• In practice we usually encounter issues In practice we usually encounter issues commonly with:commonly with:

•• AmiodaroneAmiodarone

•• Rifampicin (very potent inducer)Rifampicin (very potent inducer)

•• Antibiotics/antifungalsAntibiotics/antifungals

•• MiconazoleMiconazole

•• However interactions are complex and However interactions are complex and unpredictableunpredictable

HeparinsHeparins

•• UFH is a polysaccharide mixture and binds to UFH is a polysaccharide mixture and binds to antithrombin III which inactivates thrombin (factor II) antithrombin III which inactivates thrombin (factor II) and factor Xaand factor Xa

•• Monitor by using APTT ratio (1.5Monitor by using APTT ratio (1.5--2.5) 2.5) this screens the this screens the INTRINSIC pathway and shows any abnormality of INTRINSIC pathway and shows any abnormality of factors II, V, VIII, IX, X, XI and XII factors II, V, VIII, IX, X, XI and XII

•• LMWH largely only inactivate factor Xa, have a longer LMWH largely only inactivate factor Xa, have a longer halfhalf--life and a more predictable response, so no routine life and a more predictable response, so no routine monitoring required (except in pregnancy, high or low monitoring required (except in pregnancy, high or low body weight)body weight)

•• Fondaparinux synthetic Xa inhibitorFondaparinux synthetic Xa inhibitor

HeparinsHeparins

•• NUH use enoxaparin for VTE prophylaxis, VTE NUH use enoxaparin for VTE prophylaxis, VTE

treatment, ACS treatmenttreatment, ACS treatment

•• Also used off license for thrombus prevention in Also used off license for thrombus prevention in

AF, sub therapeutic INRAF, sub therapeutic INR’’s in patients with s in patients with

mechanical heart valves, long term VTE mechanical heart valves, long term VTE

treatment in patients unable to tolerate oral treatment in patients unable to tolerate oral

anticoagulants and VTE treatment in pregnancyanticoagulants and VTE treatment in pregnancy

•• Fondaparinux synthetic and used if patients Fondaparinux synthetic and used if patients

refuse porcine products or heparin allergyrefuse porcine products or heparin allergy

Conversion of heparin to warfarinConversion of heparin to warfarin

•• May begin concomitantly with heparin therapy May begin concomitantly with heparin therapy

•• Heparin should be continued for a minimum of Heparin should be continued for a minimum of

four to five daysfour to five days

–– Time to peak antithrombotic effect of warfarin is Time to peak antithrombotic effect of warfarin is

delayed 96 hours (despite INR)delayed 96 hours (despite INR)

•• When INR reaches desired therapeutic range, When INR reaches desired therapeutic range,

discontinue heparin (after a minimum of four to discontinue heparin (after a minimum of four to

five days)five days)

Management of Warfarin During Management of Warfarin During

Invasive ProceduresInvasive Procedures

•• For subtherapeutic or normal INR: Hold warfarin for 3For subtherapeutic or normal INR: Hold warfarin for 3––5 days pre5 days pre--procedureprocedure

•• Prophylactic enoxaparin (20Prophylactic enoxaparin (20--40mg daily) or UFH (5000u BD40mg daily) or UFH (5000u BD--TDS) if TDS) if severe renal impairment: hold warfarin 3severe renal impairment: hold warfarin 3––5 days pre5 days pre--procedure and procedure and begin LMWH/UFH therapy 1begin LMWH/UFH therapy 1––2 days pre2 days pre--procedureprocedure

•• Treatment dose enoxaparin (1.5mg/kg daily or 1mg/kg BD if MHV) Treatment dose enoxaparin (1.5mg/kg daily or 1mg/kg BD if MHV) or UFH infusion (if severe renal impairment or high risk of bleeor UFH infusion (if severe renal impairment or high risk of bleeds): ds): timings as abovetimings as above

•• Enoxaparin dose reduced in renal impairment (1mg/kg daily)Enoxaparin dose reduced in renal impairment (1mg/kg daily)

•• Restart heparin or warfarin postRestart heparin or warfarin post--op when considered safe to do soop when considered safe to do so

Effective Patient EducationEffective Patient Education

•• Teach basic concepts of safe, effective Teach basic concepts of safe, effective anticoagulationanticoagulation

•• Discuss importance of regular INR monitoringDiscuss importance of regular INR monitoring

•• Tablet strength and supplyTablet strength and supply

•• Counsel on use of other medications, alcohol, Counsel on use of other medications, alcohol, diet, exercise, smoking, long journeys, diet, exercise, smoking, long journeys, pregnancy, compression hosiery for DVTpregnancy, compression hosiery for DVT

•• Develop creative strategies for improving Develop creative strategies for improving compliancecompliance

Effective patient educationEffective patient education

•• NUH use DVD to show patients on initial clinic NUH use DVD to show patients on initial clinic visitvisit

•• Patient help line, who to contact, alert card and Patient help line, who to contact, alert card and PILPIL

•• Counseling checklist to enhance consistent Counseling checklist to enhance consistent informationinformation

•• Regular communication auditRegular communication audit

•• NPSA alert data required to be collected on this NPSA alert data required to be collected on this areaarea

Questions?Questions?