Enoxaparin and kidney failure

Drug Indications

Enoxaparin is a low molecular weight heparin (LMWH) that is widely used in clinical practice. The treatment indications are:

• treatment of deep vein thrombosis (DVT) in the presence or absence of pulmonary embolism;
• treatment of coronary diseases: unstable angina, non-Q myocardial infarction or STEMI;
• prophylaxis of venous thromboembolism in patients who undergo surgery and in non-surgical patients at risk of DVT;
• prevention of thrombosis during haemodialysis.

The use of low molecular weight heparins is also suggested in antithrombotic prophylaxis in patients with fibrillation or atrial flutter undergoing cardioversion, although it should be remembered that in Italy this indication is not recorded. For this reason, their use in the prophylaxis of cardioembolism is regarded as off-label, as also highlighted by the guidelines of the 2008 SISET (the Italian Society for the Study of Haemostasis and Thrombosis), and requires compliance with current legislation.¹

The characteristics of low molecular weight heparins

LMWHs are safer, more effective and easier to handle than unfractionated heparin (UFH) in the treatment of venous thromboembolism and is associated with a lower incidence of recurrence of thrombosis, bleeding or death.2 LMWHs have a predictable anticoagulant response, are given in fixed doses, based on body weight and renal function, and usually do not require monitoring.2-3 Moreover, the monitoring of the activity of LMWHs is not simple; however, the dosage of the anti-Xa activity is the most used method in scientific studies and clinical departments.^2-4
LMWHs are renally excreted drugs and do not have an effective antidote, so in patients with renal insufficiency there is a risk of overdose and subsequent bleeding.^2-3-4

Use in renal insufficiency

Numerous studies have shown that chronic renal insufficiency is very common in the population, especially in older patients.
The NHANES (National Health and Nutritional Examination Survey) analysis found that the prevalence of stage 3 and 4 chronic renal insufficiency (creatinine clearance between 15 and 59 ml/min in the population between 65 and 79 years of age) is over 20%, and is even higher in the older population.⁵
In patients with severe renal insufficiency (creatinine clearance <30 ml/min) treated with standard therapeutic doses of enoxaparin, an increase in anti-Xa activity and an increased risk of major bleeding was observed;2-6 an increase in major bleeding was also seen in patients with moderate renal insufficiency (creatinine clearance 30 to 50 ml/min)3. A linear correlation between creatinine clearance and anti-Xa activity was demonstrated after multiple days of enoxaparin at a therapeutic dose, with a significant increase in anti-Xa values in patients with creatinine clearance below 30 ml/min.⁶
A 2009 review indicates that creatinine clearance was calculated in most studies with the Cockroft-Gault formula.⁷
The authors agree that an assessment of renal function should be performed in all patients receiving therapeutic doses of LMWHs and that a reduction in enoxaparin dosage is required in patients with severe and moderate renal insufficiency; furthermore, the monitoring of the anti-Xa activity can reduce the risk of bleeding.^2-4.7
A study of 98 elderly patients with chronic renal insufficiency at Verona University Hospital showed that empiric adjustment of enoxaparin dosages is associated with a low risk of increased anti-Xa activity.4 The authors suggest a dose reduction to 150 IU/kg/day (therapeutic dose 200 IU/kg/day), divided into two administrations, in elderly patients with mild to moderate renal insufficiency (creatinine clearance 30 to 89 ml/min)4 although this is not recommended in the summary of product characteristics. It is also necessary to evaluate that a possible underdosage of the drug could reduce its effectiveness.⁷

Other recommendations from the literature

We report below other, albeit non-conclusive, recommendations taken from the literature:

• in the prophylaxis of venous thromboembolism a dosage reduction to 30 mg (3,000 IU) once daily should be made only in patients with severe renal insufficiency, whereas in mild to moderate renal insufficiency, there is no need for dose adjustments as far as enoxaparin is concerned;
• prolonged use for more than 10 days in patients with creatinine clearance of 30-60 ml/min may require antiXa activity dose;
• there are few data available on the treatment of venous thromboembolism; in patients with creatinine clearance <20 ml/min, consider the use of UFH, for which there is an effective antidote;
• for patients with creatinine clearance <30 ml/min a 1 mg/kg dose once a day for both unstable angina and venous thromboembolism. This should all be associated with careful clinical monitoring for early detection of any bleeding.