Summary

Heparins are commonly used to prevent venous thromboembolism. Although they are effective anticoagulants, heparins have a high risk of adverse effects if used inappropriately. Safer heparin prescribing is achieved through careful patient selection by assessing the risk of venous thromboembolism. Consider the drugs' contraindications and precautions including renal function, concomitant medication use and spinal needle insertion. Comparative drug information needs to be considered when choosing the optimal heparin for an individual patient. The timing of perioperative heparin administration depends on the choice of heparin, type of surgery and type of anaesthesia. Patients should be carefully monitored during prophylaxis.

Introduction

Heparins are effective anticoagulants and can be used to prevent venous thromboembolism in hospitalised medical and surgical patients. In Australia it has been estimated that the overall prevalence of venous thromboembolism in all hospitalised patients is 2–3 per 1000 admissions.1 There is therefore growing Australian and international encouragement for prophylaxis, so increased numbers of inpatients will be prescribed a heparin.

'Heparin' or 'heparins' refers to the following medications available in Australia:

  • unfractionated heparin
  • low molecular weight heparins – dalteparin, enoxaparin
  • synthetic selective inhibitor of activated factor X – fondaparinux
  • heparinoid – danaparoid.

Although the benefits of using heparin in venous thromboembolism prophylaxis generally outweigh the risks, harm from low-dose heparin can be severe and the risks should not be ignored. While adverse effects are less common with low-dose heparin than with therapeutic doses of heparin, bleeding can still occur if other risk factors for bleeding are present, such as renal impairment or interaction with other drugs. Also, bleeding events can be expected to increase in frequency as the number of patients prescribed heparin for venous thromboembolism prophylaxis continues to increase. For example, a program of mandatory venous thromboembolism prophylaxis with low molecular weight heparin alone or in combination with warfarin has resulted in increased bleeding rates after hip and knee arthroplasty.2 Incidents with anticoagulants including heparins (at all doses) continue to be commonly reported to incident reporting systems in Australia and the USA3,4 Clinicians must consider the patient's safety when prescribing heparin as part of a strategy for venous thromboembolism prophylaxis as discussed in publications such as 'Safe prescribing of heparins for venous thromboembolism prophylaxis: a position statement of the NSW Therapeutic Advisory Group'.5

Patients requiring venous thromboembolism prophylaxis

The risk of venous thromboembolism should be assessed in all adult patients before or on admission to hospital. Currently available guidelines differ regarding which patients require venous thromboembolism prophylaxis.6,12 An Australian guideline for venous thromboembolism prophylaxis is currently under development.13 Table 1 shows the current recommendations in the USA.11

Table 1 Recommendations for thromboembolism prophylaxis11*
Indications Procedure/condition
Surgical procedures generally requiring venous thromboembolism prophylaxis Acute spinal cord injury
Major trauma
Major surgery including:
- general cancer or non-cancer surgery
- hip and knee arthroplasty
- open gynaecological surgery
- open urological surgery
- prolonged surgery
Surgical procedures generally not requiring venous thromboembolism prophylaxis when no additional risk factors are present Elective spine surgery
Knee arthroscopy
Isolated lower extremity injuries
Laparoscopic surgery
Transurethral surgery
Vascular surgery
Medical conditions generally requiring venous thromboembolism prophylaxis Congestive heart failure
Severe respiratory disease
Immobility plus:
- cancer
- previous venous thromboembolism
- sepsis
- acute neurological disease
- inflammatory bowel disease

Mechanical methods of prophylaxis, such as stockings, are recommended in patients at high risk of bleeding.
* These recommendations are based on guidelines from the USA, pending the publication of new Australian guidelines
Prolonged surgery may increase the risk of venous thromboembolism in patients who are over 40 or who have other risk factors

Contraindications and precautions

All patients should be assessed for contraindications and the precautions needed before starting prophylaxis. Absolute contraindications to heparin include known hypersensitivity, past or present heparin-induced thrombocytopenia and active bleeding.

Caution is required when prescribing heparin to patients with conditions that may increase the risk of bleeding (see box). In these patients, the decision to prescribe heparin should be made on an individual basis balancing the relative benefit and harm. Tests for coagulation, such as prothrombin time, are not routinely required.5

Box Examples of problems that may increase risks with heparin

Bleeding disorders, e.g. haemophilia

Concomitant use of certain medications, e.g. clopidogrel

Conditions where bleeding would be catastrophic, e.g. focal lesions, haemorrhagic stroke

Creatinine clearance <30 mL/min

High risk of uncontrolled haemorrhage, e.g. acute ulcerative gastrointestinal conditions, anaemia of unknown cause

Recent surgery on eye, brain or spinal cord

Severe thrombocytopenia (platelets <50 x 109 /L)

Severe liver disease with coagulopathy and/or oesophageal varices

Spinal or epidural needle insertion (spinal tap or spinal anaesthesia)


Renal function

Patients with moderate to severe renal dysfunction have a higher risk of bleeding with some heparins. Assessment of renal function using creatinine clearance is important before prescribing low molecular weight heparins or fondaparinux. In patients with a creatinine clearance less than 30 mL/min enoxaparin dosage should be reduced to 20 mg daily and fondaparinux is contraindicated. For danaparoid, dose reductions should be considered when creatinine clearance is under 20 mL/min. Unfractionated heparin can be prescribed without dose alteration.5

Interactions

Heparin should be prescribed cautiously in patients taking drugs that can increase bleeding, for example antiplatelets, non-steroidal anti-inflammatory drugs (NSAIDs) and thrombolytics. The decision to co-prescribe heparin with these drugs should be made on an individual patient basis in consultation with senior staff and taking into account patient preference. Careful clinical review and monitoring of the patient is recommended. Low-dose aspirin required for prevention or treatment of cardiovascular disease may be continued.

Unfractionated heparin can raise potassium concentrations. This may lead to hyperkalaemia when co-prescribed with other drugs that increase potassium, for example angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, potassium sparing diuretics, potassium supplements, NSAIDs or trimethoprim. Patients receiving unfractionated heparin for more than three days who are at risk of developing hyperkalaemia should have their potassium monitored at least every four days.14

Spinal needle insertion

When heparins are prescribed for patients undergoing spinal needle insertion the risk of an epidural or spinal haematoma is increased. Insertion and removal of needles and catheters should occur when the anticoagulant effect is lowest, generally just before the next dose is due. If bleeding occurs during needle placement, the subsequent dose of heparin should be delayed for 24 hours and the patient should have neurological observations.15

Choice of heparin

Different heparins have different harm:benefit ratios, although each carries a similar bleeding risk. There are usually options available for each clinical indication, but heparins are not clinically interchangeable (unit for unit) (Table 2). When choosing a heparin consider the clinical indication, patient factors (for example renal impairment), type of surgery and anaesthesia, dosing schedule, risk of heparin-induced thrombocytopenia, reversibility and cost.5 Unfractionated heparin is not recommended for prophylaxis in hip or knee arthroplasty or trauma patients.11

Table 2 Differences between heparins when used for venous thromboembolism prophylaxis5

Unfractionated heparin Enoxaparin Dalteparin Danaparoid Fondaparinux

Elimination

Liver and reticuloendothelial system

Primarily renal

Primarily renal

Renal

Renal

Dosing in renal impairment

No dosage adjustment required

Reduce dose if CrCl <30 mL/min

Unknown

Consider dose reductions if CrCl <20 mL/min

Do not use if CrCl <30 mL/min

Use cautiously if CrCl = 30–50 mL/min

Renal function testing

Not required

At baseline

At baseline

Not required

At baseline and periodically.

Discontinue in patients who develop labile renal function or severe renal impairment

Incidence of HIT

Highest incidence

Lower incidence

Lower incidence

Can be used to treat HIT

Unknown

Platelet count monitoring at baseline17

Yes. Repeat after 24 hours in patients administered UFH in past 100 days

Yes. Repeat after 24 hours in patients administered UFH in past 100 days

Yes. Repeat after 24 hours in patients administered UFH in past 100 days

Not required

Yes

Ongoing platelet count monitoring17

Every 2–4 days in postoperative and medical patients up to 14 days or until heparin is stopped (whichever is earlier)

Every week in postoperative patients up to 14 days or until heparin is stopped (whichever is earlier)

Not required in medical or obstetric patients

Every week in postoperative patients up to 14 days or until heparin is stopped (whichever is earlier)

Not required in medical or obstetric patients

Not required

When treatment ceased

Other monitoring17

Activated partial thromboplastin time testing is not required for prophylactic dosing

Assess for bleeding

Assess for bleeding

Assess for bleeding

Functional anti-factor Xa (patients with renal impairment, or those weighing more than 90 kg)

Assess for bleeding

Assess for bleeding

Approved indication for VTE prophylaxis

Prevention of VTE in surgical and high risk medical patients

Prevention of VTE in surgical patients and in medical patients bedridden due to acute illness

Prevention of VTE in surgical patients

Prevention of VTE in patients undergoing general or orthopaedic surgery

Prevention of VTE in high-risk orthopaedic surgery (hip fracture, knee or hip replacement) and abdominal surgery

Subcutaneous dose in VTE prophylaxis

5000 units 2–3 times daily depending on risk of VTE

20–40 mg once daily depending on risk of VTE

2500–5000 units once daily depending on risk of VTE

750 anti-factor Xa units twice daily

2.5 mg once daily

Use with caution in patients who weigh <50 kg

Reversibility with protamine sulfate

Complete

Incomplete, 60% reversible

Incomplete, 60–75% reversible

Non-reversible

Non-reversible

Daily cost compared to twice-daily UFH

~1.5–2 x cost

~2 x cost

~15 x cost

~4 x cost

Refer to guidelines for the preferred heparin for each clinical indication11
VTE venous thromboembolism
CrCl creatinine clearance
UFH unfractionated heparin
HIT heparin-induced thrombocytopenia

Timing and duration of heparin administration

Care should be taken to determine the optimal time for giving perioperative heparin.5 The timing depends on the type and dosing schedule of the heparin chosen and the type of procedure and anaesthesia planned. There is no advantage in starting venous thromboembolism prophylaxis preoperatively rather than postoperatively.11 In patients undergoing neurosurgery, heparin, if indicated, should never be started preoperatively. After trauma, patients should not be started on heparin until primary haemostasis is established.11

Heparin should be continued while patients remain at increased risk of developing venous thromboembolism – up to 35 days postoperatively in some orthopaedic patients.11

Patient monitoring

While routine clotting studies are not required during prophylaxis, patients need to be assessed for bleeding. Unless they are taking danaparoid, patients will need platelet counts every few days.

Bleeding

Easy bruising and petechial haemorrhages may precede frank bleeding. Nose bleeds, haematuria or melaena may be the first sign of bleeding, so check for these signs.5 Bleeding can often be controlled by stopping the heparin. In some patients protamine sulfate may be considered for heparin reversal, however it does not reverse the effects of danaparoid and fondaparinux (Table 2). Patients with bleeding should undergo fluid management and resuscitation as required.

Thrombocytopenia

Unfractionated heparin, and to a lesser extent low molecular weight heparins, may cause heparin-induced thrombocytopenia. A diagnosis of heparin-induced thrombocytopenia requires the presence of antibodies (heparin-dependent platelet antibodies) and one of the following events:17

  • unexplained platelet count fall of 30–50% from baseline
  • venous or arterial thrombosis
  • skin lesions at heparin injection sites
  • systemic anaphylactoid reactions.

Heparin-induced thrombocytopenia usually occurs 4–10 days (sometimes weeks) after starting heparin (earlier in patients exposed to heparin in the previous three months). Management requires cessation of heparin and alternative anticoagulation (danaparoid or lepirudin). Low molecular weight heparins should not be used in patients who have a history of heparin-induced thrombocytopenia with unfractionated heparin.

A milder, reversible thrombocytopenia may also develop. In these cases antibodies are not present. If the platelet count remains greater than 100 x 109 /L, heparin may be continued.17

Platelet counts should be measured intermittently in patients prescribed unfractionated heparin or low molecular weight heparins, and at baseline in patients prescribed fondaparinux, but are not required in patients prescribed danaparoid.17 Recommendations for platelet count monitoring vary depending on the type of patient and the choice of heparin (Table 2).16,17

Future directions

The forthcoming Australian guidelines will clarify the indications for thromboembolism prophylaxis,13 however practice may soon have to change. Dabigatran and rivaroxaban have recently been approved for use in Australia. As these anticoagulants can be given orally, they may supersede heparins in some indications.

Conclusion

Heparin is an effective but high-risk drug that can cause bleeding even in low doses. Safer heparin prescribing can be achieved through careful patient selection taking into consideration the clinical indication for venous thromboembolism prophylaxis, contraindications and precautions. Heparin choice should be matched to the individual patient's requirements. Patients should be monitored for bleeding while heparin administration is continued.

References

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  2. Novicoff WM, Brown TE, Cui Q, Mihalko WM, Slone HS, Saleh KJ. Mandated venous thromboembolism prophylaxis: possible adverse outcomes. J Arthroplasty 2008;23(6 Suppl 1):15-9.
  3. Patient safety clinical incident management in NSW. Analysis of first year of IIMS data. Annual Report 2005-2006. Sydney: Clinical Excellence Commission; 2006. http:// www.cec.health.nsw.gov.au/pdf/iims_data_AnnualReport.pdf [cited 2009 Jul 14]
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  5. Safe prescribing of heparins for venous thromboembolism prophylaxis. Position statement. NSW Therapeutic Advisory Group. 2008. http:// www.ciap.health.nsw.gov.au/nswtag/publications/posstats/HeparinSafety0808.pdf [cited 2009 Jul 14]
  6. Prophylaxis of venous thromboembolism. Scottish Intercollegiate Guidelines Network; 2002. Publication no. 62. http:// www.sign.ac.uk/guidelines/fulltext/62/index.html [cited 2009 Jul 14]
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  11. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6 Suppl):381S-453S.
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  13. Clinical practice guideline for the prevention of venous thrombosis (deep vein thrombosis and pulmonary embolism) in patients admitted to Australian hospitals. Draft for public consultation. National Health and Medical Research Council. 2009. http:// www.nhmrc.gov.au/nics/programs/vtp/consultation.htm [cited 2009 Jul 14]
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  15. Horlocker TT, Wedel DJ, Benzon H, Brown DL, Enneking FK, Heit JA, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003;28:172-97.
  16. Medication safety self assessment for antithrombotic therapy in Australian hospitals (MSSA-AT). NSW Therapeutic Advisory Group, Clinical Excellence Commission. 2007.
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