UK Clinical Pharmacy Association

Dalteparin

Issues for surgery

Increased risk of venous thromboembolism if omitted.

Increased risk of bleeding if continued.

Increased risk of spinal haematoma in patients receiving neuraxial anaesthesia if continued.

Advice in the perioperative period

Elective surgery 

Check serum potassium levels and platelet count pre-operatively (see Further information).

Prophylactic doses

Last dose to be given a minimum of 12 hours prior to surgery – see below. (See also Further information.)

Timing of administration of prophylactic LMWH prior to surgery

Time of administration: Morning

Day before surgery: Administer dose as usual (to be given before 8pm)

Day of surgery: Omit morning dose

Time of administration: Evening

Day before surgery: Administer dose as usual (to be given before 8pm)

Day of surgery: N/A

Therapeutic doses

Last dose to be given a minimum of 24 hours prior to surgery – see below.

Timing of administration of therapeutic LMWH prior to surgery

Time of administration: Once daily in the morning (before 8am)

Day before surgery: Dose to be given no later than 8am

Day of surgery: Omit morning dose

Time of administration: Once daily – any other time of day (after 8am)

Day before surgery: Omit dose*

Day of surgery: Omit dose if due before surgery

* if possible (to minimise the time between last dose and operation whilst still allowing for reasonable anticoagulation coverage), consider bringing the treatment dose forward by a few hours each day over a number of days prior to surgery until patient is administering at 8am in the morning and follow advice for once daily administration in the morning (before 8am).

Time of administration: Twice daily

Day before surgery: Morning dose to be given no later than 8am. Omit evening dose.

Day of surgery: Omit morning dose.

Emergency surgery 

If there is insufficient time to follow the advice for elective surgery, and rapid reversal of the effects of LMWH are required, protamine sulfate is a specific antidote (but only partially reverses the effects) – discuss with haematologist.

Perioperative considerations

See also Further information.

Neuraxial (spinal/epidural) anaesthesia or lumbar punctures – prophylactic doses

Therapeutic anticoagulation with warfarin is an absolute contraindication to neuraxial anaesthesia. Warfarin should only be recommenced once an epidural/nerve catheter has been removed.

Insertion or removal of the catheter should be performed 12 hours after the last dose of LMWH. Once a catheter has been inserted, the next dose of LMWH should be administered a minimum of 4 hours post-insertion.

Neuraxial (spinal/epidural) anaesthesia or lumbar punctures – therapeutic doses

Insertion of the catheter should be performed 24 hours after the last dose of LMWH. The use of therapeutic LMWH whilst the catheter is in place is not recommended.

Once a catheter has been removed, LWMH administration (prophylactic and treatment doses) can resume 4 hours after removal and in the presence of adequate haemostasis.

Post-operative advice

Prophylactic doses

Commence a minimum of 2 hours post-operatively (4 hours for patients with indwelling catheters – see Perioperative considerations above) and only in the presence of adequate haemostasis. 

Treatment doses (If to be continued post-op)

Commence once adequate haemostasis has been established (except for patients with indwelling catheters – see Perioperative considerations above). Consider use of prophylactic doses of LMWH until the treatment dose can be safely resumed.

Bridging therapy

For patients normally on warfarin (or another vitamin K antagonist) follow advice as above or follow the advice provided by the pre-operative assessment team or haematology team post-operatively if appropriate.

Monitor serum potassium, especially with prolonged use (> 7 days) – see Further information.

Monitor platelet count, especially with prolonged use – see Further information.

Monitor renal function – dose adjustment may be necessary if there is a decline in renal function (consult product literature).

Interactions with common anaesthetic agents

None.

Interactions with other common medicines used in the perioperative period

Hyperkalaemia

See also Further Information.

Both LMWH and NSAIDs can increase the risk of hyperkalaemia (also see Enhanced anticoagulant effect below).

Both LMWH and trimethoprim can increase the risk of hyperkalaemia.

Enhanced anticoagulant effect

LMWH is predicted to increase the risk of bleeding events when given with NSAIDs – caution is advised, especially in those patients undergoing regional anaesthesia.

The UK manufacturer of dalteparin advises that because heparin interacts with high doses of penicillin increasing the risk of haemorrhage, an interaction with dalteparin cannot be ruled out. The clinical relevance is unclear but bear the potential interaction in mind in case of any unexpected outcome with concurrent use. This predicted interaction is not cautioned with enoxaparin or tinzaparin.

Reduced anticoagulant effect

The UK manufacturer of dalteparin advises that the anticoagulant effect might be reduced by tetracyclines (e.g. doxycycline, tigecycline). The clinical relevance is unclear but bear the potential interaction in mind in case of any unexpected outcome with concurrent use. This interaction is not cautioned with enoxaparin or tinzaparin.

The UK manufacturer of dalteparin advises that the anticoagulant effect might be reduced by cyclizine.

The UK manufacturer of enoxaparin states that systemic corticosteroids affect haemostasis, hence may reduce the anticoagulant effect. This interaction is not noted with dalteparin or tinzaparin.

Further information

Timing of pre-operative doses of prophylactic LMWH

LMWH preparations have varying licenses for surgical patients (for prophylaxis of deep-vein thrombosis (DVT)) on the timing of pre-operative doses. Depending on the LMWH and the dose, licensing varies from administration 1–2 hours pre-operatively to the evening before surgery. In practice, prophylactic doses are usually always commenced a minimum of 12 hours pre-operatively where appropriate.

Neuraxial anaesthesia

In patients undergoing epidural or spinal anaesthesia or spinal puncture, the prophylactic use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged paralysis or permanent paralysis. The risk is increased by the use of epidural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as NSAIDs and by traumatic or repeated puncture.

Treatment doses are contraindicated in patients who receive neuraxial anaesthesia due to the risk of spinal haematoma.

Thrombocytopenia and heparin-induced thrombocytopenia (HIT)

Thrombocytopenia usually occurs within 3 weeks (between 5th and 21st day) following the initiation of therapy. Signs of severe thrombocytopenia (HIT) include 30% reduction in platelet count, thrombosis or skin allergy. The risk of HIT is higher in postoperative patients, mainly after cardiac surgery, and in patients with cancer. Platelet counts should be monitored just before treatment and at regular intervals if the LMWH is continued for a prolonged period post-operatively. If HIT is suspected or confirmed, the LMWH should be stopped and an alternative anticoagulant be given – discuss with haematologist.

Hyperkalaemia

Inhibition of aldosterone secretion by LMWH can result in hyperkalaemia. Patient with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with duration of therapy (> 7 days).

Monitoring

LMWH have less effect on platelet aggregation than unfractionated heparin. They have no significant effect on blood coagulation tests such as activated partial thromboplastin time (APTT). Therapy may be monitored by measurement of plasma anti-factor Xa activity but monitoring is less frequently required than with heparin since LWMH has a more predictable effect. Routine monitoring is not usually required but may be necessary in patients at increased risk of bleeding (e.g. renal impairment, or those at extremes of body weight).

References

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 28th August 2019]

Low-molecular-weight Heparins. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 28th August 2019]

Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. British Journal of Anaesthesia. 2011; 107 (S1):i96 – i106

Summary of Product Characteristics – Fragmin® (dalteparin) 5000 IU. Pfizer Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text May 2016]

Summary of Product Characteristics – Clexane® (enoxaparin) pre-filled syringes. SANOFI. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text September 2018]

Summary of Product Characteristics – innohep® (tinzaparin) 20,000 IU/ml. Leo Laboratories Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text November 2018]

Davies G and Checketts MR. Regional anaesthesia and antithrombotic drugs. Continuing Education in Aanesthesia, Crtical Care & Pain. 2012; 12: 1

The Association of Anaesthetists of Great Britain & Ireland, The Obstetric Anaesthetists’ Association and Regional Anaesthesia UK. Regional Anaesthesia and Patients with Abnormalities of Coagulation. Anaesthesia. 2013; 68:966-72

Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 28th August 2019]