Enoxaparin

Enoxaparin is a low molecular weight heparin made by depolymerising heparin. It inhibits factor Xa more than thrombin, has predictable subcutaneous absorption, and does not need routine laboratory monitoring. It is used to prevent and treat venous thromboembolism and in acute coronary syndromes. It accumulates in kidney impairment and is only partly reversed by protamine. It is widely available in East Africa, although cost is a barrier.

Classification. Low molecular weight heparin; indirect factor Xa inhibitor.

Mechanism. Binds antithrombin, increasing inactivation of factor Xa (anti Xa to anti IIa ratio about 3.6 to 1) and, less strongly, thrombin.

Pharmacodynamics. Peak anti Xa activity 3 to 5 hours after subcutaneous injection; duration 12 to 24 hours. Little effect on aPTT.

Pharmacokinetics. Subcutaneous bioavailability about 100%. Half life 4 to 7 hours (longer, up to 12 to 20 hours, with kidney impairment). Cleared mainly by the kidneys. Does not cross the placenta or enter milk in clinically significant amounts.

Prevention of venous thromboembolism, adult.

• Medical patients at risk: 40 mg SC once daily (20 mg if creatinine clearance is under 30 mL/min).

• General surgery at moderate risk: 20 mg SC once daily, starting 2 hours before surgery.

• High risk surgery (orthopaedic, cancer): 40 mg SC once daily starting 12 hours before surgery, continued for 7 to 10 days (28 to 35 days after hip surgery or cancer surgery).

• Trauma: 30 mg every 12 hours.

Treatment of deep vein thrombosis and pulmonary embolism, adult. 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily for at least 5 days and until the INR is 2.0 or more for 24 hours when warfarin is used; for cancer related thrombosis, 1 mg/kg every 12 hours, for 3 to 6 months.

Unstable angina and non ST elevation myocardial infarction, adult. 1 mg/kg SC every 12 hours with aspirin for 2 to 8 days (until stable).

ST elevation myocardial infarction, adult.

• Under 75 years: 30 mg IV bolus, then 1 mg/kg SC (maximum 100 mg for the first two doses) within 15 minutes, then 1 mg/kg every 12 hours.

• 75 years and over: no bolus; 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses).

• Creatinine clearance under 30 mL/min: 1 mg/kg once daily.

Pregnancy (prevention and treatment). Prevention: 40 mg once daily (adjust by weight). Treatment: 1 mg/kg every 12 hours with anti Xa monitoring.

Kidney impairment (creatinine clearance under 30 mL/min). Prevention 20 mg once daily; treatment 1 mg/kg once daily.

Children (specialist). Treatment: 1 mg/kg every 12 hours (over 2 months); prevention: 0.5 mg/kg every 12 hours; infants under 2 months: 1.5 mg/kg for treatment.

Contraindications. Active major bleeding; history of heparin induced thrombocytopenia; severe thrombocytopenia; haemorrhagic stroke; acute bacterial endocarditis; hypersensitivity (including to pork products).

Warnings. Bleeding; spinal or epidural haematoma (wait 12 hours after prophylactic doses and 24 hours after treatment doses before needle placement or removal, and 4 hours after catheter removal before the next dose); heparin induced thrombocytopenia (rarer than with unfractionated heparin); hyperkalaemia; osteoporosis in long term use; accumulation in kidney impairment, obesity (weight under 40 kg or over 150 kg) and pregnancy (use anti Xa monitoring); prosthetic mechanical valves (not adequately studied).

Adverse effects. Bleeding, injection site haematoma, thrombocytopenia, raised liver enzymes, hyperkalaemia, rarely skin necrosis or allergic reaction.

Interactions. Aspirin, clopidogrel, non steroidal anti-inflammatory drugs, warfarin, direct oral anticoagulants, thrombolytics: bleeding. Drugs raising potassium (angiotensin converting enzyme inhibitors, spironolactone): hyperkalaemia.

Reversal. Protamine sulphate 1 mg for each 1 mg of enoxaparin given within 8 hours (0.5 mg after 8 to 12 hours); the neutralisation is only about 60%.

Special groups.

• Pregnancy: first choice anticoagulant; use weight based dosing and stop 24 hours before elective delivery or neuraxial anaesthesia.

• Breastfeeding: safe.

• Patients of African ancestry: no dose change.

• Older adults: use creatinine clearance to adjust; higher bleeding risk.

• Kidney impairment: creatinine clearance under 30 mL/min: reduce the dose to 1 mg/kg once daily for treatment and 20 mg once daily for prevention, and monitor anti Xa; avoid if under 15 mL/min (use unfractionated heparin).

• Liver impairment: use with care.

Formulations. Prefilled syringes 20, 40, 60, 80, 100, 120, 150 mg; multi dose vial 300 mg/3 mL.

Administration. Deep SC injection into the abdominal wall, alternating sides; do not expel the air bubble from the prefilled syringe; do not rub. IV bolus for ST elevation myocardial infarction.

Baseline. Platelet count, haemoglobin, creatinine clearance, liver function, weight, pregnancy status.

Monitoring. Platelet count at baseline and every 2 to 3 days from days 4 to 14 (when risk of heparin induced thrombocytopenia is more than 1%). Anti Xa level 4 hours after the third dose in pregnancy, obesity, kidney impairment and children (target 0.6 to 1.0 units/mL for twice daily dosing; 1.0 to 2.0 units/mL for once daily). Creatinine at least every 3 months in long courses. Potassium.

Stopping. Stop after the planned course or when oral anticoagulation is therapeutic; no taper.

Common prescribing errors. Full dose when creatinine clearance is under 30 mL/min; not weighing the patient; giving IM; needle placement too soon after a dose; omitting platelet counts; overlap with warfarin shorter than 5 days.