Enoxaparin in Patients with Moderate Renal Impairment

Enoxaparin sodium, a heparin with a low molecular weight, allows for simplified dosing without the need for vigilant monitoring through laboratory tests. As enoxaparin relies on renal function for excretion, there may be an accumulation of enoxaparin in patients with moderate renal impairment, which may lead to an accumulation of its anticoagulant effect in patients with declining renal function. To date, however, there has been no recommended dose adjustment for these patients.

For this study [Arch Intern Med. 2012;172(22):1713-1718], investigators from the Minneapolis Veterans Affairs Health Care System conducted a review of data that compared bleeding events in patients with moderate renal impairment with those in patients with normal renal function. Normal renal function was defined as creatinine clearance (CrCl) >80 mL/min, and moderate renal impairment was defined as CrCl of 30 to 50 mL/min.

The final study population consisted of patients who received enoxaparin sodium at a therapeutic dosage of 1 mg/kg of body weight every 12 hours or 1.5 mg/kg every 24 hours. Primary outcome of the study was major bleeding, defined as any bleeding resulting in hospital admission or death, lengthened hospital stay, or an emergency department visit. The secondary outcome was any evidence of new, progressing, or recurring thromboembolism during the same period.

The investigators analyzed data for 605 enoxaparin patients whose prescriptions were dispensed between June 1 and November 30, 2009. After exclusions, 164 patients were selected for the study; 105 were considered to have normal renal function, and 59 had moderate renal impairment.

In addition to the selected differences in renal function, the group with moderate renal impairment was older (mean [SD], 76 years [9.8] vs 61 years [9.9]) and had a greater percentage with platelet counts less than 100 x 10³/µL. The normal renal function group had a greater percentage with elevated liver enzyme levels.

The mean baseline international normalized ratio was similar between the groups, as were baseline risk factors and use of bridge therapy. The mean duration of enoxaparin treatment was slightly longer in the normal renal function group (12.8 days vs 11.9 days). A greater percentage of patients with normal renal function were taking a nonsteroidal anti-inflammatory drug.

The primary outcome of major bleeding occurred in 6 of 105 patients (5.7%) with normal renal function versus 13 of 59 patients (22.0%) with moderate renal impairment. There were no deaths.

The unadjusted odds ratio (OR) for major bleeding was 4.7 (95% confidence interval [CI], 1.7-13.0; P=.002). With adjustment for differences in risk factors using multivariable logistic regression, the odds ratio was 3.9 (95% CI, 0.97-15.6). There was no recurrent thromboembolism.

Patients undergoing bridge therapy had more bleeding than patients receiving new anticoagulation therapy (13.7% vs 8.1%).  A high frequency of major bleeding (5 of 17 patients [29.4%]) was noted in patients undergoing cardiac ablation procedures receiving bridge therapy with standard doses of enoxaparin. When these procedures were excluded, the overall incidence of major bleeding remained substantial (18.9%) in the group with moderate renal impairment.

The authors said that the rate of major bleeding (OR, 4.7) in patients with moderate renal impairment, with bleeding severe enough to warrant hospital admission occurring in 1 of 7.5 patients in the group, was “disturbing.” These numbers, combined with previous evidence and knowledge of the pharmacokinetics of enoxaparin, prompted the investigators to encourage regulators, agencies, the manufacturer, and/or guideline writing organizations to consider revising dosing and/or monitoring guidelines in patients with moderate renal impairment.