SIMPLE GUIDELINE FOR MANAGEMENT OF SEVERE DIC in Obstetric/ICU setting

Guidelines for Anticoagulation

(please ignore page numbers)

THIS GUIDELINE DOES NOT COVER EVERY EVENTUALITY

1. Thromboprophylaxis .......................................................................3

1.1. Surgical Thromboprophylaxis ............................................................................................................................4

1.2 Medical Thromboprophylaxis.............................................................................................................................5

1.3 Obstetric – Post Partum Prophylaxis .................................................................................................................5

2. Cardiology – Treatment Regimens............................................................................................................................6

2.1. ST Elevation Myocardial Infarction (STEMI)......................................................................................................6

2.2. Treatment of Unstable Angina Pectoris/Non ST-Elevation Myocardial Infarction (UAP/NSTEMI) ...................6

2.3. Atrial Fibrillation (AF) .........................................................................................................................................7

2.4. Renal Impairment ..............................................................................................................................................7

2.5. Obesity...............................................................................................................................................................8

2.6. Anaesthesia/PTCA ............................................................................................................................................8

2.7. LMW Heparin Monitoring and Reversal.............................................................................................................8

2.8. Unfractionated Heparin (Treatment) ..................................................................................................................8

2.8a. Anticoagulation following Thrombolysis with rTPA ............................................................................................8

2.8b. Anticoagulation for Patients with Temporary Pacing Wires or Swan- Ganz Catheters .....................................9

2.8c. Other Indications for Anticoagulation ...............................................................................................................10

3. Treatment of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) ..............................................................10

3.1 Low Molecular Weight (LMW) Heparin ............................................................................................................10

3.2 Renal Impairment ............................................................................................................................................10

3.3 Obesity.............................................................................................................................................................11

3.4 Anaesthesia .....................................................................................................................................................11

3.5 LMW Heparin Monitoring and Reversal...........................................................................................................11

3.6 Unfractionated Heparin (Treatment) ................................................................................................................11

4. Anticoagulation and Surgery....................................................................................................................................13

4.1. Oral Anticoagulation and Surgery....................................................................................................................13

4.2. Heparins and Surgery – History of Venous Thromboembolism ......................................................................14

4.3. Heparins and Surgery – Arterial Thromboembolism .......................................................................................14

4.4. Heparins and Surgery – Prosthetic and Mechanical Heart Valves..................................................................15

4.5. Heparins and Surgery – Other Conditions and Comments .............................................................................15

4.6. Regional Anaesthesia and Prophylaxis ...........................................................................................................15

5. Heparin Induced Thrombocytopenia Syndrome (HITS) ..........................................................................................16

5.1. General Information .........................................................................................................................................16

5.2. Treatment of HITS ...........................................................................................................................................16

5.3. Thromboprophylaxis for a patient with HITS - Danaparoid .............................................................................17

6. Haemodialysis Anticoagulation................................................................................................................................18

7. Oral Anticoagulation – Warfarin...............................................................................................................................18

7.1. INR targets.......................................................................................................................................................18

7.2. Albumin ............................................................................................................................................................18

7.3. Warfarin Initiation Guideline.............................................................................................................................19

7.4. Recommended Warfarin Dose Adjustments ...................................................................................................19

7.5. Post Acute Community Care ...........................................................................................................................20

7.6. Treatment Strategy for Warfarin Reversal.......................................................................................................21

7.7. Duration of Oral Anticoagulation......................................................................................................................22

7.8. Drug Interactions With Warfarin ......................................................................................................................22

7.9 Medication and Blood Sampling Times ...........................................................................................................23

8. Contributors .............................................................................................................................................................23

9. References ..............................................................................................................................................................23


Abbreviations key: LMW = Low Molecular Weight

APTT = Activated Partial Thromboplastin Time LMWH = Low Molecular Weight Heparin

AT111 = Antithrombin 111 NYHA = New York Heart Association (classification of cardiac failure)

BMI = Body Mass Index MRI = Magnetic Resonance Imaging

CT = Computed Tomography PE = Pulmonary Embolism

DVT = Deep Vein Thrombosis PT = Prothrombin Time

GFR = Glomerular Filtration Rate PTCA = Percutaneous transluminal coronary angioplasty

HITS = Heparin Induced Thrombocytopenia Syndrome SC = Subcutaneous

HRT = Hormone Replacement Therapy TEDS (GCS) =Thromboembolic disease stockings

(graduated compression stockings) INR = International Normalised Ratio TIA = Transient Ischaemic Attack IPC = Intermittent pneumatic compression VTE = Venous Thromboembolism

WARNING:

Do NOT initiate LMW Heparin treatment if the diagnosis is uncertain and

urgent surgery may be indicated. In these situations commence therapy with unfractionated heparin.

WARNING REGARDING USE OF HEPARINS:

Patients actively bleeding or at a high risk of bleeding, for example with thrombocytopenia, haemorrhagic stroke or undergoing neurosurgery or ophthalmic surgery, require specialist consideration and consultation before commencing therapy with heparins.


1. Thromboprophylaxis

All hospitalised patients should be evaluated for risk of venous thrombosis.

Standard procedures should include early mobilisation, TED stockings etc. The need for further thromboprophylaxis is based on the risk status of the patient.

Risk depends upon the type of surgery and is modified by additional factors including:

Age, malignancy, obesity, previous DVT/PE, varicose veins, thrombophilic disorders (inherited, acquired).

Thromboprophylaxis


1.1. Surgical Thromboprophylaxis

Standard Risk Patients

Unfractionated heparin: 5,000 units by subcutaneous injection twice a day or three times a day.

OR

Enoxaparin (Clexane®): 20 mg by subcutaneous injection once daily.

OR

Dalteparin (Fragmin®): 2,500 units by subcutaneous injection once daily.

If it is elected to give preoperative heparin:

Unfractionated heparin, should be given 6 hours before surgery, then 6 hours after surgery, then continued until the patient is mobile or for 7 to 10 days postoperatively, whichever is the longest.

or

LMW heparin should be given 12 hours before surgery and then 6 to 12 hours after surgery. Continue giving dose every night after surgery until the patient is mobile or for 7 to 10 days postoperatively, whichever is the longest.

High risk Patients

These patients include:

Patients undergoing elective hip or knee replacement and after hip fracture.

Patients undergoing any general surgery who have additional risk factors such as malignancy, previous DVT/PE

or thrombophilic disorder.

Enoxaparin (Clexane®): 40 mg by subcutaneous injection once daily.

OR

Dalteparin (Fragmin®): 5,000 units by subcutaneous injection once daily.

If the patient is small (less than 50 kg) and/or elderly (75 years or older) and/or renally impaired (creatinine

clearance less than 30 mL/min):

Enoxaparin (Clexane®): 20 mg by subcutaneous injection once daily.

OR

Dalteparin (Fragmin®): 2,500 units by subcutaneous injection once daily.

Duration of Prophylaxis:

If it is elected to give preoperative LMW heparin it should be given 12 hours before surgery and then 6 to

12 hours after surgery. Continue giving dose every night after surgery until the patient is mobile or for 7

to 10 days postoperatively, whichever is the longest.

The decision to extend prophylaxis for 2 to 6 weeks post-discharge can be made according to each patient’s risk

of developing a DVT.

High risk categories of patients would include those who have had a previous DVT and those who remain immobile.

Post-operative prophylaxis in routine circumstances is started approximately six to twelve hours after

surgery. If the risk of peri-operative bleeding is considered to be high then the pre-operative dose may be withheld, while the first post-operative dose can be given 24 hours or more after surgery (e.g. in spinal surgery). If the risk of thrombosis is considered high, it may be given earlier or even intra-operatively.


1.2 Medical Thromboprophylaxis

A large multicentre randomised trial of thromboprophylaxis in high risk medical patients has demonstrated the efficacy and safety of LMW heparin (enoxaparin) in comparison with placebo (Medenox Trial). Accordingly, the Haematology Department recommends the following medical patients receive thromboprophylaxis using LMW heparin until they are fully mobilised:

Medical condition with projected hospital stay of six days or longer:

Congestive cardiac failure (NYHA III or IV) Inflammatory bowel disease

Severe chronic airways obstruction Acute rheumatic disorder

AND

One or more of the following risk factors for venous thromboembolism:

Age 75 years or greater Hormone replacement therapy Malignancy History of or prior DVT/PE Varicose veins

Enoxaparin (Clexane®): 40 mg by subcutaneous injection daily

OR

Dalteparin (Fragmin®): 5,000 units by subcutaneous injection daily.

Medical condition with projected hospital stay of less than 6 days: No thromboprophylaxis required.

1.3 Obstetric – Post Partum Prophylaxis

(A) General - Hydration, early mobilisation.

(B) Enoxaparin (Clexane®) 40mg SC daily until discharge for:

All Caesarean deliveries and extended pelvic surgery

All morbidly obese women (early pregnancy BMI > 40) All vaginal deliveries with 4 or more risk factors

Risk Factors:

General Pregnancy Related

Age > 35 Pre-Eclampsia

Booking BMI > 30 Immobility for 4 days

Parity greater than or equal to 4 Labour > 12 hours

Major intercurrent illness Forceps/Ventouse Delivery

Major current infection Major blood loss

Gross varicose veins

Heterozygous for Factor V (Leiden) or Prothrombin Gene Mutation

DVT in a first degree relative

There will be particular circumstances where IPC or TEDS (GCS) may be appropriate.

NOTE (1) For Regional Anaesthesia – See Section 4.6

(C) Therapeutic Warfarin (INR 2-3) or Enoxaparin (Clexane®) 40 mg SC daily for 8 weeks for:

Previous spontaneous VTE (i.e. no probable cause)

Lupus Anticoagulant or High Titre Anticardiolipin Antibody

AT III, Protein C, Protein S deficiency

Homozygous for Factor V Leiden or Prothrombin Gene Mutation, or double heterozygote

Paralysis of lower limbs

Homozygous Sickle Cell Disease

NOTE (2) Patients with previous VTE or thrombophilic state may require therapeutic or prophylactic anticoagulation during pregnancy. They should be assessed on a “case-by-case” basis.


2. Cardiology – Treatment Regimens

2.1. ST Elevation Myocardial Infarction (STEMI)

These patients are usually treated with primary angioplasty (Please refer to the WSAHS Primary Angioplasty

Protocol), and should not be given any anticoagulation until after discussion with the consultant cardiologist.

They should be given aspirin 300mg orally stat, but not clopidogrel. Clopidogrel should be avoided because

of the possibility of surgery in some patients.

Rarely, patients may undergo thrombolysis, in which case they should have anticoagulation as below:

Anticoagulation following thrombolysis varies depending on the agent used.

a) Following thrombolysis with recombinant tissue plasminogen activator (rTPA), e.g. tenecteplase

(Metalyse®), alteplase (Actilyse®) or reteplase (Rapilysin®) a modified dose heparin infusion should be commenced. Please see section 2.8a.

b) Following streptokinase, anticoagulation is not routinely indicated. Only patients with a high risk of embolic event (large anterior MI, AF, previous embolus or intracardiac thrombus) may be considered for IV heparin 6 hours after STK, with the aim of elevating APTT to 1.5-2 times normal.

2.2. Treatment of Unstable Angina Pectoris/Non ST-Elevation Myocardial Infarction

(UAP/NSTEMI)

All patients with either UAP or NSTEMI should be given aspirin orally 300mg stat, then 100-150mg daily.

Patients with any high risk features (please refer to WSAHS Acute Chest Pain Protocol) should also be given

clopidogrel orally 300mg stat, then 75mg daily.

High risk patients should also be given enoxaparin (Clexane®) at the dose of 1mg/kg body weight bd (up to

a maximum of 80mg bd) subcutaneously. Note that the maximum dose cap is lower than in other protocols as these patients are usually also on double anti-platelet therapy. It should not be used in patients with severe

renal impairment (creatinine clearance < 30ml/min). Patients with mild to moderate renal impairment (creatinine

clearance 30-80mL/min) usually do not require dose adjustment but they should be monitored closely for bleeding complications. Enoxaparin should be used at half the usual dose in patients over 75 years old, after discussion with the patient’s cardiologist, though it is safe in those with normal renal function based on estimates of creatinine clearance.

Enoxaparin should be omitted 24 hours prior to planned percutaneous coronary interventions. Patients not treated with enoxaparin should instead be given full dose IV heparin as per the deep vein thrombosis/ pulmonary embolism protocol. (see Section 3.6).

The duration of therapy is to be specified by the cardiologist (usually a minimum of two days and a maximum of eight days).


2.3. Atrial Fibrillation (AF)

Acute Onset AF

For patients with acute recent onset AF requiring cardioversion, simultaneous administration of heparin (either

enoxaparin or unfractionated heparin) is indicated at full anticoagulant dose.

Clexane® (enoxaparin): 1 mg/kg every 12 hours by subcutaneous injection. Maximum dose is 100mg every 12 hours.

Chronic AF

For patients who have chronic AF and are being commenced on warfarin, simultaneous administration of heparin

(either with enoxaparin or unfractionated heparin) is NOT indicated. Warfarin should be commenced as per initiation

protocol in Section 7. Oral Anticoagulation – Warfarin.

2.4. Renal Impairment

LMW heparins are excreted to a small extent by the kidneys and so may accumulate in patients with significant renal impairment. Accordingly, it is necessary to calculate creatinine clearance prior to commencing full-dose LMW

heparin.

Creatinine clearance (mL/min) for females = (140 - Age) x Body Weight (kg)

Creatinine (µmol/L)

For males multiply by 1.22 times the value estimated according to the above equation (to account for the increased muscle to ideal body weight ratio in comparison to females).

Please consider using ideal body weight in the above equation: Ideal body weight for male = 50 kg + 0.9 kg/ each cm above 152 cm

Ideal body weight for female = 45.5 kg + 0.9 kg/ each cm above 152 cm

Note: if a patient’s actual weight is less than the ideal body weight, the actual weight should be used

Every patient older than 50 years must have a creatinine clearance calculated before LMW heparin is

commenced.

A dose adjustment is required for patients with renal impairment (creatinine clearance < 30 mL/minute) according to the table below. Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30 to 50 mL/minute) and mild (creatinine clearance 50 to 80 mL/minute) renal impairment, careful clinical monitoring is advised.

Normal dosing (30 mL/min)

Renal impairment (10 to 30 mL/min)

Severe renal impairment( 10 mL/min)

UAP/NSTEMI:

Clexane® (enoxaparin): 1 mg/kg

(maximum dose 80mg) twice daily. If

75 years or older, use half the usual dose.

UAP:

LMW heparin contraindicated – Use unfractionated heparin.

UAP:

LMW heparin contraindicated

– Use unfractionated heparin.

AF:

Clexane® (enoxaparin): 1mg/kg

(maximum dose 100mg) twice daily

AF:

Clexane® (enoxaparin): 1mg/kg once daily

AF:

LMW heparin contraindicated – Use unfractionated heparin.

See also section 2.7 LMW Heparin Monitoring and Reversal.


2.5. Obesity

Dose is calculated based on patient’s actual body weight.

Clexane® (enoxaparin): Maximum dose varies with the indication for anticoagulation as in the table above.

2.6. Anaesthesia/PTCA

See Section 4. Anticoagulation and Surgery.

2.7. LMW Heparin Monitoring and Reversal

Monitoring LMW Heparin

Monitoring of anti-Xa levels is NOT routinely necessary in uncomplicated patients, but is appropriate in those patients with renal failure.

When required, monitor with plasma anti-factor Xa levels (citrate tube) at 3 to 5 hours after dose.

For anti-Xa assays during working hours, it is necessary to phone the haematology coagulation laboratory

(extension 56209, 57430 and 57371) to arrange for immediate testing.

Anti-Xa assays are not routinely available outside working hours without approval from the haematologist on- call.

Therapeutic range: anti-Xa = 0.5 - 1.2 units/mL at 3 to 5 hours after dose.

Reversal of Anticoagulant Activity

LMW heparin effect can be partially neutralised by protamine ( ~ 60%) as well as fresh frozen plasma. Protamine dose for Clexane® (enoxaparin): protamine 1 mg per 1 mg of Clexane® (enoxaparin) Protamine dose for Fragmin® (dalteparin): protamine 1mg per 100units of Fragmin® (dalteparin)

2.8. Unfractionated Heparin (Treatment)

General guidelines

Unfractionated heparin – there must be a strong indication for the use of unfractionated heparin in preference to low molecular weight heparin (e.g. specific cardiology indication or potential surgery candidate within the next 24 hours.)

Check APTT/PT prior to anticoagulation (if baseline APTT is significantly prolonged, then there is possibility of a lupus anticoagulant and Haematologist on-call should be contacted regarding use of LMW heparin).

There are three different protocols used in cardiology patients, depending on the indication.

2.8a. Anticoagulation following Thrombolysis with rTPA

Preparation of Heparin Syringe

For all patients prepare unfractionated heparin syringe as follows:

(heparin sodium 25,000 units per 50 mL of sodium chloride 0.9%)

Add 5 mL of heparin sodium (5,000 units/1 mL strength ampoules) to 45 mL of sodium chloride 0.9%. Mix well. Final volume = 50 mL. Use a syringe pump.

Heparin concentration = 500 units per mL (100 units per 0.2 mL).

On initiation of thrombolysis, patients should be given (see Table 1):

60units/kg bolus IV (maximum dose 4000units)

Followed by an IV infusion of 12units/kg/hour (maximum rate 1000units/hour or 2mL/hr).

Coagulation studies should be performed after 3 hours to achieve an APTT between 50-70seconds and the infusion rate adjusted accordingly. See Table 2 for a guide on how to adjust infusion rates.

The infusion should be continued for at least 48 hours.


Table 1: Initial IV bolus and infusion rates.

Body

Weight

(kg)

Bolus (units, 60units/kg, Max.

dose 4000units)

Starting infusion (units/hr,

12 units/kg/hr, max

1000units/hr)

Starting

infusion

(mL/hr)

36- 39

2250

450

0.9

40- 44

2500

500

1.0

44- 48

2750

550

1.1

48- 52

3000

600

1.2

53- 56

3250

650

1.3

57- 60

3500

700

1.4

61- 64

3750

750

1.5

65- 69

4000

800

1.6

69- 73

4000

850

1.7

73- 77

4000

900

1.8

77- 81

4000

950

1.9

> 82

4000

1000

2.0

Table 2: Infusion rate adjustment guide.

APTT(s)

Infusion rate adjustment(mL/hr)

Check APTT in 3-5 hours

<40

+0.4

Yes

40-49

+0.2

Yes

50-70

No change

Check daily.

71-90

-0.2

Yes

91-140

-0.4

Yes

>140

Stop for 60min and -0.4

Yes

Note: Elderly patients may require smaller doses than younger adults.

2.8b. Anticoagulation for Patients with Temporary Pacing Wires or Swan- Ganz Catheters

For patients with temporary pacing wires or Swan-Ganz catheters in situ, low dose IV heparin is used to reduce the risk of thromboembolism.

Add 3 mL of heparin sodium (5,000 units/1 mL strength ampoules, i.e. 15,000units of heparin) to 47 mL of sodium chloride 0.9%. Mix well. Final volume = 50 mL. Use a syringe pump.

Heparin concentration = 300 units per mL (60 units per 0.2 mL). Infuse over 24 hours.


2.8c. Other Indications for Anticoagulation

For all other indications in cardiology patients for anticoagulation, e.g. NSTEMI patients with severe renal impairment, atrial fibrillation, prosthetic mechanical mitral valves, left ventricular mural thrombus, please

refer to the guidelines for anticoagulation with unfractionated heparin for deep vein thrombosis/ pulmonary embolism (see Section 3.6).

3. Treatment of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE)

3.1 Low Molecular Weight (LMW) Heparin

LMW heparin is the treatment of choice for most patients with established DVT or PE.

For uncomplicated distal DVT below (distal to) the popliteal vein, the once daily LMW heparin regimen is

indicated.

For DVTs extending above (proximal to) the popliteal vein either once daily or twice daily LMW heparin

regimens are acceptable.

For PE either once daily or twice daily LMW heparin regimens are acceptable.

Twice daily regimens:

Enoxaparin (Clexane®): 1 mg/kg twice daily by subcutaneous injection

OR

Dalteparin (Fragmin®): 100 units/kg twice daily by subcutaneous injection.

Once daily regimens:

Enoxaparin (Clexane®): 1.5 mg/kg once daily by subcutaneous injection.

OR

Dalteparin (Fragmin®): 200 units/kg once daily by subcutaneous injection.

Start warfarin therapy from day 1 (see section 7. Oral Anticoagulation – Warfarin) overlapping with LMW heparin for at least 5 days and until INR is in the therapeutic range for ≥ 2 days prior to ceasing LMW heparin.

3.2 Renal Impairment

LMW heparins are excreted to a small extent by the kidneys and so may accumulate in patients with significant renal impairment. Accordingly, it is necessary to calculate creatinine clearance prior to commencing full-dose LMW

heparin.

Creatinine clearance (mL/min) for females = (140 - Age) x Body Weight (kg)

Creatinine (µmol/L)

In males multiply by 1.22 the value estimated according to the above equation (to account for the increased muscle to ideal body weight ratio in comparison to females).

Please consider using ideal body weight in the above equation:

Ideal body weight for male = 50 kg + 0.9 kg/ each cm above 152 cm

Ideal body weight for female = 45.5 kg + 0.9 kg/ each cm above 152 cm

Note: if a patient’s actual weight is less than the ideal body weight, the actual weight should be used

Every patient older than 50 years must have a creatinine clearance calculated before LMW heparin is

commenced.

A dose adjustment is required for patients with renal impairment (creatinine clearance < 30 mL/minute) according to the table below. Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30 to

50 mL/minute) and mild (creatinine clearance 50 to 80 mL/minute) renal impairment, careful clinical monitoring is advised.


Normal dosing ( 30 mL/min)

Renal Impairment

(10 to 30 mL/min)

Severe renal impairment

( 10 mL/min)

Twice daily regimen:

Enoxaparin (Clexane®): 1mg/kg twice daily

Dalteparin (Fragmin®): 100 units/kg twice daily

Enoxaparin (Clexane®): 1mg/kg once daily

Dalteparin (Fragmin®): 100 units/kg once daily

LMW heparin contraindicated – Use unfractionated heparin.

Once daily regimen:

Enoxaparin (Clexane®): 1.5mg/kg once daily

Dalteparin (Fragmin®): 200 units/kg once daily

Enoxaparin (Clexane®): 1mg/kg once daily

Dalteparin (Fragmin®): 100 units/kg once daily

LMW heparin contraindicated – Use unfractionated heparin.

See also section 3.5 LMW Heparin Monitoring and Reversal.

3.3 Obesity

In obese patients twice daily regimens should be used.

Dose is calculated based on patient’s actual body weight (to a maximum of 100 kg bodyweight).

Enoxaparin (Clexane®):. Maximum dose is 100 mg every 12 hours.

OR

Dalteparin (Fragmin®): Maximum dose is 10,000 units every 12 hours.

3.4 Anaesthesia

See Section 4. Anticoagulation and Surgery.

3.5 LMW Heparin Monitoring and Reversal

Monitoring LMW Heparin

Monitoring of anti-Xa levels is NOT routinely necessary in uncomplicated patients, but is appropriate in those patients with renal failure.

When required, monitor with plasma anti-factor Xa levels (citrate tube) at 3 to 5 hours after dose.

For anti-Xa assays during working hours, it is necessary to phone the haematology coagulation laboratory

(extension 56209, 57430 and 57371) to arrange for immediate testing.

Anti-Xa assays are not routinely available outside working hours without approval from the haematologist on- call.

Therapeutic range: anti-Xa = 0.5 - 1.2 units/mL at 3 to 5 hours after dose.

Reversal of Anticoagulant Activity

LMW heparin effect can be partially neutralised by protamine ( ~ 60%) as well as fresh frozen plasma. Protamine dose for reversal of enoxaparin (Clexane®): protamine 1 mg per 1 mg of enoxaparin. Protamine dose for reversal of dalteparin (Fragmin®): protamine 1 mg per 100 units of dalteparin.

3.6 Unfractionated Heparin (Treatment)

General guidelines

Unfractionated heparin – there must be a strong indication for the use of unfractionated heparin in preference to low molecular weight heparin (e.g. potential surgery candidate within the next 24 hours, specific cardiology indications, severe renal impairment 10 mL/min.)

Check APTT/PT prior to anticoagulation (if baseline APTT is significantly prolonged, then there is possibility of a lupus anticoagulant and Haematologist on-call should be contacted regarding use of LMW heparin).


Give heparin 5,000 units as an intravenous bolus.

Then infuse heparin at 18 units/kg/hour (select appropriate infusion rate from Table 1) up to an initial maximum

of 1,900 units/hour.

Maintain APTT at 50 to 90 seconds.(i.e at 1.5-2.5 times the control) Adjust infusion rate according to Table 2 and repeat APTT at 6 hours.

Repeat APTT either 6 hours after every dose adjustment and/or daily once stabilised.

Check platelet count second daily for Heparin Induced Thrombocytopenia (HITS). For massive DVT and PE, heparin should be given for at least 7 to 10 days.

Start warfarin from day 1 or 2 – see Section 7. Oral Anticoagulation – Warfarin.

Overlap warfarin with heparin for at least 5 days and until INR is in the therapeutic range for ≥ 2 days prior to ceasing heparin.

Preparation of Heparin Syringe

For all patients prepare unfractionated Heparin syringe as follows:

(heparin sodium 25,000 units per 50 mL of sodium chloride 0.9%)

Add 5 mL of heparin sodium (5,000 units/1 mL strength ampoules) to 45 mL of sodium chloride 0.9%. Mix well. Final volume = 50 mL. Use a syringe pump.

105 1900 3.8 " >
Heparin concentration = 500 units per mL (100 units per 0.2 mL).

Table 1 – Heparin Infusion Weight Based Nomogram with Rate of Administration

Weight (kg)

units/hour

mL/hour

28 – 30

500

1

31 – 32

550

1.1

33 - 35

600

1.2

36 – 38

650

1.3

39 – 41

700

1.4

42 – 43

750

1.5

44 – 46

800

1.6

47 – 49

850

1.7

50 – 52

900

1.8

53 – 55

950

1.9

56 – 57

1000

2

58 – 60

1050

2.1

61 – 63

1100

2.2

64 – 66

1150

2.3

67 – 68

1200

2.4


Table 2 – Guidelines for Adjustment of Heparin Dose

APTT

(seconds)

Bolus

(units)

Stop Infusion

(minutes)

Rate change

Next APTT

<40

5000

0

Increase by 200 units/hour (i.e. 0.4 mL/hour)

6 hours

40 - 49

Nil

0

Increase by 100 units/hour (i.e. 0.2 mL/hour)

6 hours

50 - 90

Nil

0

Remain unchanged

next morning

91 - 105

Nil

0

Decrease by 100 units/hour (i.e. 0.2 mL/hour)

6 hours

106 - 150

Nil

0

Decrease by 200 units/hour (i.e. 0.4 mL/hour)

6 hours

>150

Nil

for 60 minutes

Decrease by 200 units/hour (i.e. 0.4 mL/hour)

6 hours

Heparin concentration = 100 units per 0.2 mL

Note: Elderly patients may require smaller doses than younger adults.

4. Anticoagulation and Surgery

A number of procedures can be performed (with care) under varying degrees of anticoagulation. It is not always necessary to stop therapy, but consultant advice is required.

4.1. Oral Anticoagulation and Surgery

Step 1: Stop warfarin four days before surgery

Step 2: Use LMW heparin or unfractionated heparin as indicated in the table below

Indication for anticoagulation

Before Surgery

After Surgery

Acute venous thromboembolism

– month 1 post-DVT

Full anticoagulation1

Full anticoagulation1

Acute venous thromboembolism

– month 2 and 3 post-DVT

Nil

Full anticoagulation1

Recurrent venous thromboembolism

Nil

Prophylactic anticoagulation2

Acute arterial embolism

– Month 1 post arterial embolism

Full anticoagulation1

Full anticoagulation1

Mechanical heart valve

Full anticoagulation1

Prophylactic anticoagulation2

Congestive cardiac failure

Nil

Prophylactic anticoagulation2

Nonvalvular atrial fibrillation

Nil

Prophylactic anticoagulation2

1 Full anticoagulation: either subcutaneous LMW heparin or IV unfractionated heparin at FULL therapeutic doses.

Full dose subcutaneous LMW heparin or IV unfractionated heparin carries significant risk of post- operative bleeding. It is safe to start prophylactic anticoagulation 6 hours after surgery whereas a period of 24 hours should elapse before full dose anticoagulation is started.

See Sections 4.2 onwards for doses.

2 Prophylactic anticoagulation: subcutaneous LMW heparin at doses recommended for prophylaxis against venous thromboembolism in high-risk patients.


Warfarin should be ceased for four days prior to planned surgery, i.e. 4 doses omitted.

The INR should be measured the day before surgery. If the INR is ≥ 1.5, then 1 mg only of Vitamin K should be administered intravenously.

If the INR is < 1.5, surgery may be safely undertaken.

Warfarin should be recommenced post-operatively at the patient’s regular dose, with no loading dose. It should be restarted on the evening of the day of surgery.

Overlap warfarin with either LMW heparin or unfractionated heparin for at least 5 days and until INR is in the

therapeutic range for ≥ 2 days prior to ceasing heparin.

4.2. Heparins and Surgery – History of Venous Thromboembolism

For patients with a history of venous thromboembolism (VTE): Month 1 Post DVT

Elective surgery should be avoided in the first month after an acute episode of VTE. If this is not possible then give either full dose LMW heparin or unfractionated heparin before and after the procedure while the INR is below 2.

After the first post-operative day - : Enoxaparin (Clexane®): 1 mg/kg twice daily OR 1.5mg/kg daily by

subcutaneous injection

OR

Dalteparin (Fragmin®): 100 units/kg twice daily by subcutaneous injection.

Last dose of full dose LMW heparin before surgery should be given at least 24 hours before surgery.

First dose of full dose LMW heparin after surgery should be given according to the risk of post-operative bleeding determined in consultation with the surgeon.

24 hours should elapse after surgery before the next full anticoagulant dose of LMW heparin is given or even longer if the risk of bleeding is considered to be high e.g. 48 to 72 hours for major surgery.

This can be dispensed on an outpatient basis and administered by the patient, a relative, a PACC nurse or local medical centre

OR

Intravenous unfractionated heparin

This should be ceased six to eight hours before surgery.

It should not be restarted until at least 24 hours after major surgery and even longer if the risk of bleeding is considered high e.g. 48 to 72 hours. It should be restarted without a bolus, at the expected maintenance infusion rate. See Section 3.6 for Unfractionated Heparin Treatment Guidelines.

Month 2 and 3 Post DVT

For patients who have had a venous thromboembolism more than 1 month but less than 3 months ago, anticoagulation pre-operatively is not required. Post-operatively however, the risk of venous thrombosis remains high so full dose anticoagulation should be administered as outlined above.

Recurrent DVT

For patients who are on long-term anticoagulants ( > 3 months since last episode), the risk of thrombosis is not high enough to warrant either pre-operative or post-operative therapy with full dose heparin. Subcutaneous low

dose heparin or LMW heparin, in the dose used for prophylaxis against venous thromboembolism should be

administered.

4.3. Heparins and Surgery – Arterial Thromboembolism

For patients at risk of arterial thromboembolism:

Elective surgery should be avoided in the first month after an arterial embolism but if surgery is essential, pre- operative full dose LMW heparin or unfractionated heparin should be given (as above).


Post-operative heparin is recommended for such patients only if the risk of bleeding is low.

4.4. Heparins and Surgery – Prosthetic and Mechanical Heart Valves

Prosthetic/mechanical heart valves

For those patients with prosthetic/mechanical heart valves and requiring general surgery the following is recommended:

Warfarin should be omitted for FOUR days prior to surgery (omit 4 doses).

Patients should be commenced on LMW heparin during the pre-operative period only:

Enoxaparin (Clexane®): 1 mg/kg twice daily by subcutaneous injection

OR

Dalteparin (Fragmin®): 100 units/kg twice daily by subcutaneous injection

The last dose of LMW heparin should be given 24 hours or more prior to surgery, that is, on the morning of the day before surgery.

Given the significant risk of post-operative bleeding on full-dose anticoagulation, patients should receive post- operative prophylactic doses of LMW heparin (approximately six to twelve hours after surgery):

Enoxaparin (Clexane®): 40 mg by subcutaneous injection daily

OR

Dalteparin (Fragmin®): 5,000 units by subcutaneous injection daily

Warfarin should be recommenced on the evening of the day of surgery at the patient’s regular maintenance dose. Overlap warfarin with either LMW heparin or unfractionated heparin for at least 5 days and

until INR is in the therapeutic range for ≥ 2 days prior to ceasing heparin.

4.5. Heparins and Surgery – Other Conditions and Comments

In all other patients who receive anticoagulants to prevent arterial embolism, such as those with congestive cardiac failure or a history of non-valvular atrial fibrillation, the risk of embolism is not high enough to warrant either pre- operative or post-operative therapy with full dose heparin. Full dose heparin therapy should, in fact, be avoided after major surgery because of the high risk of bleeding.

Subcutaneous low-dose unfractionated heparin (at 5,000 units subcutaneously bd or tds) or LMW heparin (in the

dose used for prophylaxis against venous thromboembolism in high-risk patients) is recommended for hospitalised patients whose risk of arterial embolism does not justify the use of full dose heparin.

However, neither hospitalisation to administer subcutaneous heparin nor the administration of subcutaneous heparin

to outpatients appears to be justified.

4.6. Regional Anaesthesia and Prophylaxis

Insertion and removal of a spinal or epidural catheter (neuraxial blockade) is associated with an increased risk of spinal haematoma in the presence of anticoagulation.

No LMW heparin for at least 12 hours BEFORE insertion or removal of an epidural/spinal catheter (24 hours if therapeutic dosages).

No LMW heparin for at least 2 hours AFTER insertion or removal of an epidural/spinal catheter.

sInsertion:

Pre: This dose should either be omitted or given at least 12 hours before insertion of a spinal catheter. A longer interval (24 hours) is required if the patient is on therapeutic dosages.

Post: Give the first post-operative dose at least 2 hours after needle insertion unless there is any macroscopic blood

in tap, in which case the anaesthetist’s discretion should be used in the timing of this dose.


Removal:

Pre: At least 12 hours should elapse between the last dose of LMW heparin and removal of the spinal catheter.

Post: As least 2 hours should elapse between removal of the spinal catheter and the next dose of LMW heparin.

Prophylactic LMW heparin doses:

Enoxaparin (Clexane®): 40 mg or 20 mg by subcutaneous injection daily

OR

Dalteparin (Fragmin®): 5,000 units or 2,500 units by subcutaneous injection daily

For prophylactic dosing see section 1.1 Surgical thromboprophylaxis

NOTE: When using unfractionated heparin, six hours should elapse from the last dose of heparin before catheter removal and two hours should elapse before the next dose of heparin.

5. Heparin Induced Thrombocytopenia Syndrome (HITS)

5.1. General Information

Consult Haematologist on-call.

Occurs after 4 to 10 days after the commencement of heparin (intravenous or subcutaneous). Can occur more quickly if the patient has been exposed to heparin in the previous 100 days.Thrombocytopenia occurs with at least a 50% fall from baseline.

All patients having any unfractionated heparin, all patients having therapeutic LMW heparin and all post operative patients having prophylactic LMW heparin should have platelet counts commencing day 4 and then every second or third day until day 14.

Tests for heparin antibodies are not clinically useful.

Associated with paradoxical thrombosis, either arterial or venous. This risk can persist for a number of months after recovery.

Treatment: Cease heparin and administer lepirudin.

Do not commence LMW heparin when HITS has developed on unfractionated heparin.

5.2. Treatment of HITS

LEPIRUDIN PROTOCOL

Do a baseline APTT. Treatment should not be initiated in patients with an APTT of 90seconds or more in order

to avoid overdosing.

0.4 mg/kg bodyweight intravenously as an initial bolus dose given over 15 to 20 seconds.

This is followed by 0.15 mg/kg bodyweight/hour as a continuous intravenous infusion for two to ten days or longer if clinically needed.

The dose depends on the patient's bodyweight (see tables below). In patients with a bodyweight of greater than

110 kg the dose should not be increased beyond that for a bodyweight of 110 kg.

Patients will need to be reanticoagulated with warfarin.

INTRAVENOUS BOLUS

Lepirudin concentration 5mg/mL - See manufacturer information for reconstitution and dilution instructions. Examples for standard injection volume according to bodyweight

Body weight

(kg)

Injection volume (mL)

Dose (0.4 mg/kg)

Dose (0.2 mg/kg)

50

4.0

2.0

60

4.8

2.4

70

5.6

2.8

80

6.4

3.2

90

7.2

3.6

100

8.0

4.0

110

8.8

4.4


INTRAVENOUS INFUSION

Lepirudin solution concentration 2mg/mL – See manufacturer information for reconstitution and dilution instructions.

Examples for standard infusion rate (mL/hour) according to bodyweight.

Body weight

(kg)

Infusion rate (mL/hour)

Dose (0.15 mg/kg/hour)

Dose (0.1 mg/kg/hour)

50

3.8

2.5

60

4.5

3.0

70

5.3

3.5

80

6.0

4.0

90

6.8

4.5

100

7.5

5.0

110

8.3

5.5

LEPIRUDIN MONITORING

Dose (infusion rate) should be adjusted according to the APTT.

The target range for APTT during treatment should be 50 – 90 seconds.

Lepirudin should not be started in patients presenting with an APTT of 90seconds or more.

Check APTT again four hours after starting infusion and adjust dose if required. Then check APTT daily.

More frequent APTT monitoring is highly recommended in patients with renal impairment or serious liver injury

or with an increased risk of bleeding.

If the APTT is above the target range, the infusion should be stopped for two hours. At restart, the infusion rate should be decreased by 50% (no additional intravenous bolus should be administered). The APTT should be checked again four hours later.

If the APTT is below the target range, the infusion rate should be increased in steps of 20%. The APTT should

be checked again four hours later.

In general, an infusion rate of 0.21 mg/kg/hour should not be exceeded without checking for coagulation abnormalities which might be preventive of an appropriate APTT response.

LEPIRUDIN IN RENAL IMPAIRMENT

Lepirudin is almost exclusively excreted and metabolised renally.

In all patients with renal impairment, the bolus dose is to be reduced to 0.2 mg/kg bodyweight. See table below for guidelines on maintenance dose reduction.

Additional APTT monitoring is mandatory.

Lepirudin – reduction of maintenance dose in patients with renal impairment.

Creatinine Clearance (mL/min)

Adjusted maintenance dose

(% of original dose)

45 - 60

50%

30 - 44

30%

15 - 29

15%

below 15*

Avoid or STOP infusion!*

* In hemodialysis patients or in cases of acute renal failure (creatinine clearance below 15 mL/min, infusion of

lepirudin is to be avoided or stopped).

Only if APTT values have fallen below the lower therapeutic level (50seconds) may further IV bolus doses of 0.1

mg/kg bodyweight be considered every other day.

5.3. Thromboprophylaxis for a patient with HITS - Danaparoid

Use danaparoid 750 units by subcutaneous injection twice daily.

For elderly and/or renally impaired patients second and subsequent doses may need to be reduced. Consult

Haematologist.


6. Haemodialysis Anticoagulation

Haemodialysis

Anticoagulation during haemodialysis procedure to “prevent clotting of the circuit and the dialyser” should not be altered without discussion with the patient’s nephrologist.

Warfarin to Prevent Fistula Thrombosis

The target INR for patients receiving warfarin to prevent thrombosis of their AV fistula varies, depending on comorbid disease and vascular access. In patients with fistula thrombosis within the month prior to surgery, full dose anticoagulation is required in the immediate pre-operative period once warfarin is ceased. Discuss with patient’s nephrologist if in doubt.

Full-dose LMW Heparin

See sections 2.4 and 3.2 Renal Impairment.

7. Oral Anticoagulation – Warfarin

7.1. INR targets

A patient’s response to warfarin is governed by a multitude of factors including: the balance of the four vitamin K dependent clotting factors (with half-lives ranging from 6 to 48 hours), Vitamin K status and thus dietary habits, age, warfarin dose and other medications the patient is taking.

More problems are caused by too much unnecessary interference, rather than too little. Common causes of therapeutic instability with warfarin, in order of importance are: 1) Poor compliance, 2) Intercurrent illness, 3) Concomitant medication, 4) Dietary habits (most common variations in dietary intake, including alcohol, have little effect – however dietary extremes are to be avoided).

There is a delay in response of the INR of 2 to 3 days to any changes in warfarin dose.

INR is used only for patients on warfarin.


For all other patients use prothrombin time.

In the initiation phase, INR should be measured daily or second daily.

Overlap warfarin with either LMW heparin or unfractionated heparin for at least 5 days and until INR is in the

therapeutic range for ≥ 2 days prior to ceasing heparin.

All patients should be given an anticoagulant booklet, counselled by the ward pharmacist and encouraged to keep a record of warfarin doses and INR results.

7.2. Albumin

Check albumin: Patients with a serum albumin less than 30 g/L are very sensitive to warfarin and may require

consultation with haematology.

7.3 Warfarin Initiation Guideline

Use of this warfarin initiation guideline allows the majority of patients to rapidly and safely achieve a stable INR

within the target range. This guideline helps protect the elderly from over anticoagulation during warfarin initiation.

This is a guideline and some flexibility in the protocol for testing INR may be necessary in particular circumstances.

This guideline is valid only if pretreatment INR is <1.4 and the patient is clinically stable. Check INR prior to warfarin therapy and then on Day 3 (or 4 if inconvenient)

Treatment day

Warfarin dose

if first INR on day 3

Warfarin dose

if first INR on day 4

1

10mg

Age < 70

5mg

5mg

Age >70 years

Weight <50kg

Chronic or intercurrent illness

2

5mg

5mg

3

INR < 2.0

INR 2.0 – 3.0

INR > 3.0

5mg

4mg

Omit dose

5mg

4

INR – adjust warfarin dose according to schedule below

Continue LMW heparin

Overlap warfarin with either LMW heparin or unfractionated heparin for at least 5 days and until INR is in the

therapeutic range for ≥ 2 days prior to ceasing heparin.

Thereafter INR should be monitored two or three times weekly until there are three consecutive readings within the therapeutic range, then at least weekly for four weeks and then, if stable, with progressive less frequency.

7.4. Recommended Warfarin Dose Adjustments

Recommended Warfarin Dose Adjustments from Day 4

For patients not actively bleeding

INR > 7.0

Consult expert (see flowchart in 7.5)

INR > 5.0 High risk

Consult expert (see flowchart in 7.5)

INR > 5.0 Low risk

Omit warfarin – restart at half dose once INR < 5.0

INR 4.0 - 5.0

Omit for one night or halve previous dose initially and adjust according to response.

INR 3.0 - 4.0

Watch or reduce dose by 20 - 25% (usually about 1 mg/day)

INR 2.0 - 3.0

Continue dose

INR 1.5 – 2.0

Watch or increase dose by 20 - 25% (usually about 1 mg/day)

INR < 1.5

Increase dose by 30 - 40% (usually 2 mg) initially and adjust according to response.

Note: More problems are caused by too much unnecessary interference, rather than too little.


7.5. Post Acute Community Care

GUIDELINE for HOME ANTICOAGULATION

This guideline is valid only if pretreatment INR is <1.4 and the patient is clinically stable. FBC,APTT, EUC and LFTs should be normal – discuss any abnormalities with Haematologist on-call.

Refer patients with DVT to Thrombosis & Haemostasis Clinic: Phone 9845 6274

(Mon - Fri, 9am – 5pm).

Treatment day

Warfarin dose

Instructions

1

Age < 70 yrs 10mg

Continue LMW heparin

Age > 70 yrs

Weight < 50kg 5mg

Multiple comorbidities

2

5mg

Continue LMW heparin

3

INR < 2.0 5mg

INR 2.0 – 3.0 4mg

INR > 3.0 Omit dose

Continue LMW heparin. Adjust dose of warfarin

4

INR – adjust Warfarin dose according to schedule below.

Continue LMW Heparin

Low Molecular Weight Heparin should be overlapped with warfarin for at least five days and until the INR is

in the therapeutic range for two consecutive readings.

Thereafter INR should be monitored two or three times weekly until there are three consecutive readings within the therapeutic range, then at least weekly for four weeks and then, if stable, with progressive less frequency.

Recommended Warfarin Dose Adjustments from Day 4

For patients not actively bleeding

INR > 7.0

Consult expert

INR > 5.0

Omit Warfarin – restart at half dose once INR < 5.0

INR 4.0 - 5.0

Omit for one night or halve previous dose initially and adjust according to response.

INR 3.0 - 4.0

Watch or reduce dose by 20-25% (usually about 1mg/day)

INR 2.0 - 3.0

Continue dose

INR 1.5 – 2.0

Watch or increase dose by 20-25% (usually about 1mg/day)

INR < 1.5

Increase dose by 30-40% (usually 2mg) initially and adjust according to response.


Common causes of therapeutic instability with Warfarin, in order of importance are: Poor compliance

Intercurrent illness

Concomitant medications

Most common variations in dietary intake, including moderate quantities of alcohol, have little effect – dietary extremes are to be avoided.


7.6. Treatment Strategy for Warfarin Reversal

1 Major bleeding complication classification:

1. Intracranial (CT or MRI documented)

5. Pericardial

2. Retroperitoneal (CT or MRI documented)

6. Non-traumatic intra-articular

3. Intra-ocular (excludes conjunctival)

7. Any invasive procedure to stop bleeding

4. Spontaneous muscle haematoma associated with compartment syndrome

8. Active bleeding from any orifice plus either BP 90 mmHg systolic, oliguria, 20

g/L fall in haemoglobin.

2 Minor bleeding complication classification: Any other bleeding that would not influence your decision to anticoagulate a patient

3 IV Vitamin K rarely causes anaphylaxis. Administer by slow IV bolus over at least 30 seconds. Withhold in patients with prior severe allergic reaction. IV vitamin K has a significant effect on the INR within 4 to 6 hours.

4 Prothrombinex-HT : is a concentrate of human blood coagulation factors: II, IX and X. It is indicated for urgent reversal of warfarin anticoagulation. Consultation with a haematologist is recommended. Prothrombinex-HT use is contraindicated in thrombosis or disseminated intravascular coagulation. It should be used in caution in hepatic dysfunction. Product is refrigerated and is available from blood bank.

5 Oral Vitamin K: use the injectable form (10mg/mL strength) by drawing up the dose in a syringe and to give orally it can be diluted in a small amount of water.

6 High risk patients - correction should be considered in high risk patients whose risk of bleeding is approximately 15 fold higher. High risk patients include those with increased age, previous CVA, renal failure, previous MI, previous GI bleed, anaemia or diabetes mellitus.

7 Low risk patients do not require INR reversal at INR 7 to 9.


7.7. Duration of Oral Anticoagulation

The duration of oral anticoagulation varies with the clinical circumstances. Consult haematologist. As a general rule for some indications:

If a readily identifiable precipitating factor is present, e.g. recent surgery then duration of therapy is 6 weeks after mobilisation.

For a first spontaneous proximal DVT or PE then duration of therapy is 6 months. For other clinical scenarios, review by a haematologist is indicated.

7.8. Drug Interactions With Warfarin

A careful drug history needs to be taken before warfarin is commenced. When medications are altered (started, stopped or changed), increased monitoring for one or two weeks should be instituted. Medications affecting anticoagulant activity may also include over the counter medications, complementary and herbal medications.

Drugs which may increase anticoagulant activity

Drugs which significantly decrease anticoagulant activity

Common drugs influencing platelet function

Alcohol Alteplase Amiodarone Amitriptyline1

Anabolic steroids

Anaesthetics

(inhalation) Angelica (Dong Quai) Aspirin (not low dose) Azathioprine1

Aztreonam Capcitabine Carboplatin Celecoxib Cephalosporins Cephalothin Cephazolin Chloramphenicol Cimetidine Ciprofloxacin Clarithromycin Clindamycin

Corticosteroids1

Co-trimoxazole

Cyclosporin1

Cyclophosphamide1

Cytotoxics1

Danazol Danshen Dexamethasone

Dextran

Dextropropoxyphene

Diazoxide Diclofenac Diflunisal Disopyramide Disulfiram

Dong Quai (Angelica) Doxorubicin Doxycycline Erythromycin Ethacrynic acid Etoposide

Fenofibrate Fenugreek Flucloxacillin

Fluconazole Fluorouracil (5-FU) Fluoxetine Flutamide Fluvoxamine

Garlic Gemcitabine Gemfibrozil1

Glibenclamide Glucagon Ibuprofen

Ifosphamide/mesna Indomethacin Influenza vaccine Interferon alpha 2b Interferon beta Isoniazid Itraconazole Ketoconazole Ketoprofen Ketorolac Lansoprazole Leflunomide Lepirudin

Liothyronine2

Levonorgestrel Macrolides Mefenamic acid Meloxicam Methotrexate Methyldopa Methylphenidate Methylsalicylate

(ointment) Metronidazole Mexilitine

Miconazole (oral gel

only, NOT topical) Nevirapine Norfloxacin

NSAIDs

Omeprazole

Oral contraceptives Orlistat Paracetamol

(high doses)

Paroxetine Penicillins Phenytoin (Initial inhibition followed by induction) Piroxicam Quetiapine

Quinidine1

Quinine Quinolones Raloxifene

Reteplase

Ritonavir Roxithromycin Saquinavir Sertraline Simvastatin SSRI

Statins Streptokinase Sulindac Sulphamethoxazole Sulphinpyrazone Sulphonamides Tamoxifen Tenecteplase Terbinafine Testosterone Tetracyclines Tetracyclic

antidepressants1

Thyroxine2

Tiaprofenic acid Ticarcillin Ticlopidine Tinidazole Tramadol Tricyclic

antidepressants1

Trimethoprim & Sulfamethoxazole Urokinase Vancomycin Vincristine

Vitamin E1

Alcohol (chronic excess) Aminoglutethimide

1

Amitriptylline

Antithyroid drugs

1

Azathioprine

Barbiturates

Carbamazepine

2

Carbimazole

Cholestyramine

1

Corticosteroids

1

Cyclosporin

1

Cyclophosphamide

1

Cytotoxics

Enteral Feeds

1

Gemfibrozil

Griseofulvin Hypericium Indinivir Mercaptopurine Penicillins Phenobarbitone Phenytoin

2

Propylthiouracil

1

Quinidine

Rifampicin Spironolactone St John’s Wort Sucralfate Sulfasalazine Teicoplanin

Tetracyclic antidepressants1

Tricyclic antidepressants 1

Vitamin E1

Vitamin C Vitamin K

Abciximab Aspirin Clopidogrel Diclofenac Diflunisal Dipyridamole Eptifibratide Ephedra Feverfew

Fish oil supplement

Garlic

Ginger

Ginkgo biloba Ginseng Guarana Ibuprofen Indomethacin Kava Ketoprofen Ketorolac

Mefenamic Acid Naproxen NSAIDS Piroxicam Sulindac Ticlodipine Tirofiban

Vitamin E

1 Increased or decreased anticoagulant activity has been reported 2 The effect is caused by altering underlying thyroid status

This is not an all-encompassing list of drug interactions. Please consult current product information when prescribing medications concurrently with warfarin


7.9 Medication and Blood Sampling Times

Patients are to routinely receive warfarin doses at 1800 hours each day.

Blood samples for INR are to be obtained between 0900 and 1100 the next morning.

8. References

1. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. MJA 2004;181(9):492-497

2. Buckley NA, Dawson AH. Drug interactions with warfarin. MJA 1992;157:479-83.

3. Clexane (enoxaparin) product information. Lane Cove: Aventis Pharma Pty Limited. Date of TGA Approval or Manufacturer's

Last Amendment: 02/05/2002.

4. Cohen M, Demers C, Gurfinkel EP, Turpie AGG, Fromell GJ, Goodman S, et al. A comparison of low molecular weight

heparin with unfractionated heparin for unstable coronary artery disease. New England Journal of Medicine 1997;337(7):447-

52.

5. Fiessinger JN, Lopez-Fernandez M, Gatterer E, Granquist S, Kher A, Olsson CG, et al. Once daily subcutaneous dalteparin,

a low molecular weight heparin, for the treatment of acute deep vein thrombosis. Thrombosis and Haemostasis

1996;76(2):195-9.

6. Fragmin (dalteparin) product information. Rydalmere: Pharmacia Australia Pty Limited. Date of TGA Approval or

Manufacturer’s Last Amendment: 05/02/2002.

7. Gallus AS, Baker RI, Chong BH, PA Ockelford, Street AM. Consensus guidelines for warfarin therapy: recommendations from the Australasian Society of Thrombosis and Haemostasis. MJA 2000;172:600-605.

8. Green D, Hirsh J, Heit J, Prins M, Davidson B, Lensing AWA. Low molecular weight heparin: a critical analysis of clinical

trials. Pharmacol Rev 1994;46(1):89-109.

9. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79(1):1-17.

10. Hirsh J, Siragusa S, Cosmi B, Ginsberg JS. Low molecular weight heparins (LMWH) in the treatment of patients with acute venous thromboembolism. Thrombosis and Haemostasis 1995;74 (1):360-3.

11. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. New Engl J Med 1997;336 (21):1507-11.

12. Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low molecular weight heparins: a meta-analysis. Arch Intern Med 1995;155 (Mar 27):601-7.

13. Lindmarker P, Holmstrom M, Granquist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with

continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thrombosis and Haemostasis

1994;72(2):186-90.

14. Nurmohamed MT, Rosendaal FR, Buller HR, Dekker E, Hommes DW, Vandenbroucke JP, et al. Low molecular weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-5.

15. Orgaran (Danaparoid) product information. Lane Cover: Organon Australia Pty Limited. Date of TGA Approval or

Manufacturer’s Last Amendment: 01/05/1998.

16. Prothrombinex-HT product information. Sydney: CSL. Date of TGA Approval or Manufacturer’s Last Amendment: 21/08/02.

17. Refludan (Lepirudin) product information. Melbourne: Pharmion Pty Limited. Date of TGA Approval or Manufacturer's Last

Amendment: 02/05/2002.

18. Samama et al. A comparison of Enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. New Engl J Med 1999;341(11): 793-800

19. Schunemann HJ, Cook D, Grimshaw J, Liberati A, Heffner J, Tapson V, Guyatt G. Antithrombotic and thrombolytic therapy:

from evidence to application. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest

2004;126:688S-696S.

20. Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low molecular weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996;100:269-77.

21. Speight TM, Holford NHG ed. Avery’s Drug Treatment. 4th ed. Auckland. ADIS International, 1997.

22. Stockley IH. Drug Interactions.4th ed. London,The Pharmaceutical Press, 2002.

23. Weitz JI. Low molecular weight heparins. New Engl J Med 1997;337 (10):688-98.

24. A Working Group on behalf of the Obstetric Medicine Group of Australasia. Anticoagulation in pregnancy and the puerperium

MJA 2001; 175: 258-263

25. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr. ACC/AHA guidelines for the management of patients with ST- elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004. Available at www.acc.org/clinical/guidelines/stemi/index.pdf.

26. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable

Angina and Non-ST-Segment Elevation Myocardial Infarction. A Report of the American College of Cardiology/ American

Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina).

27. Aroney C, Boyden N, Jelinek MV et al. Management of unstable angina guidelines- 2000. MJA 16 Oct 2000; 173 Supplement: S65-88.

28. Yusuf S, Zhao F, Mehta SR et al. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes

without ST-Segment Elevation. NEJM Aug 2001;345(7):494-502.

29. Cohen M, Demers C, Gurfinkel EP, et al, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-52.

30. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation

1999;100:1593-601.

31. Spinler SA, Inverso SM, Cohen M et al. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J. 2003

Jul;146(1):33-41.

The guidelines have been researched using the most up to date information retrieval sources available to the contributors. These sources, though extensive, do not represent the full world-wide complement in this area.

 
  • Follow us on