Enoxaparin

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Enoxaparin is low molecular weight heparin (LMWH) and was first approved for medical use in 1993 and is derived from heparin. It has FDA approval for the following clinical conditions - acute coronary syndromes, deep venous thrombosis (DVT) treatment and prophylaxis, treatment for pulmonary embolism (PE), venous thromboembolism (VTE) treatment, and prophylaxis in a variety of scenarios, percutaneous coronary intervention (PCI), and periprocedural anticoagulation, among others. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of enoxaparin, pertinent for interprofessional team members in treating patients with conditions where this agent is indicated.

Objectives:

  • Describe the therapeutic mechanism of action of enoxaparin.
  • Review the many indications for enoxaparin use.
  • Summarize the adverse event profile of enoxaparin use.
  • Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using enoxaparin.

Indications

Two low molecular heparins are available in the United States: dalteparin and enoxaparin. Enoxaparin is low molecular weight heparin (LMWH) and was first approved for medical use in 1993 and is derived from heparin.

FDA-approved Indications

  • Prophylaxis of deep vein thrombosis (DVT) in hip replacement surgery, abdominal surgery, knee replacement surgery, or medical patients with severely limited mobility during acute illness[1][2]
  • Inpatient management of acute deep vein thrombosis with or without pulmonary embolism[3]
  • Outpatient management of acute deep vein thrombosis without pulmonary embolism[4]
  • Prophylaxis of ischemic complications of Non-ST-elevation myocardial infarction (NSTEMI) and unstable angina[5]
  • Treatment of acute ST-segment elevation myocardial infarction managed medically or with the subsequent percutaneous coronary intervention[6]

Off-label Use

  • Primary prevention of venous thromboembolism (VTE)
  • Treatment for prosthetic valve thrombosis in pregnancy
  • Treatment for VTE in pregnancy[7]
  • Antiphospholipid antibody syndrome
  • Arterial thromboembolism prophylaxis
  • Cerebral thromboembolism
  • Periprocedural anticoagulation[8]
  • Venous thromboembolism secondary to malignancy[9]

Mechanism of Action

Enoxaparin is low molecular weight heparin (LMWH) with a mean molecular weight of 4000 to 5000 Daltons. It has a quick onset of action when given in the intravenous form. Enoxaparin is an indirect anticoagulant that binds and potentiates antithrombin III (serine protease inhibitor) through a specific pentasaccharide sequence to form a complex that irreversibly inactivates factor Xa. The primary difference between unfractionated heparin and enoxaparin is their relative inhibition of thrombin (factor-IIa) and factor-Xa. Smaller heparin fragments cannot bind antithrombin and thrombin simultaneously. Due to their smaller chain length and lower molecular weight, LMWH has better activity against factor-Xa and inhibits thrombin to a lesser degree. Thus, enoxaparin has less activity against factor IIa (thrombin) than unfractionated heparin. The anti-factor Xa-to-IIa activity ratio for the LMWHs varies from 2:1 to 4:1.[10]

Pharmacokinetics

Absorption: Peak effect of enoxaparin is observed approximately 4 hours after administration. Anti-Factor Xa activity is detected in plasma for about 12 hours.[11]

Distribution:  The apparent volume of distribution of enoxaparin estimated by anti-Factor-Xa activity is approximately 4.3 Liters.

Metabolism: It is metabolized in the liver by desulfation and depolymerization to lower molecular weight fragments with reduced biologic activity.

Excretion: Enoxaparin follows first-order kinetics and is eliminated primarily in the urine. The elimination half-life of enoxaparin is approximately 3 to 4.5 hours following a single dose. Following repeated doses, the half-life of enoxaparin increases to approximately 7 hours. As enoxaparin is primarily eliminated by renal excretion, there is a concern for drug accumulation and bleeding risk in patients with renal impairment.[10][12]

Administration

Enoxaparin has an advantage over heparin because of its bioavailability. Ninety percent of the drug is available when given in the subcutaneous form. Enoxaparin can also be administered in intravenous formulations.[10] The intravenous formulation should not be mixed or co-administered with other medications. The port should be flushed before use with normal saline or 5% dextrose water. An IV injection is usually given during the primary PCI and at the time of STEMI. Subcutaneous administration should alternate between the left or right anterolateral and left or right posterolateral abdominal wall. There is a small risk of bruising that can be minimized by not rubbing the injection site. There is no topical form available. Intramuscular administration is generally avoided. One mg of enoxaparin is equal to 100 units of anti-Xa activity. The dose of enoxaparin depends upon indications, adverse events profile, and renal/hepatic impairment. 

Venous Thromboembolism Prophylaxis: Recommended dose of enoxaparin is 40 mg SC once daily, according to the ACCP(American College of Chest Physicians) clinical practice guidelines.[13]

Treatment of Acute Deep Vein Thrombosis with or without Pulmonary Embolism: The recommended dose of enoxaparin is 1 mg/kg SC every 12 hours or 1.5 mg/kg SC daily. Anticoagulation should be started immediately in the case of suspected or proven pulmonary embolism. Patients with pulmonary embolism usually require inpatient therapy, according to the PERT Consortium.[14][15]

STEMI: According to the ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines for ST-elevation myocardial infarction (STEMI), in patients treated with fibrinolytic therapy, doses are suggested according to age and renal function. If the age of patients <75 years, 30 mg IV bolus, followed in 15 minutes by 1 mg/kg SC every 12 hours, is recommended. If the age is ≥75 years, no IV bolus is recommended, and  0.75 mg/kg subcutaneously every 12 h (maximum 75 mg for the first two doses) is administered. For creatinine clearance is <30 mL/min, 1 mg/kg subcutaneously every 24 hours is recommended regardless of age.[16]

NSTEMI: The suggested dose of enoxaparin in Non-ST-elevation myocardial infarction is 1 mg/kg SC every 12 hours. Guidelines suggest decreasing the dose of enoxaparin to 1 mg/kg SC once daily in patients with creatinine clearance <30 mL/min. Enoxaparin is continued for the duration of hospitalization or until percutaneous coronary intervention.[17]

Use in Specific Patient Populations

Patients with Hepatic Impairment: A clinical trial demonstrated that enoxaparin decreased the rate of portal vein thrombosis and hepatic decompensation and increased the probability of survival by preventing microvascular thrombosis in patients with cirrhosis. An increased risk of bleeding on anticoagulation therapy is seen in patients with liver cirrhosis due to disequilibrium between procoagulant and anticoagulant states. In addition, older age, increased INR, female sex, prior history of bleeding, hypertension, peptic ulcer disease, active cancer, hypertension, prior stroke, renal impairment, and alcohol abuse augments the risk of bleeding in patients with cirrhosis. In liver cirrhosis, enoxaparin can increase the risk of bleeding; caution is required before initiating enoxaparin.[18] 

Patients with Renal Impairment: In patients with renal impairment, increased bleeding tendency is seen due to increased exposure to enoxaparin. Dose adjustment of enoxaparin is recommended in patients with severe renal impairment (creatinine clearance <30 mL/min), with 1 mg/kg once daily and simultaneous monitoring of factor anti-Xa activity. Usually, no dose adjustment is required if creatinine clearance is >30 mL/min.[19]

Pregnancy Considerations: Pregnant women have a significantly increased risk of thromboembolism than nonpregnant women. Venous thromboembolism (VTE) is the major cause of maternal mortality in the United States. Enoxaparin doesn't cross the placenta and is considered safe in pregnancy. According to ACOG (American College of Obstetricians & Gynecologists) guidelines, enoxaparin, 40 mg SC once daily, is recommended for VTE prophylaxis. Therapeutic anticoagulation with enoxaparin, 1 mg/kg every 12 hours, is recommended for women with acute thromboembolism during the current pregnancy and women with a history of recurrent thrombosis.[7]

Breastfeeding Considerations: Available evidence suggests that maternal enoxaparin in doses up to 40 mg daily does not cause adverse drug reactions in breastfed infants. Enoxaparin has a high molecular weight and is not expected to be excreted into breast milk or absorbed from the infant's gastrointestinal tract. Therefore, no special precautions are required.[20]

COVID-19 Considerations: In 2022, the American Society of Hematology (ASH) guidelines advised using prophylactic intensity over therapeutic-intensity anticoagulation for patients with critical illness due to COVID-19 (who do not have suspected or confirmed venous thromboembolism). The guidelines suggested that higher intensity anticoagulation may be reasonable for patients evaluated to be at low bleeding risk and high thrombotic risk.[21]

Adverse Effects

Enoxaparin has a similar adverse effect profile as heparin. Because of the reduced effectiveness of the antidote (e.g., protamine), bleeding complications can be severe and life-threatening. Following are the important adverse drug reactions of enoxaparin.

  • Bleeding: the most common adverse effect
  • Heparin-induced thrombocytopenia[22]
  • Injection site bleeding or pain
  • Nausea, confusion, headache 
  • Hypoaldosteronism
  • Gastrointestinal bleeding
  • Rectal sheath hematoma[23]
  • Osteoporosis[24]
  • Hepatotoxicity: transaminitis with the hepatocellular injury pattern (unlikely to cause clinically apparent liver injury)[25]
  • Bullous hemorrhagic dermatitis[26]

Contraindications

  • Known hypersensitivity to enoxaparin (urticaria, anaphylactoid reactions, anaphylaxis) or any heparin products[27][28]
  • Active major bleeding such as gastrointestinal bleed
  • History of heparin-induced thrombocytopenia within the past 100 days or presence of circulating antibodies[29]
  • History of hypersensitivity to benzyl alcohol in neonates (benzyl alcohol is present in the multiple-dose formulation of enoxaparin)[30]

Warning and Precautions

  • Active gastric or duodenal ulcers[31]
  • Hemorrhagic cerebrovascular accident
  • Severe uncontrolled hypertension 
  • Hemophilia 
  • Thrombocytopenia
  • Increased risk of bleeding following the percutaneous coronary intervention[32]
  • Pregnant patients with mechanical heart valves[33]
  • Elderly patients due to increased risk of bleeding[34]
  • Patients with extremes of body weight (obesity or low body weight)[35][36][37]

Boxed Warning (FDA)

There is an increased risk of epidural and spinal hematoma in patients anticoagulated with low molecular weight heparins (LMWH), including enoxaparin, in patients who are administered neuraxial anesthesia or undergoing spinal puncture.[38] These hematomas may lead to permanent paralysis. Factors increasing the risk of developing epidural or spinal hematomas include indwelling epidural catheters, advanced age, renal failure, and concurrent use of drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs, platelet inhibitors, and other anticoagulants. In addition, prior history of traumatic or repeated epidural or spinal puncture and spinal deformities can increase the risk of developing spinal surgery. Therefore, the placement or removal of a spinal catheter should be deferred for at least 12 hours after administering prophylactic doses of enoxaparin. Longer delays (24 hours) are suggested for patients administered higher therapeutic doses of enoxaparin (dose of enoxaparin 1.5 mg/kg once daily or 1 mg/kg twice daily). A postprocedure dose of enoxaparin should be given four hours after catheter removal.[39][40][41]

Monitoring

Bleeding

The patient should be monitored closely for signs and symptoms of bleeding. Advanced age, female sex, and concomitant use of antiplatelet drugs are the most common risk factors for bleeding. Bleeding is less common with enoxaparin, so monitoring factor Xa is unnecessary in most cases. If bleeding is suspected, an anti-factor Xa level can be measured to adjust the dose accordingly, but it does not correlate with an impact on clinical outcome. Renal failure and obesity are the most common indication to monitor enoxaparin as it increases the chances of bleeding.[42]

Enoxaparin has a good safety and side effect profile. Dose adjustment is necessary for advanced age and renal insufficiency. A therapeutic dose is usually 1 mg/kg every 12 hours, but dose adjustment is required if the patient is over 75 years old. ACCP guidelines suggest that the anti-Xa levels should be measured 4 hours after enoxaparin administration at a steady state.[43]

Thrombocytopenia

Thrombocytopenia can occur, but it is less common than conventional heparin. If the patient develops heparin-induced thrombocytopenia (HIT), the drug should be discontinued, and the platelet count monitored.

Renal impairment

Enoxaparin dose requires adjustment with a creatinine clearance of less than 30 mL/minute.[44]

Surgery

According to the American College of Chest Physicians, a last presurgical dose of enoxaparin should be administered at least 24 hours before surgery. Treatment can be restarted 12 hours after surgery if indicated.[8]

Toxicity

Clinical practice guidelines recommend protamine sulfate for the reversal of enoxaparin-associated bleeds dependent on the time from the last administration and dose of enoxaparin. Protamine sulfate is a cationic peptide that binds to low molecular weight heparin, forming an ionic complex with no anticoagulant activity.[45] The use of protamine sulfate correlates with fewer bleeding complications post PCI. 

As with most anticoagulants, bleeding is the major complication with low molecular weight heparin-like enoxaparin. The incidence rate is reported to be less than 3%. Given the subcutaneous administration of LMWH, there is a high risk of minor bruising at the injection site. The subcutaneous injection has a bioavailability of around 100%. In the event of significant bleeding, protamine sulfate can be used to reverse the anticoagulant effects of LMWH partially. Protamine neutralizes about 60% of LMWH anticoagulant activity. For LMWH administered within the previous 8 hours, the recommended dose is 1mg protamine sulfate per 1mg of enoxaparin or 100 anti-factor-Xa units of dalteparin.[42] 

According to the ACCP guidelines, the maximum single dose of protamine sulfate is 50 mg. If bleeding persists, a second dose of 50 mg protamine sulfate can be administered. Smaller doses of protamine sulfate can be administered if the time since LMWH administration is greater than 8 hours.[43] Universal Heparin Reversal Agent (UHRA) is specifically invented to neutralize the activity of heparin-based anticoagulants. UHRA is a synthetic multivalent polymer that is currently in clinical trials. The preliminary results are promising, showing that UHRA directly binds UFH and enoxaparin and can reverse the activity of heparin and enoxaparin.[46]

Heparin-induced thrombocytopenia is an infrequent but potentially life-threatening complication of enoxaparin therapy. The development of antibodies against heparin-bound platelet factor 4 (PF4) generally occurs 5–10 days after administration. The antibody-heparin-PF4 complex binds and activates platelets resulting in thrombosis and thrombocytopenia. 4T score (thrombocytopenia, timing of platelet count fall, thrombosis, other causes of thrombocytopenia), serotonin release assay, and anti-PF4/heparin antibodies are used for diagnosis.[47][48] Argatroban and lepirudin direct thrombin inhibitors are FDA-approved for the treatment of HIT.[49] Argatroban therapy decreased amputation, thrombotic complications, and mortality in clinical trials. Bivalirudin is used for patients undergoing percutaneous cardiac intervention having HIT or at risk for developing HIT. (American society of hematology)[22]

Enhancing Healthcare Team Outcomes

Managing bleeding complications of enoxaparin is challenging. It requires collaboration between interprofessional health care team members such as clinicians (MD, DO, NP, PA), specialists, nurses, laboratory technicians, and pharmacists. The management of bleeding should not be delayed, and intervention should ensue as soon as possible. A blood bank should be contacted for the potential need for an urgent transfusion. As discussed above, protamine sulfate is the drug of choice in this situation. A conservative approach is necessary for the consideration of acute bleeding. Anticoagulation should be stopped with the reversal of anticoagulation. Fluid resuscitation is also essential if the patient is hemodynamically unstable.

The nurse should explain the procedure to the patient if the clinician prescribes enoxaparin for home administration. The pharmacist should consult with the prescriber regarding dosing; this should be with the initial prescription of enoxaparin and protamine in the event of reversal. The patient should receive education to report to the emergency department if any signs or symptoms of bleeding occur. Interprofessional collaboration is vital to improving patient outcomes related to enoxaparin therapy. All team members must maintain open communication with the rest of the care team and keep accurate records regarding enoxaparin therapy. The study reported a significant decrease in venous thromboembolism in hospitalized patients with an interprofessional team of hospitalists, intensivists, vascular, trauma, orthopedic surgeons, nurses, an inpatient pharmacy director, and a clinical pharmacist.[50] [Level 5]

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Author

Aamani Jupalli

Editor:

Arshad Muhammad Iqbal

Updated:

8/28/2023 10:12:06 PM

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