anticoagulation - haughton thornley medical centres · 2011-03-13 · • anticoagulation is the...

AnticoagulationMedicine > Cardiology > Anticoagulation

Published: 03-Feb-2011 Valid until: 20-Jul-2011 Printed on: 13-Mar-2011 © Map of Medicine Ltd This pathway was published by Tameside & Glossop. A printed version of this document is not controlled so may not be up-to-date with thelatest clinical information.

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R

Anticoagulation

Clear indications foranticoagulation

Contraindications toanticoagulation

Anticoagulation inincreased bleeding riskcases

Patient education andwritten guidance

Follow-up

Go to warfarin

Parenteralanticoagulants

New antithromboticmedications

Perioperativemanagement ofantithrombotic therapy

Oral anticoagulants

Consider choice ofanticoagulant

Anticoagulation inpregnancy

Management ofcomplications

Venousthromboembolicdisease

Refer to relevantspecialist

Atrial fibrillation (AF)

Valvular and structuralheart disease

Peripheral arteryocclusive disease

Non-ST-segmentelevationacute coronarysyndromes(NSTE-ACS )

Management ofvitamin K antagonists

Further management

Backgroundinformation

Updates to thispathway

Information resourcesfor patients and carers



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1 Background information

Quick info:Scope:

• indications for and contraindications to anticoagulation and discussion of possible agents, including parenteral ones

• complications of anticoagulation, including managing bleeding and excessive anticoagulation

• pharmacology and management of vitamin K antagonists, specifically warfarin

• commencement, monitoring and discontinuation of anticoagulation therapy

• discussion of some newer anticoagulation agents appearing on the market

• perioperative/procedural management of anti-thrombotic therapy

• consideration of patient self-testing and management of anticoagulation

• discussion of complication of heparin therapy, specifically Heparin Induced Thrombocytopenia (HIT)

• specific discussion of anticoagulation in the following examples:

• venous thromboembolic disease

• atrial fibrillation (AF)

• valvular and structural heart disease

• non-ST-segment elevation acute coronary syndromes (NSTE-ACS)

• peripheral artery occlusive disease

• discussion of anticoagulation in pregnancy, specifically with regard to treatement of venous thromboembolism (VTE) andthrombophilia

• primary and secondary care settings, for adults over age 18 years

Definition:

• anticoagulation is the prevention of coagulation, via the administration of an anticoagulant to render the blood sufficientlyincoagulable, ie stops blood from clotting

• anticoagulation is common in both primary and secondary care settings

• warfarin:

• is a coumarin derivative

• produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2, 3 epoxide (vitamin Kepoxide)

• induces hepatic production of partially decarboxylated proteins with reduced coagulant activity, by inhibiting the vitamin Kconversion cycle

This information was drawn from the following references:[1] Contributors representing the Royal College of Physicians; 2010.[2] Hirsh J, Fuster V, Ansell J et al. American Heart Association/American College of Cardiology Foundation Guide to WarfarinTherapy. Circulation 2003; 107: 1692-1711.[3] Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2010.

2 Information resources for patients and carers

Quick info:Patients and carers in England and Wales can access this pathway through NHS Choices at http://healthguides.mapofmedicine.com/choices/map/anticoagulation1.htmlThe following resources have been produced by organisations certified by The Information Standard:

• 'Blood clotting' (URL) from Datapharm at http://www.medguides.medicines.org.uk

• 'Blood clotting tests' (URL) from Patient UK at http://www.patient.co.uk

Information for carers and people with disabilities is available at:

• 'Caring for someone' (URL) from Directgov at http://www.direct.gov.uk

• 'Disabled people' (URL) from Directgov at http://www.direct.gov.uk

Explanations of clinical laboratory tests used in diagnosis and treatment are available at ‘Understanding Your Tests’ (URL) from LabTests Online-UK at http://www.labtestsonline.org.uk.

http://healthguides.mapofmedicine.com/choices/map/anticoagulation1.html

http://healthguides.mapofmedicine.com/choices/map/anticoagulation1.html

http://www.theinformationstandard.org/

http://www.medicines.org.uk/guides/blood%20clotting

http://www.medguides.medicines.org.uk

http://www.patient.co.uk/health/Blood-Test-Clotting-Tests.htm

http://www.patient.co.uk

http://www.direct.gov.uk/en/CaringForSomeone/index.htm

http://www.direct.gov.uk

http://www.direct.gov.uk/en/DisabledPeople/index.htm

http://www.direct.gov.uk

http://www.labtestsonline.org.uk

http://www.labtestsonline.org.uk



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The Map of Medicine is committed to providing high quality health and social care information for patients and carers. For details onhow these resources are identified, please see Map of Medicine Patient and Carer Information.NB: This information appears on each page of this pathway.

3 Updates to this pathway

Quick info:Date of publication: 30-Jul-2010Three floating nodes now appear at the top of each pathway page. These provide:

• easy access to scope and background information on each page of the pathway whilst reducing repetition between nodes

• easy access to patient resources/leaflets

• information on pathway updates

This pathway has been updated with the following guidelines:

• [2] Hirsh J, Fuster V, Ansell J et al. American Heart Association/American College of Cardiology Foundation Guide to WarfarinTherapy. Circulation 2003; 107: 1692-1711.

• [4] Bates SM, Greer IA, Pabinger I et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy.American College of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 844S-886S.

• [5] Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 454S-545S.

• [6] Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs. American College of Chest Physicians Evidence-based clinicalpractice guidelines (8th edition). Chest 2008; 133: 234S-256S.

• [7] Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): 3rd edn – 2005 update. Br J Haematol2006; 132: 277-85.

• [8] Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation. American College of Chest PhysiciansEvidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 546S-592S.

• [9] Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants. American College of Chest Physicians Evidence-basedclinical practice guidelines (8th edition). Chest 2008; 133: 141S-159S.

• [10] Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 160S-198S.

• [11] Salem DN, O'Gara PT, Madias C et al. Valvular and structural heart disease. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 593S-629S.

• [12] Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy. American College ofChest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 299S-339S.

• [13] Harrington RA, Becker RC, Cannon CP, et al. Antithrombotic therapy for non-ST-segment elevation acute coronarysyndromes. American College of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133:670S-707S.

• [14] Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 815S-843S.

• [15] Schulman S, Beyth RJ, Kearon C et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment. AmericanCollege of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 257S-298S.

• [16] Warkentin, TE, Greinacher A, Koster A et al. Treatment and prevention of heparin-induced thrombocytopenia. AmericanCollege of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 340S-380S.

• [17] Institute for Clinical Systems Improvement (ICSI). Anticoagulation therapy supplement. Bloomington, MN: ICSI; 2005.

Further information has been provided by the following references: [1,3,18-22]. For further information, please see this pathway'sProvenance certificate.Practice-based knowledge has been contributed to this pathway by:

• Dr Pier Lambiase: Consultant Cardiologist, The Heart Hospital, London (Clinical Facilitator)

• Dr Stephen Furniss: Consultant Cardiologist, Eastbourne DGH

• Dr Yassir Javaid: GP (special interest in cardiology), South Northamptonshire Community Heart Failure Clinic, DanetreHospital, Daventry

• Dr Steve W Parry: Consultant Geriatrician, Freeman Hospital, Newcastle



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The pathway has been completely restructured and redrafted in line with the Map of Medicine's editorial methodology and to bring itin line with current clinical practice.NB: This information appears on each page of this pathway.

4 Anticoagulation

Quick info:Anticoagulation:

• the prevention of coagulation, via the administration of an anticoagulant to render the blood sufficiently incoagulable, ie stopsblood from clotting

• common in both primary and secondary care settings

Indications to consider:

• contraindications

• increased bleeding risk

• pregnancy

This information was drawn from the following references:[1] Contributors representing the Royal College of Physicians; 2010.[3] Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2010.

5 Contraindications to anticoagulation

Quick info:contraindications to anticoagulation [1,3]:

• contraindications to warfarin therapy are not absolute and depend upon clinical scenario

• use judgement in balancing risk of thromboembolism against risk of bleeding if anticoagulated

• give clear reason and state in notes why patient is excluded from anticoagulation

• contraindications include:

• active bleeding, eg:

• peptic ulcer disease

• other gastrointestinal (GI) sources

• coagulopathy, eg:

• disorders of platelet number

• disorders of platelet function

• previous haemorrhagic stroke

• cognitive or social problems (may interfere with appropriate follow-up, monitoring and dosage), eg:

• patients considered to be at risk of non-compliance

• history of recurrent falls (three or more in past year)

• excess alcohol consumption

• uncontrolled blood pressure (BP) more than 180/100mmHg

• regular non-steroidal anti-inflammatory drug (NSAID) usage

• planned major surgery or invasive procedure

• allergy to warfarin − may cause:

• rash

• diarrhoea

• nausea

• hepatitis

References:[1] Contributors representing the Royal College of Physicians; 2010.[3] Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2010.



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6 Anticoagulation in increased bleeding risk cases

Quick info:Patients with increased bleeding risk [1,3]:

• some factors that increase risk of bleeding also increase risk of thrombosis, so are not absolute contraindications toanticoagulation

• consider these factors when weighing up potential benefits and risks of commencing anticoagulant therapy

• patients who have greater risk of bleeding with warfarin include those who:

• are over age 75 years

• are taking:

• antiplatelet therapy (aspirin or clopidogrel); or

• non-steroidal anti-inflammatory drugs (NSAIDs); or

• multiple medications (polypharmacy)

• have past history of bleeding, eg:

• gastrointestinal (GI) source

• cerebral bleed

• have uncontrolled hypertension

• have history of poor control while on anticoagulant therapy

References:[1] Contributors representing the Royal College of Physicians; 2010.[3] Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2010.

7 Anticoagulation in pregnancy

Quick info:Management of venous thromboembolism (VTE) and thrombophilia, and use of antithrombotic agents, during pregnancy [4]:

• for pregnant women in general:

• substitute vitamin K antagonists (VKA) with:

• unfractionated heparin (UFH); or

• low-molecular-weight heparin (LMWH)

• except in women with mechanical heart valves − see below

• for pregnant patients with acute VTE:

• continue subcutaneous (SC) LMWH or UFH throughout pregnancy

• continue anticoagulants for at least 6 weeks postpartum (for total minimum therapy duration of 6 months)

• for pregnant patients with single prior episode of VTE associated with transient risk factor that is no longer present and nothrombophilia:

• clinical surveillance antepartum; and

• anticoagulant prophylaxis postpartum

• for pregnant patients with history of single prior episode of VTE who are not receiving long-term anticoagulant therapy:

• antepartum prophylactic LMWH or UFH; or

• intermediate-dose LMWH or UFH; or

• clinical surveillance throughout pregnancy plus postpartum anticoagulants

• if higher risk of thrombophilia, in addition to postpartum prophylaxis and instead of clinical surveillance:

• antepartum prophylactic; or

• intermediate-dose LMWH; or

• prophylactic or intermediate-dose UFH

• for pregnant patients with multiple episodes of VTE who are not receiving long-term anticoagulants:

• antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH; or



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• intermediate or adjusted-dose UFH; then

• postpartum anticoagulants

• for pregnant patients with prior VTE who are receiving long-term anticoagulants:

• LMWH or UFH throughout pregnancy, either:

• adjusted-dose LMWH or UFH; or

• 75% of adjusted-dose LMWH; or

• intermediate-dose LMWH; then

• resume long-term anticoagulants postpartum

• for pregnant patients with no prior history of VTE but antithrombin deficiency:

• antepartum prophylaxis; and

• postpartum prophylaxis

• for pregnant patients with thrombophilia but no prior VTE:

• antepartum clinical surveillance; or

• prophylactic LMWH or UFH; and

• postpartum anticoagulants

• for women with recurrent early pregnancy loss or unexplained late pregnancy loss:

• screen for antiphospholipid antibodies

• for women with these pregnancy complications who test positive for antiphospholipid antibodies (APLAs) and have no history ofvenous or arterial thrombosis:

• antepartum prophylactic or intermediate-dose UFH or prophylactic LMWH; and

• aspirin

• for pregnant patients with mechanical heart valves:

• include assessment of additional risk factors for thromboembolism, including:

• valve type

• position

• history of thromboembolism

• adjusted-dose LMWH throughout pregnancy; or

• adjusted-dose UFH throughout pregnancy; or

• one of these two regimens until thirteenth week, with warfarin substitution until close to delivery, then restart LMWH or UFH

• if very high risk of thromboembolism and concerns about efficacy and safety of LMWH or UFH:

• VKAs throughout pregnancy; then

• replace with UFH or LMWH close to delivery; after

• thorough discussion of potential risks and benefits

Reference:[4] Bates SM, Greer IA, Pabinger I et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. AmericanCollege of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 844S-886S.

8 Clear indications for anticoagulation

Quick info:

Indications are not absolute and depend on clinical scenario − indications include [1,3]:

• venous thromboembolic disease

• atrial fibrillation (AF)

• valvular and structural heart disease

• non-ST-segment elevation acute coronary syndromes (NSTE-ACS)

• peripheral artery occlusive disease

References:[1] Contributors representing the Royal College of Physicians; 2010.



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[3] Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2010.

9 Venous thromboembolic disease

Quick info:Antithrombotic therapy for venous thromboembolic disease [ACCP]:

• for patients with objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE):

• use anticoagulant therapy with:

• subcutaneous (SC) low-molecular-weight heparin (LMWH); or

• monitored intravenous (IV) or SC unfractionated heparin (UFH); or

• unmonitored weight-based SC UFH; or

• SC fondaparinux

• for patients with high clinical suspicion of DVT or PE:

• treat with anticoagulants whilst awaiting outcome of diagnostic tests

• for patients with confirmed PE:

• evaluate early the risk/benefit analysis of thrombolytic therapy:

• for those with haemodynamic compromise − short-course thrombolytic therapy

• for those with non-massive PE − do not use thrombolytic therapy

• for patients with acute DVT or PE:

• treat initially with LMWH, UFH or fondaparinux for at least 5 days

• initiate use of vitamin K antagonists (VKAs) with LMWH, UFH, or fondaparinux on first day; and

• discontinue heparin preparations when international normalised ratio (INR) is 2.0 or more for at least 24 hours

• for patients with DVT or PE secondary to a transient (reversible) risk factor:

• treat with VKA for 3 months

• for patients with unprovoked DVT or PE:

• treat with VKA for at least 3 months; then

• evaluate for risks to benefits of indefinite therapy

• for patients with VTE and cancer:

• treat for at least 3 months with LMWH; then

• treat with LMWH or VKA if cancer is active

• for prevention of post-thrombotic syndrome (PTS) after proximal DVT:

• use elastic compression stocking

• for DVT of the upper extremity:

• use similar treatment as for DVT of the leg

• for extensive superficial vein thrombosis:

• treat with prophylactic or intermediate doses of LMWH; or

• treat with intermediate doses of UFH for 4 weeks

Reference:[5] Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 454S-545S.

10 Consider choice of anticoagulant

Quick info:Anticoagulants include [6]:

• parenteral anticoagulants

• oral anticoagulants

• new antithrombotic medications



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Choice of anticoagulant [1]:

• depends on clinical scenario

• generally patients given anticoagulants other than warfarin include those who [7]:

• have contraindications to warfarin, but not to other anticoagulants, eg allergy

• are pregnant

• have cancer

• are intravenous (IV) medication users

• low-molecular-weight heparin (LMWH) is easier to administer than unfractionated heparin (UFH), without need for continuousIV infusion and regular blood tests to remain within therapeutic range (activated partial thromboplastin time [APTT] must bemonitored when using UFH)

• patients with cancer or IV drug users are generally prescribed LMWH (benefits and risks better than with warfarin)

• pregnant patients requiring anticoagulation need specialised management

• evidence suggests that LMWH is as at least as effective as UFH or warfarin in anticoagulation of venous thromboembolism(VTE)

• exercise caution when using LMWH in patients with renal impairment − relatively contraindicated in patients receiving dialysis orthose with creatinine clearance (CrCl) of less than 30mL/minute

• once daily dosing with LMWH appears to be as effective as twice daily dosing, but evidence is inconclusive:

• possibility that risk of recurrence of VTE may be increased in once daily dosing

• when deciding on dosing regimen, consider convenience and compliance benefits of once daily dosing against possibleincreased risk of venous thrombosis

• when using heparin, important to remain alert for heparin induced thrombocytopaenia (HIT):

• if UFH is used, check platelet count every second day for first 14 days, or until cessation

• suspect in any patient with reaction at site of injection, or systemic reaction to IV administration of heparin

• suspect in any patient with fall in platelet count of more than 50%

• seek specialist advice if any suggestion of HIT

• if heparin results in excessive anticoagulation that requires reversal, use protamine sulphate:

• LMWH is not fully reversed by any agent − protamine sulphate is only partially effective

• seek specialist advice

References:[1] Contributors representing the Royal College of Physicians; 2010.[6] Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs. American College of Chest Physicians Evidence-based clinicalpractice guidelines (8th edition). Chest 2008; 133: 234S-256S.[7] Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): 3rd edn – 2005 update. Br J Haematol 2006;132: 277-85.

11 Atrial fibrillation (AF)

Quick info:Indications for anticoagulation in patients with atrial fibrillation (AF) are not absolute and depend on patient's thromboembolic risk [1]:

• AF where patient is at increased risk of thromboembolic events:

• patients considered to be at high risk should be anticoagulated unless contraindicated − those with:

• previous stroke (CT scan first to exclude haemorrhagic stroke; commence warfarin 2 weeks post-cerebrovascularaccident and delay initiation in presence of large infarct)

• transient ischaemic attack (TIA; following CT scan to exclude recent infarct or haemorrhage); or

• systemic embolism (following control of hypertension)

• age 75 years or above with hypertension, diabetes mellitus (DM) or vascular disease (coronary or peripheral)

• evidence of cardiac failure, valve disease, left ventricular dysfunction (LVD) on echocardiogram

• patients considered to be at intermediate risk may be considered for prophylaxis, either with anticoagulation or dailyaspirin unless contraindicated, ie:

• age 65 years or above with no high risk factors



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• age 75 years or below with hypertension, vascular disease, DM

• patients below age 65 years with AF and no risk factors are considered to be at low risk of thromboembolism − may bemanaged with daily aspirin unless contraindicated, without need for anticoagulation

• if undergoing cardioversion:

• 3 weeks prior to and 4 weeks after cardioversion if AF is of unknown or more than 48 hours duration

• following successful cardioversion, continue long-term anticoagulation if high-risk factors for recurrence of AF, eg previousfailed conversion

• see 'Atrial fibrillation' pathway

Specific antithrombotic therapy in AF [8]:

• for patients with AF, including those with paroxysmal AF, who have had prior ischemic stroke, transient ischemic attack (TIA), orsystemic embolism:

• use long-term anticoagulation with oral vitamin K antagonists (VKA), eg warfarin

• for patients with AF, including those with paroxysmal AF, who have two or more risk factors for ischemic stroke:

• use long-term anticoagulation with oral VKA

• for patients with AF, including those with paroxysmal AF, with only one risk factor:

• use long-term antithrombotic therapy, either as:

• anticoagulation with oral VKA (eg warfarin); or

• aspirin

• for patients with AF, including those with paroxysmal AF, are age 75 years or below, and with no other risk factor:

• use long-term aspirin therapy

• for patients with atrial flutter:

• follow same risk-based assessment as for AF

• for patients with AF and mitral stenosis:

• use long-term anticoagulation with oral VKA

• for patients with AF and prosthetic heart valves:

• use long-term anticoagulation with oral VKA at intensity appropriate for specific type of prosthesis

References:[1] Contributors representing the Royal College of Physicians; 2010.[7] Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): third edition - 2005 update. Br J Haematol2006; 132: 277-85.[8] Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation. American College of Chest PhysiciansEvidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 546S-592S.

12 Parenteral anticoagulants

Quick info:Parenteral anticoagulants [9]:

• are rapidly acting

• are usually used for initial treatment of arterial or venous thromboembolism (VTE)

• include indirect anticoagulants and direct anticoagulants/thrombin inhibitors

Indirect anticoagulants [9]:

• activity mediated by plasma cofactors − have little or no intrinsic anticoagulant activity

• activate antithrombin, an endogenous inhibitor of various activated clotting factors

• include:

• unfractionated heparin (UFH):

• heterogenous mixture of glycosaminoglycans that bind to AT via unique pentasaccharide sequence, and catalyzeinactivation of thrombin factor Xa and other clotting factors

• heparin binds to cells and other plasma proteins, giving it unpredictable pharmacokinetic and pharmacodynamicproperties, that can lead to non-haemorrhagic side effects, eg heparin-induced thrombocytopenia (HIT) and osteoporosis



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• low-molecular-weight heparins (LMWHs):

• derived from UFH by chemical or enzymatic depolymerization

• have greater inhibitory activity against activated factor X (factor Xa) than thrombin, and exhibit less binding to cells andproteins than heparin

• have more predictable pharmacokinetic and pharmacodynamic properties, longer half-life than heparin, and lower risk ofnon-haemorrhagic side effects

• can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring

• have replaced UFH for many clinical indications, based on their greater convenience

• fondaparinux:

• synthetic pentasaccharide

• catalyzes inhibition of factor Xa (but not thrombin) in AT-dependent manner

• binds only to AT (therefore HIT and osteoporosis unlikely to occur)

• has excellent bioavailability when administered subcutaneously

• has longer half-life than LMWHs

• is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring

• contraindicated in patients with renal insufficiency, creatinine clearance (CrCl) less than 30mL/minute

• danaparoid:

• approved as alternative to heparin in HIT patients

• danaparoid sodium is mixture of glycosaminoglycans (heparan sulfate, dermatan sulfate, and chondroitin sulfate)

• catalyzes inhibition of factor Xa in AT-dependent manner

• has low specific anti-Xa activity

• has half-life of approximately 25hours

Monitoring of LMWHs [9]:

• monitoring antithrombotic effect:

• do not monitor routine coagulation in patients

• in pregnant women, monitor anti-Xa levels

• dosing and monitoring in special situations:

• in obese patients, consider weight-based dosing

• in patients with severe renal insufficiency (CrCl less than 30mL/minute) requiring therapeutic anticoagulation, consider usingUFH instead of LMWH

• in patients with severe renal insufficiency (CrCl less than 30mL/minute) requiring therapeutic anticoagulation, consider usinghalf recommended dose

Direct anticoagulants/thrombin inhibitors [9]:

• do not require plasma cofactors to express activity − have intrinsic activity

• bind to thrombin and block its enzymatic activity

• include the following, which are approved as alternatives to heparin in HIT patients:

• hirudin

• bivalirudin

• argatroban

• recommendations:

• in patients receiving lepirudin or desirudin and having renal insufficiency (CrCl less than 60mL/minute but more than 30mL/minute), reduce dose and monitor medication using activated partial thromboplastin time (APTT)

• in patients with CrCl less than 30mL/minute, do not use lepirudin or desirudin

• in patients requiring anticoagulation who have previously received lepirudin or desirudin, do not repeat use of thesemedications due to risk of anaphylaxis

• monitoring:

• in patients receiving argatroban who are being transitioned to vitamin K antagonist (VKA), use factor X levels (measuredusing chromogenic assay) to adjust dose of VKA

Reversal of anticoagulant effects [9]:



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• no specific antidotes for direct thrombin inhibitors, but recombinant factor VIIa:

• reverses effect in healthy volunteers

• reduces bleeding in animals

• utility in patients has not been established

• haemodialysis or haemoperfusion can remove bivalirudin or argatroban (rarely necessary due to their short half-lives)

• dialysis with special membranes can remove hirudin

Reference:[9] Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants. American College of Chest Physicians Evidence-based clinicalpractice guidelines (8th edition). Chest 2008; 133: 141S-159S.

13 Oral anticoagulants

Quick info:Oral anticoagulants [10]:

• are employed for long-term therapy

• include vitamin K antagonists (VKA), eg warfarin

Warfarin:

• most commonly used for long-term anticoagulation [7]

• most common VKA in clinical use [7]

• taken orally [1]

• highly water soluble [10]

• rapidly absorbed from gastrointestinal (GI) tract [10]

• has high bioavailability [10]

• reaches maximal blood concentrations approximately 90 minutes after oral administration [10]

• takes several days to have anticoagulant effect [1]

• prevents production of vitamin K dependent clotting factors (II, VII, IX, X) and proteins C and S [1]

International normalised ratio (INR) [1]:

• test used to monitor effect of warfarin

• reflection of time taken for blood to clot

• standardised between different laboratories throughout world

References:[1] Contributors representing the Royal College of Physicians; 2010.[7] Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): 3rd edn – 2005 update. Br J Haematol 2006;132: 277-85.[10] Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 160S-198S.

14 New antithrombotic medications

Quick info:New antithrombotic (antiplatelet, anticoagulant, and fibrinolytic) medications are being developed to address the limitations ofexisting agents, and are currently in phase II or III clinical testing [6].New antiplatelet agents [6]:

• target thromboxane A2, adenosine diphosphate (ADP) or thrombin receptors on platelets

• most new ADP receptor antagonists target P2Y12

• thrombin receptor antagonists target PAR-1

• include:

• thromboxane A2 receptor antagonists:

• S18886



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• ADP receptor antagonists:

• prasugrel

• cangrelor

• AZD6140

• PAR-1 antagonists:

• SCH-530348

• E5555

New anticoagulants [6]:

• inhibit initiation of coagulation (target tissue factor/factor VIIa complex)

• inhibit propagation of coagulation (target factor IXa or factor Xa, or their cofactors, factor VIIIa and factor Va)

• attenuate fibrin generation (target thrombin)

• are direct inhibitors (bind directly to target enzyme and block substrate interactions)

• are indirect inhibitors (exert anticoagulant effects by binding to naturally occurring plasma cofactors, thusaccelerating interaction with clotting enzymes)

• include:

• inhibitors of initiation of coagulation:

• tifacogin

• NAPc2

• factor VIIai

• inhibitors of propagation of coagulation:

• factor IXa inhibitors

• factor Xa inhibitors

• factor Va inhibitors:

• drotrecogin

• ART-123

• inhibitors of fibrin formation:

• flovagatran

• pegmusirudin

• odiparcil

• ximelagatran

• dabigatran etexilate

Fibrinolytic therapy - strategies to enhance endogenous fibrinolysis [6]:

• type 1 plasminogen activator (PAI-1) inhibitors

• activated thrombin activatable fibrinolysis (TAFIa) inhibitors

• activated factor XIII (factor XIIIa) inhibitors

• new fibrinolytic agents include:

• alfimeprase

• BB10153

• desmoteplase

Reference:[6] Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs. American College of Chest Physicians Evidence-based clinicalpractice guidelines (8th edition). Chest 2008; 133: 234S-256S.

15 Valvular and structural heart disease

Quick info:Antithrombotic therapy for valvular and structural heart disease [11]:



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• for patients with rheumatic mitral valve disease complicated singly or in combination by presence of atrial fibrillation (AF),previous systemic embolism, or left atrial thrombus:

• use vitamin K antagonist (VKA) therapy

• for patients with rheumatic mitral valve disease and normal sinus rhythm, without left atrial enlargement:

• do not use antithrombotic therapy unless separate indication exists

• for patients with mitral valve prolapse (MVP), not complicated by AF, who have not had systemic embolism, unexplainedtransient ischemic attacks (TIAs), or ischemic stroke:

• do not use antithrombotic therapy

• for patients with mitral annular calcification complicated by systemic embolism or ischemic stroke:

• use antiplatelet agent (APA) therapy

• for patients with isolated calcific aortic valve disease:

• do not use antithrombotic therapy

• use APA therapy for those who have experienced ischemic stroke

• for patients with stroke associated with aortic atherosclerotic lesions:

• use low-dose aspirin therapy

• for patients with cryptogenic ischemic stroke and patent foramen ovale (PFO):

• use APA therapy

• for patients with mechanical heart valves:

• use VKA therapy

• for patients with mechanical heart valves and history of vascular disease, or who have additional risk factors forthromboembolism:

• add low-dose aspirin to VKA therapy

• do not add aspirin to long-term VKA therapy in patients with mechanical heart valves who are at particularly high risk ofbleeding

• for patients with bioprosthetic heart valves:

• use aspirin

• for patients with bioprosthetic heart valves and additional risk factors for thromboembolism:

• use VKA therapy

• for patients with infective endocarditis:

• do not use antithrombotic therapy, unless separate indication exists

Reference:[11] Salem DN, O'Gara PT, Madias C et al. Valvular and structural heart disease. American College of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 593S-629S.

16 Perioperative management of antithrombotic therapy

Quick info:Perioperative management of antithrombotic therapy [12]:

• for patients receiving vitamin K antagonists (VKAs):

• bridge anticoagulation with:

• therapeutic-dose subcutaneous (SC) low-molecular-weight heparin (LMWH); or

• intravenous (IV) unfractionated heparin (UFH)

• if have:

• mechanical heart valve; or

• atrial fibrillation (AF); or

• venous thromboembolism (VTE) at high risk for thromboembolism

• for patients requiring urgent surgical or other invasive procedures:

• continue antiplatelet therapy (eg with aspirin and clopidogrel), if patient has:

• bare metal coronary stent and require surgery within 6 weeks of stent placement



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• medication-eluting coronary and require surgery within 12 months of stent placement

• for patients requiring dental, dermatologic, or opthalmologic procedures:

• continue VKAs around time of procedure, if undergoing:

• minor dental procedures (additionally co-administer oral prohemostatic agent)

• minor dermatologic procedures

• cataract removal

Reference:[12] Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 299S-339S.

17 Management of vitamin K antagonists

Quick info:Initiation and maintenance dosing in most patients beginning vitamin K antagonist (VKA) therapy [10]:

• initiate oral anticoagulation with doses of 5-10mg for first 1-2 days

• base subsequent dosing on international normalised ratio (INR) response

• avoid pharmacogenetic-based initial dosing to individualise warfarin dosing

In other populations [10]:

• use starting dose of 5mg or less

• base subsequent dosing on INR response in patients who:

• are elderly

• are debilitated

• are malnourished

• have congestive heart failure (CHF)

• have liver disease

• have had recent major surgery

• are taking medications known to increase sensitivity to warfarin, eg amiodarone

Frequency of monitoring [10]:

• for patients beginning VKA therapy, start INR monitoring after initial two or three doses of oral anticoagulation therapy

• for patients receiving stable dose of oral anticoagulants, monitor at interval of less than 4 weeks

Management of non-therapeutic INRs [10]:

• for patients with INRs above therapeutic range but less than 5.0, and with no significant bleeding:

• lower dose or omit a dose

• monitor more frequently

• resume therapy at appropriate dose when INR is at therapeutic level

• do not reduce dose if only minimally above therapeutic range, or associated with transient causative factor

• for patients with INRs of 5.0 or more but less than 9.0, and no significant bleeding:

• omit next one or two doses

• monitor more frequently

• resume therapy at appropriate dose when INR is at therapeutic level; or

• omit a dose and administer vitamin K orally, particularly if patient is at increased risk of bleeding

• if more rapid reversal is required because patient requires urgent surgery:

• give vitamin K orally (reduction of INR should occur in 24 hours)

• if INR is still high, give additional vitamin K orally

• for patients with INRs of 9.0 or more, and no significant bleeding:

• hold warfarin therapy

• administer higher dose of vitamin K orally (INR should be reduced substantially in 24-48 hours)

• monitor INR frequently



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• administer additional vitamin K if necessary

• resume therapy at appropriate dose when INR reaches therapeutic range

• for patients with serious bleeding and elevated INR:


• give vitamin K by intravenous (IV) or subcutaneous (SC) route

• supplement with any of the following (depending on urgency of situation):

• fresh frozen plasma

• prothrombin complex concentrate (PCC)

• recombinant factor VIIa

• repeat vitamin K administration every 12 hours for persistent INR elevation

• for patients with life-threatening bleeding (eg intracranial haemorrhage) and elevated INR:


• administer any of the following:

• fresh frozen plasma

• PCC

• recombinant factor VIIa

• supplement with vitamin K, and repeat if necessary depending on INR

• for patients with mild to moderately elevated INRs without major bleeding:

• administer vitamin K orally (not subcutaneously)

Management of variable INRs [10]:

• for patients receiving long-term warfarin therapy with variable INR response not attributable to any usual known cause ofinstability:

• give trial of daily low-dose oral vitamin K

• closely monitor INR and warfarin dose adjustment, to counter initial lowering of INR in response to vitamin K

Management of INRs in antiphospholipid syndrome [10]:

• for patients with lupus inhibitor, no additional risk factors, and no lack of response to therapy:

• target therapeutic INR of 2.5 (range: 2.0-3.0)

• for patients with recurrent thromboembolic events, therapeutic INR, or other additional risk factors for thromboembolic events:

• target INR of 3.0 (range: 2.5–3.5)

Optimal management of VKA therapy [10]:

• manage oral anticoagulation therapy:

• in systematic and coordinated manner

• incorporate patient education

• carry out systematic INR testing, tracking, follow-up, and good patient communication of results and dosing decisions(anticoagulation management service, AMS)

Patient self-testing and patient self-management [10]:

• encourage patient self-management (PSM) in patients suitably selected and trained

Reference:[10] Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists. American College of ChestPhysicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 160S-198S.

18 Non-ST-segment elevation acute coronary syndromes(NSTE-ACS)

Quick info:Antithrombotic therapy for coronary artery disease [13]:

• for all patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), without clear allergy to aspirin provideaspirin immediately and recommend a daily oral dose of aspirin

• for NSTE-ACS patients with at least moderate risk for ischemic event and will undergo early invasive management strategy:



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• use 'upstream' treatment with either clopidogrel; or glycoprotein IIb/IIIa inhibitor (eptifibatide or tirofiban)

• for NSTE-ACS patients with at least moderate risk for ischemic event and will undergo early conservative or delayed invasivestrategy of management use 'upstream' treatment with clopidogrel

• for NSTE-ACS patients undergoing percutaneous coronary intervention (PCI) use treatment with both clopidogrel and IVglycoprotein IIb/IIIa inhibitor

• for all patients with NSTE-ACS use anticoagulation with:

• unfractionated heparin (UFH); or

• low-molecular-weight heparin (LMWH); or

• bivalirudin; or

• fondaparinux

Reference:[13] Harrington RA, Becker RC, Cannon CP, et al. Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes.American College of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 670S-707S.

19 Peripheral artery occlusive disease

Quick info:Antithrombotic therapy for peripheral artery occlusive disease [14]:

• for pulmonary artery disease (PAD) patients with clinically manifest coronary or cerebrovascular disease:

• use lifelong antiplatelet therapy

• for pulmonary artery disease (PAD) patients without clinically manifest coronary or cerebrovascular disease:

• use lifelong antiplatelet therapy

• for patients with PAD and intermittent claudication:

• do not use anticoagulants

• for patients with short-term (less than 14 days) arterial thrombosis or embolism:

• use intra-arterial thrombolytic therapy (if at low risk of myonecrosis and ischemic nerve damage developing during the time,to achieve revascularisation)

• for patients undergoing major vascular reconstructive procedures:

• use intravenous (IV) unfractionated heparin (UFH) before applying vascular cross clamps

Reference:[14] Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease. American College of Chest PhysiciansEvidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 815S-843S.

21 Management of complications

Quick info:Haemorrhagic complications of anticoagulant and thrombolytic treatment exist, as no anticoagulant agent is safe across allindications regarding major haemorrhage [15].Comparisons between different medications may yield different relative risks, depending on [15]:

• selected intensity of treatment

• concomitant or antecedent anticoagulant

• antiplatelet or thrombolytic medications

• characteristics of patient population

• condition being treated

Treatment for reduction of thromboembolic events and considerations for the risk of bleeding [15]:

• vitamin K antagonists (VKAs):

• studies show increase in risk of major bleeding in patients treated with VKA compared to controls is low in well-controlledpatients



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• good evidence that VKA therapy, targeted international normalised ratio (INR) of 2.5 (range: 2.0-3.0), is associated with lowerrisk of bleeding than therapy targeted at INR of more than 3.0

• major determinants of VKA-induced bleeding include:

• intensity of anticoagulant effect

• underlying patient characteristics

• length of therapy

• heparins:

• risk factors associated with heparin-associated bleeding include:

• aspirin

• concomitant thrombolytic therapy or glycoprotein IIb/IIIa antagonists

• renal failure

• patient age

• sex

• induce bleeding by:

• inhibiting blood coagulation

• impairing platelet function

• increasing capillary permeability

• producing thrombocytopenia (rarely an important cause of bleeding)

• fondaparinux:

• associated with lower risk of bleeding

• direct thrombin inhibitors:

• determinants of bleeding not well characterised

• thrombolytic therapy:

• increases risk of major bleeding by 1.5-3 times in patients with:

• acute venous thromboembolism (VTE)

• ischemic stroke

• ST-segment elevation myocardial infarction (STEMI)

Treatment and prevention of heparin-induced thrombocytopenia (HIT) [16]:

• for patients receiving heparin with risk of HIT considered more than 1%:

• monitor platelet count

• for patients receiving heparin or have received heparin in last 2 weeks:

• investigate for diagnosis of HIT within 5-14 days following initiation of heparin, if:

• platelet count falls by 50% or more; and/or

• thrombotic event occurs

• for patients with strongly suspected or confirmed HIT (even if complicated by thrombosis):

• use alternative, non-heparin anticoagulant

• do not use VKA therapy until platelet count has recovered substantially (usually to at least 150x109 per L)

• initiate VKA therapy only with low maintenance doses

• continue with non-heparin anticoagulant until:

• platelet count has reached stable plateau

• INR has reached intended target range

• after minimum overlap of at least 5 days between non-heparin anticoagulation and VKA therapy

• for patients receiving VKAs at time of HIT diagnosis:

• use vitamin K

References:[15] Schulman S, Beyth RJ, Kearon C et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment. AmericanCollege of Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 257S-298S.



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[16] Warkentin, TE, Greinacher A, Koster A et al. Treatment and prevention of heparin-induced thrombocytopenia. American Collegeof Chest Physicians Evidence-based clinical practice guidelines (8th edition). Chest 2008; 133: 340S-380S.

22 Patient education and written guidance

Quick info:Discuss with patient [1]:

• benefits of anticoagulation (usually decreased risk of thrombosis)

• potential risks of anticoagulation (usually increased risk of bleeding)

• factors within clinical scenario that have particular bearing on risks and benefits

• adverse effects of anticoagulation:

• bleeding:

• risk assessment of bleeding related to warfarin per year of therapy − 2-4% risk of bleeding requiring transfusion; 0.2% riskof fatality

• encourage patients to be alert for symptoms of bleeding, eg: blood in bowel motions, haemoptysis, bruising, severeheadaches

• specifically for warfarin:

• skin necrosis (capillary thrombosis within subcutaneous [SC] fat related to depleted levels of proteins C or S)

• 'purple toe' syndrome (microemboli released from systemic circulation)

Advise if patient to commence warfarin [1]:

• regular international normalised ratio (INR) checks required

• important to take warfarin at same time each day

• missed dose advice

• factors that can affect INR, eg:

• medication including alternative medication and over-the-counter medications

• foods that may interact with warfarin, eg:

• green leafy vegetables

• broccoli

• cauliflower

• liver

• exercise levels

• alcohol consumption (affects warfarin metabolism)

• other medical conditions

• need to avoid non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin

• importance of reliable contraception − patient must seek medical advice if planning to become pregnant

• seek medical advice in particular, when:

• complications occur

• changes occur that may affect INR

• any procedure (including dental or surgery) is to be undertaken

• important to notify healthcare providers (including dentists and pharmacists) that patient is on warfarin

Provide patient with written guidance (short-term and long-term) [1]:

• give written summary of education material

• issue yellow anticoagulant record book ('yellow book') that contains information and advice, to:

• record results of blood tests

• record amount of warfarin patient should be taking

• detail date of next blood test

• copies of 'yellow book' available from Health Authorities

Reference:



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[1] Contributors representing the Royal College of Physicians; 2010.

24 Follow-up

Quick info:Include review of individual circumstances that commonly change, in follow-up of patients for whom ongoing anticoagulation is notinitially appropriate [1]:

• reconsider risks and benefits of anticoagulation on regular basis for sub-groups of patients, including those with:

• worsening cardiac failure and increasing risk of mural thrombus following myocardial infarction (MI)

• decreasing left ventricular ejection fraction (LVEF) and dilated cardiomyopathy

• increasing age or other factors that increase thromboembolic risk, and atrial fibrillation (AF) currently being managed onaspirin alone

Reference:[1] Contributors representing the Royal College of Physicians; 2010.



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Key Dates

Published: 03-Feb-2011, by Tameside & GlossopValid until: 20-Jul-2011

Evidence summary for Anticoagulation

The pathway is based on our interpretation of the following guidelines (1, 2, 3, 4, 5, 6, 7, 8, 9, [914]). All of these guidelineshave been graded for quality and prioritised for inclusion based on their methodological quality. All intervention nodes (ie.those concerning therapy and therapeutic advice) have been graded for the quality of the evidence underlying them. Key non-interventional nodes have been referenced but not graded.Update: This pathway was updated in November 2006 based on NICE guidance ([914]).

References

This is a list of all the references that have passed critical appraisal for use in the pathway AnticoagulationID Reference1 Contributors representing the Royal College of Physicians. 2010.2 Hirsh J, Fuster V, Ansell J et al. American Heart Association/American College of Cardiology Foundation

guide to warfarin therapy. Circulation 2003; 107: 1692-1711.http://circ.ahajournals.org/cgi/reprint/107/12/1692

3 Map of Medicine (MoM) Clinical Editorial team and Fellows. London: MoM; 2010.4 Bates SM, Greer IA, Pabinger I et al. Venous thromboembolism, thrombophilia, antithrombotic therapy,

and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8thEdition). Chest 2008; 133: 844S-886S.http://chestjournal.chestpubs.org/content/133/6_suppl/844S.full.pdf

5 Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: AmericanCollege of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:454S-545S.http://chestjournal.chestpubs.org/content/133/6_suppl/454S.full.pdf

6 Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 234S-256S.http://chestjournal.chestpubs.org/content/133/6_suppl/234S.full.pdf

7 Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): third edition--2005update. Br J Haematol 2006; 132: 277-285.http://www.ncbi.nlm.nih.gov/pubmed/16409292

8 Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: American College ofChest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 546S-592S.http://chestjournal.chestpubs.org/content/133/6_suppl/546S.full.pdf

9 Hirsh J, Bauer KA, Donati MB et al. Parenteral anticoagulants: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 141S-159S.http://chestjournal.chestpubs.org/content/133/6_suppl/141S.full.pdf

10 Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists: AmericanCollege of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S-198S.http://chestjournal.chestpubs.org/content/133/6_suppl/160S.full.pdf

11 Salem DN, O'Gara PT, Madias C et al. Valvular and structural heart disease: American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 593S-629S.http://chestjournal.chestpubs.org/content/133/6_suppl/593S.full.pdf

12 Douketis JD, Berger PB, Dunn AS et al. The perioperative management of antithrombotic therapy:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest2008; 133: 299S-339S.http://chestjournal.chestpubs.org/content/133/6_suppl/299S.full.pdf

13 Harrington RA, Becker RC, Cannon CP et al. Antithrombotic therapy for non-ST-segment elevation acutecoronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines(8th Edition). Chest 2008; 133: 670S-707S.http://chestjournal.chestpubs.org/content/133/6_suppl/670S.full.pdf

14 Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease: American College ofChest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 815S-843S.http://chestjournal.chestpubs.org/content/133/6_suppl/815S.full.pdf

http://circ.ahajournals.org/cgi/reprint/107/12/1692

http://chestjournal.chestpubs.org/content/133/6_suppl/844S.full.pdf



http://www.ncbi.nlm.nih.gov/pubmed/16409292










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ID Reference15 Schulman S, Beyth RJ, Kearon C et al. Hemorrhagic complications of anticoagulant and thrombolytic

treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Chest 2008; 133: 257S-298S.http://chestjournal.chestpubs.org/content/133/6_suppl/257S.full.pdf

16 Warkentin TE, Greinacher A, Koster A et al. Treatment and prevention of heparin-inducedthrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8thEdition). Chest 2008; 133: 340S-380S.PM:18574270

17 Institute for Clinical Systems Improvement (ICSI). Anticoagulation therapy supplement. Bloomington, MN:ICSI; 2005.

18 Fitzmaurice DA, Gardiner C, Kitchen S et al. An evidence-based review and guidelines for patient self-testing and management of oral anticoagulation. Br J Haematol 2005; 131: 156-165.http://www.ncbi.nlm.nih.gov/pubmed/16197444

19 Heneghan C, Alonso-Coello P, Garcia-Alamino JM et al. Self-monitoring of oral anticoagulation: asystematic review and meta-analysis. Lancet 2006; 367: 404-411.http://www.ncbi.nlm.nih.gov/pubmed/16458764

20 Rasmussen MS, Jorgensen LN, Wille-Jorgensen P. Prolonged thromboprophylaxis with low molecularweight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev 2009; CD004318.http://www.ncbi.nlm.nih.gov/pubmed/19160234

21 Ray CEJr, Prochazka A. The need for anticoagulation following inferior vena cava filter placement:systematic review. Cardiovasc Intervent Radiol 2008; 31: 316-324.http://www.ncbi.nlm.nih.gov/pubmed/18080710

22 British National Formulary (BNF). BNF 58. London: BMJ Group and RPS Publishing; 2009.


PM:18574270





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