Consensus Guidelines for Australian Clinicians for the usage of anti-coagulants during heparin-based product shortages

Appendix 2: Anticoagulants and Antithrombotics: Alternatives for Prophylaxis & Treatment

Guidelines to assist with contingency planning to manage the clinical implications of a shortage of heparin based products.

Page last updated: 16 July 2008

Information in the following tables is drawn from the published literature and consensus opinion of Australian experts across the relevant craft groups available in the timeframe. As such, the information provides a guide to clinical usage, informed by the evidence, and must be considered in the context of each patient’s clinical and other circumstances.

The best evidence from the published literature suggests there are (i) indications where LMWH is difficult to substitute with UFH or alternative anticoagulants (eg treatment of VTE in pregnancy), (ii) indications where intravenous or SC UFH can be safely and effectively substituted but will impact hospital protocols and service provision (eg medical inpatients, prophylaxis in general surgery).and (iii) indications where SC UFH is less effective than LMWH or not effective (eg orthopaedic surgery, abdominal cancer surgery).

The evidence base for effectiveness and safety of the non pharmacological measures for VTE prophylaxis is less robust than for pharmacological measures2 and informed consent would be needed for surgery to proceed.

Pharmacological Anticoagulants and antithrombotics2

Intravenous and subcutaneous (IV & SC)

Unfractionated heparin (UFH)Use in prophylaxis and treatment of thromboembolic disease. Can be used as IV bolus or infusion.
Requires regular APTT to monitor anticoagulation.
UFH can be given for VTE therapy via weight-adjusted dose SC, with minimal need for dose-adjustment according to APTT. Two regimens have been studied 3, 4
Second daily FBC to monitor for HITTS. (NB: Expect 5 additional cases of HITTS per 1000 pts treated with UFH rather than LMWH.
Low molecular weight heparin Enoxaparin (Clexane) Dalteparin ( Fragmin) Fondaparinux (synthetic product - Arixtra)Use in prophylaxis and treatment of thromboembolic disease. Clexane used SC
Fragmin SC (or rarely by IV infusion)
Fondaparinux SC for major hip surgery and total knee replacement
Lepirudin (Refludan) Danaparoid(Orgaran)For use in heparin-induced thrombocytopaenic thrombosis (HITTS)
(See note on additional risk of HITTS above)
Direct thrombin inhibitor Bivalirudin (Angiomax)Indicated for use during percutaneous coronary intervention

Oral agents

Warfarin
(Coumadin, Marevan)
Long term prophylaxis and treatment of thromboembolic disease. Can be used for VTE prophylaxis after hip or knee replacement. Requires monitoring with regular INR, initially daily until stable and therapeutic.
Clopidogrel
Dipyridamole (Persantin)
No role in venous disease and thromboprophylaxis Clopidogrel could be used in some middle and low priority interventional radiology procedures to reduce risk of acute arterial thrombosis. Not available on PBS for non-cardiac risk patients.
If clopidogrel used, would require use of arterial closure devices in these pts to reduce risk of bruising or haemorrhage (eg Star Close device from Abbott, Angio Seal device from St Jude).

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Pharmacological Anticoagulants and antithrombotics2

Mechanical methods of prophylaxis2

Main mechanical methods include:
  • Graduated compression stockings (GCSs)
  • Intermittent pneumatic compression (IPC) devices and
  • The venous foot pump (VFP) Also:
Inferior vena cava filters – uncommon use – only in specially selected patients and

Intraoperative intermittent calf stimulators
Main advantage of mechanical methods is lack of bleeding potential.

Therefore, primarily useful for pts with high bleeding risks or as an adjunct to pharmacological methods.

Work by increasing venous outflow and/or reducing stasis within the leg veins.

All three modalities reduce the risk of DVT in a number of patient groups but less study on them and generally, less efficacious than pharmacological methods for prevention of DVT.

Essential to select the correct size of the device, apply properly, and ensure that only removed for only a short time each day. Nursing and physiotherapy initiatives should ensure that the devices do not impede ambulation.

Note: Care with proper use of, and optimal compliance with, the mechanical device
GCS (further detail)GCS reduce venous stasis in the limb by applying a graded degree of compression to the ankle and calf, with greater pressure being applied distally.

GCS should be used routinely for surgical inpatients and are effective in decreasing risk of DVT, either alone, or in combination with pharmacological prophylaxis in high risk patients5, 6

GCS should not be used in patients with peripheral arterial disease.
IPC (further detail)Intermittent pneumatic leg compression has both local and systemic effects.
  • Prevents venous thrombosis by enhancing blood flow in the deep veins of the legs, thereby preventing venous stasis.7
  • Reduces plasminogen activator inhibitor-1 (PAI-1) levels via an unknown mechanism and consequently increases endogenous fibrinolytic activity.

May cause discomfort in some patients

Should not be used in patients with overt evidence of ischaemia due to peripheral vascular disease.

Contraindicated in patients who have been on bed rest or immobilized for more than 72 hours without prophylaxis, as may cause a newly formed clot to dislodge.

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Treatment and/or prophylaxis regimens/alternatives

Venous thrombo-embolic disorders2

Treatment and/or prophylaxis regimens/alternatives

Venous thrombo-embolic disorders2
Acute DVT, recommend initial treatment with LMWH or UFH for at least 5 days; warfarin together with LMWH or UFH on the first treatment day and discontinuation of heparin when the INR is stable and > 2.0 for two consecutive readings
If IV UFH – continuous infusion with dose adjustment to achieve and maintain a therapeutic APTT prolongation - regular daily measurements required

OR

SC UFH - initial dose of 35,000 Units/24 h SC, with subsequent dosing to maintain the APTT in the therapeutic range

OR

Initial treatment with LMWH SC once or twice daily- routine monitoring with anti-factor Xa level measurements is not recommended
If IV UFH – continuous infusion with dose adjustment to achieve and maintain a therapeutic APTT prolongation - regular daily measurements required

OR

SC UFH - initial dose of 35,000 Units/24 h SC, with subsequent dosing to maintain the APTT in the therapeutic range

OR

Initial treatment with LMWH SC once or twice daily- routine monitoring with anti-factor Xa level measurements is not recommended
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Acute Coronary Syndromes2

Treated by percutaneous intervention (primary angioplasty) - emergency

Early intervention

+/- GPIIb/IIIa inhibitor eg abciximab
(Reopro)
IV bolus of UFH is used at the time of the procedure– usually 2 boluses in total. Monitoring with activated clotting time (ACT)
Delayed interventionUFH or LMWH while patient is waiting for angioplasty, LMWH ceased 12 hours before angioplasty and UFH used at the time of angioplasty

OR

Infusion of UFH or SC Clexane until intervention or for
48–72 hours 8
Non emergency percutaneous intervention (primary angioplasty)Bivalirudin for the duration of the procedure. Consider postponing elective angioplasty.
Treatment with fibrinolytic therapy (TPA/RPA)In addition a bolus of IV UFH (5000 Units) + 48 hours of UFH infusion

OR

60 Units/kg ( max 4000 Units) followed by an initial infusion of 12 Units/kg/hr (max 1000 Units/hr), adjusted to APTT8

OR

24-48 hours of Clexane (pts <75 years)

Note: Anticoagulation NOT recommended after thrombolysis using non fibrin specific product such as streptokinase.
Fibrinolysis or PCIBivalirudin can be used in patients with HITTS
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Pregnancy

Patients requiring anticoagulation in pregnancySC Clexane or Fragmin.

Risk of osteoporosis with long term UFH prophylaxis (up to 9 months) to mother and foetus.

LMWHs have potential advantages over UFH during pregnancy because they cause less HITTS, have a longer plasma half-life and a more predictable dose response than UFH, with the potential for once-daily administration, and are likely associated with a lower risk of heparin-induced osteoporosis.

UFH could be considered where there is an absolute need for anticoagulation and the risk of no anticoagulation outweighs the risk to the foetus.

Warfarin

Warfarin can be used in the mid-trimester according to established protocols if the risks and benefits are understood by the mother.

Women should be changed from warfarin to heparin as early as possible but no later that 7 weeks of pregnancy (5 weeks post conception) to prevent the teratogenic effects of warfarin.

After 12 weeks (10 weeks post conception) there are circumstances where warfarin can be reintroduced. Close monitoring of INR is essential.

Warfarin is then discontinued at 34 weeks and heparin reintroduced.
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Critical Care

Multiple traumaLMWH is effective and superior to low dose heparin for patients who have suffered multiple trauma.

LMWH prophylaxis should be started as soon as it has been considered safe to do so. Intermittent pneumatic compression has been recommended, when feasible, because it eliminates any risk for bleeding.
Patients at high risk for bleedingMechanical prophylaxis with GCS and/or IPC recommended until bleeding risk decreases
ICU patients who are at moderate risk for VTE (eg medically ill or postoperative patients)Low dose UFH or LMWH prophylaxis
Patients who are at higher risk, such as that following major trauma or orthopedic surgeryLMWH prophylaxis recommended
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Elective Orthopaedic Surgery2, 9

Consider rescheduling if safe and appropriate

Consider day-5 doppler in high risk patients
Total hip replacementClexane (enoxaparin) 30mg SC 12 hourly or 40mg SC daily. LMWH usually started post-op in Australia because of practice of admitting pts to hospital on day of procedure. Continue with Clexane for 4-5 weeks post operatively.
OR
Fondaparinux (2.5 mg started 6 to 8 h after surgery) and follow up with
LMWH for 5 weeks
OR
Clexane as above, with adjusted-dose warfarin started after surgery (INR target, 2.5; INR range, 2.0 to 3.0) for the next 5 weeks (note requires regular laboratory testing of INR and usually takes some time to achieve stable level – 10-11 days) OR
Low dose UFH in preoperative period with postoperative dose adjusted heparin to maintain APTT around the upper range of normal is safe and effective but is less practical than LMWH treatments.
Follow up with warfarin for 5 weeks if indicated for VTE prophylaxis
OR
Warfarin, starting on eve of surgery and aiming for INR of 2-3 is suitable for elective hip replacement. Needs INR testing and dose adjustment.
Hip fracture surgeryClexane (enoxaparin) 40mg SC daily or (Fragmin) dalteparin 5000 Units
SC daily. LMWH usually started post-op in Australia because of practice of admitting pts to hospital on day of procedure. Continue with LMWH for 28-35 days post operatively.
OR
Fondaparinux, (2.5 mg started 6 to 8 h after surgery) and follow up with LMWH for 5 weeks
OR
LMWH as above, with adjusted-dose warfarin started after surgery (INR target, 2.5; INR range, 2.0 to 3.0) for the next 5 weeks (note requires regular laboratory testing of INR and usually takes some time to achieve stable level – 10-11 days)
OR
UFH 5000 Units SC tds. Follow up with warfarin for 5 weeks if indicated for VTE prophylaxis
OR
Warfarin, starting on eve of surgery and aiming for INR of 2-3 is suitable for HFS. Needs INR testing and dose adjustment
Total knee replacementLMWH 30mg SC bd., for 7-14 days postoperatively
OR
Fondaparinux (2.5 mg started 6 to 8 h after surgery) OR
Adjusted-dose warfarin started on the eve of surgery (INR target, 2.5; INR range, 2.0 to 3.0) for the next 5 weeks ( note this requires regular laboratory testing of INR)
OR
UFH in preoperative period with postoperative dose adjusted heparin to maintain APPT around the upper range of normal in conjunction with GCS and IPC. UFH not recommended as sole prophylaxis.
ArthroscopyEarly mobilisation
Pharmacological prophylaxis not required.
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General, Vascular, Gynaecologic and Urologic Surgery2

Low risk general surgery, minor procedure, <40, no additional risk factorsRecommend against the use of specific prophylaxis other than early and persistent mobilization.

Not required in caesarean section unless other risk factors for VTE present
Moderate-risk general surgery patients are those patients undergoing a non major procedure and are between the ages of 40 and 60 years or have additional risk factors, or those patients who are undergoing major operations and are < 40 years of age with no additional risk factorsProphylaxis with UFH, 5,000 Units SC bd, OR
LMWH, according to manufacturer’s specifications (different for Fragmin and Clexane) combined with GCS and/or IPC
Higher-risk general surgery patients are those undergoing non major surgery and
are > 60 years of age or have additional risk factors, or patients undergoing major
surgery who are > 40 years of age or have additional risk factors.
Recommend thromboprophylaxis with UFH, 5,000 Units SC tds,

OR
LMWH, according to manufacturer’s specifications (different for Fragmin and Clexane) combined with GCS and/or IPC
General surgery patients with a high risk of bleedingUse of mechanical prophylaxis with properly fitted
GCS and/or IPC,

Commence pharmacological prophylaxis when bleeding risk decreases
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Renal dialysis

Patients undergoing haemodialysis

Typically, patients have 3-4 sessions of haemodialysis per week.

There are an estimated 7 500 haemodialysis patients in Australia.

These patients are high priority for heparin based products in the event of a shortage.
Anticoagulation is essential

Clexane may be substituted with unfractionated heparin, Fragmin or fondaparinux (Arixtra).

Home therapy patients will need retraining if shifted from Clexane to unfractionated heparin.

Warfarin is NOT an alternative anticoagulant in haemodialysis.