Enoxaparin‐Associated Spontaneous Retroperitoneal Hematoma in Elderly Patients with Impaired Creatinine Clearance: A Report of Two Cases

To the Editor: Enoxaparin is being increasingly used in preference to unfractionated heparin because of its ease of administration, lack of need for monitoring, higher bioavailability, and relative superiority in the management of acute coronary syndromes (ACS).1 We report two elderly patients with impaired creatinine clearance (ClCr) who spontaneously developed retroperitoneal hematomas while receiving enoxaparin therapy for ACS. We argue that this drug should be used with caution in geriatric patients with impaired ClCr and suggest treatment options based on the available medical literature. Case 1: An 86-year-old woman (weight 70 kg) being treated for acute pyelonephritis developed a non-ST-elevation myocardial infarction (NSTEMI) on the second day of her hospital stay. Her treatment regimen included enoxaparin 70 mg every 12 hours subcutaneously, metoprolol, captopril, aspirin, and nitroglycerin. Her serum creatinine was 1.9 mg/dL, with an estimated ClCr of 23 mL/min (based on Cockroft-Gault formula). On Day 4, she complained of left hip pain that did not respond to analgesics. She subsequently became hypotensive and tachycardic, and her hemoglobin decreased by 2 g/dL from the admission value. Abdominal computed tomography (CT) revealed a large left retroperitoneal hematoma. Case 2: A 76-year-old woman (weight 73 kg) was admitted for new-onset atrial fibrillation in the setting of a NSTEMI. She was treated with enoxaparin 70 mg every 12 hours subcutaneously, metoprolol, digoxin, aspirin, and nitroglycerin. Her serum creatinine was 1.5 mg/dL, with an estimated ClCr of 35 mL/min (based on Cockroft-Gault). On Day 5, the patient complained of severe right-sided flank pain. Examination disclosed ecchymotic discoloration of the right abdominal wall, and there was a significant drop (3.5 g/dL) in her hemoglobin value. Abdominal CT disclosed a large right retroperitoneal hematoma (Figure 1). Computed tomographic scan of the abdomen. Circle with number 1 illustrates a large retroperitoneal hematoma displacing the right kidney anteriorly and also involving the right psoas muscle. Platelet count, international normalized ratio, and activated partial thromboplastin time were within normal range in both cases. Both patients were resuscitated with packed red blood cells and fresh frozen plasma with subsequent clinical improvement, although both needed prolonged hospitalization for rehabilitation. Enoxaparin has a greater potential to inhibit Factor Xa than thrombin. Anti-Xa activity (0.5–1.0 U/mL) measured 4 hours after its third dose is an indicator of its therapeutic bioavailability. Enoxaparin is excreted renally, and a linear relationship exists between enoxaparin and anti-Xa activity.2 Patients with a ClCr less than 30 mL/min demonstrated a 65% increase in anti-Xa activity.2 Although recent studies1 support the use of enoxaparin in the management of ACS, it is noteworthy that these studies excluded patients with ClCr less than 30 mL/min. Yet, in clinical practice, enoxaparin therapy is being offered to many elderly subjects with ACS in whom a “normal” serum creatinine value may still represent significantly reduced ClCr. Recent medical literature suggests that impaired ClCr was the common denominator in all reported cases of spontaneous retroperitoneal hematoma associated with enoxaparin therapy.3–7 Recent studies8,9 have showed that using 65% of the recommended enoxaparin dose minimizes life-threatening hemorrhagic complications in those with ACS and severe renal impairment (ClCr<30 mL/min). Other authors believe that maintaining the anti-Xa activity in its therapeutic range would minimize enoxaparin-associated hemorrhagic complications, particularly in high-risk patients,4 but it is important to recognize that enoxaparin-associated hemorrhagic complications have been described in patients whose anti-Xa activity were within the therapeutic range.5,10 Thus, the reliability and cost-effectiveness of monitoring anti-Xa activity requires further consideration. As our cases illustrate, elderly patients receiving conventional doses (1 mg/kg every 12 hours) of enoxaparin are still at increased risk of bleeding complications. Although no definite guidelines are available for dosage adjustment of enoxaparin therapy in patients with impaired renal function, caution should be exercised in treating these subjects. We suggest that when treating geriatric patients with severe renal impairment the therapeutic dose of enoxaparin be reduced to 65% of its recommended dose to minimize life-threatening hemorrhagic complications. Also, in patients with mild (ClCr=30–50 mL/min) to moderate (ClCr=50–80 mL/min) renal dysfunction who are receiving enoxaparin therapy, careful monitoring is advised awaiting further studies to delineate the exact dose-adjustment guidelines for these patients.