Enoxaparin


Article Author:
Aamani Jupalli


Article Editor:
Arshad Muhammad Iqbal


Editors In Chief:
Evelyn Metz
Julie Sewell
Aditya Arya


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Khalid Alsayouri
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Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/18/2019 3:59:37 AM

Indications

There are two low molecular heparins available in the market: dalteparin and enoxaparin. Enoxaparin is low molecular weight heparin (LMWH) and was first approved for medical use in 1993 and is derived from heparin. It has approval for the following clinical conditions[1][2][3]:

  • Acute coronary syndromes such as ST-elevation myocardial infarction, Non-ST elevation myocardial infarction, and unstable angina
  • Deep venous thrombosis (DVT) treatment
  • Deep venous thrombosis (DVT) prophylaxis
  • Treatment for pulmonary embolism (PE)
  • Venous thromboembolism secondary to malignancy
  • Primary prevention of venous thromboembolism (VTE)
  • Treatment for prosthetic valve thrombosis in pregnancy
  • Treatment for VT in pregnancy
  • Antiphospholipid antibody syndrome
  • Arterial thromboembolism prophylaxis
  • Cerebral thromboembolism
  • Percutaneous coronary intervention (PCI)
  • Periprocedural anticoagulation

Mechanism of Action

Enoxaparin is a type of low molecular weight heparin (LMWHs) with a mean molecular weight of 4000 to 5000. It has an immediate onset of action when given in the intravenous form. It binds to and potentiates antithrombin III, a serine protease inhibitor, to form a complex that irreversibly inactivates factor Xa.[4] Enoxaparin has less activity against factor IIa (thrombin) compared to unfractionated heparin. 

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 be also be administered in intravenous formulations.[4] 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 time of 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 usual dose is 1 milligram/kilogram every 12 hr. However, dosing can be variable depending on the clinical situation. For example, in acute coronary syndrome 1 milligram/kg every 12 hr is indicated if the patient is less than 75 years of age.  But 0.75 milligrams/kg every 12 hr is the dose if the patient is 75 years of age or older.

Adverse Effects

The drug has the same side effect profile as heparin. Because of the reduced effectiveness of the antidote (eg protamine), bleeding complications can be severe and life-threatening. Following are the few side effect of enoxaparin[5][6]:

  • Bleeding; most common adverse effect 
  • Heparin-induced thrombocytopenia, though less common than conventional heparin
  • Injection site hemorrhage or pain
  • Nausea, confusion, headache 
  • Hypoaldosteronism
  • Gastrointestinal bleeding
  • Rectal sheath hematoma
  • Liver injury

Contraindications

Following are the most common contraindications:

1. Known hypersensitivity to enoxaparin (urticaria, anaphylactic reactions) or any heparin products

2. Active major bleeding such as GI bleed

3. History of heparin-induced thrombocytopenia within the past 100 days

4. Active gastric or duodenal ulcers

5. Hemorrhagic cerebrovascular accident

6. Severe uncontrolled hypertension 

7. Hepatic disease

8. Hemophilia 

9. Thrombocytopenia of less than 50 x 103

10. Caution should is necessary if the patient has a spinal catheter. Pregnant patients with mechanical heart valves, elderly patients, patients with weight less than 45 kg in a female patient or  under57 kg in male patients, acute endocarditis or acute pericarditis also require caution when administering enoxaparin.

Monitoring

Beeding:  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 responsible for the bleeding.  Bleeding is less common with enoxaparin, so factor Xa monitoring is not necessary in most cases. However, if bleeding is suspected, 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.[7] 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 more than 75 years old.

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 less than 30 mL/minute.[8]

Surgery:  According to the American College of Chest Physicians, a last pre-surgical dose of enoxaparin should be administered at least 24 hours before surgery.  Treatment can be restarted 12 hrs after surgery if indicated.

Toxicity

Clinical practice guidelines recommend protamine sulfate for the reversal of enoxaparin associated bleeds dependent on the time from last administration and dose of enoxaparin. Protamine sulfate is a cationic peptide that binds to low molecular weight heparin thereby forming an ionic complex with no anticoagulant activity.[9] The use of protamine sulfate correlates with less bleeding complications post PCI. 

As with most anticoagulants, bleeding is the most major complication with LMWHs. The incidence rate is reported to be less than 3%. Given the subcutaneous form of administration of LMWH, there is a high risk of minor bruising at the injection site. Subcutaneous injection has a bioavailability of around 100%. In the event of significant bleeding, protamine sulfate can be used to partially reverse the anticoagulant effects of LMWH. 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.[7]

Enhancing Healthcare Team Outcomes

The management of bleeding complications of enoxaparin is challenging, and it requires the inclusion of health care teams such as the physician, nurses, laboratory technician, and the pharmacist. The management should not be delayed, and intervention should take place as soon as possible. Blood bank should be contacted for possible need of 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. The anticoagulation should be stopped with the reversal of anticoagulation. Fluid resuscitation is also important if the patient is hemodynamically unstable.

If the drug is prescribed for home administration, the nurse should explain the procedure of administration. The patient should receive education to report to the emergency department is any signs or symptoms of bleeding occur.


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Enoxaparin - Questions

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For which of the following patients should the dose of enoxaparin be adjusted?



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A 62-year-old male is hospitalized with atrial fibrillation and placed on enoxaparin 30 mg IV followed by 1 mg/kg SQ every 12 hours. How should the level of anticoagulation be followed?



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A client who has just had a left hip replacement is started on the low molecular weight heparin, enoxaparin, by the physician. Which of the following are advantages of enoxaparin over unfractionated heparin? Select all that apply.



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Enoxaparin - References

References

Yamamoto S,Sakakura K,Taniguchi Y,Yamamoto K,Wada H,Momomura SI,Fujita H, Safety of Reversing Anticoagulation by Protamine Following Elective Transfemoral Percutaneous Coronary Intervention in the Drug-Eluting Stent Era. International heart journal. 2018 May 30;     [PubMed]
Velicki L,Cemerlić-Adić N,Bogdanović D,Mrdanin T, Rectus sheath haematoma: enoxaparin-related complication. Acta clinica Belgica. 2013 Mar-Apr;     [PubMed]
van Gameren M,Lemmert ME,Wilschut JM,Daemen J,De Jaegere PPT,Zijlstra F,Van Mieghem NMDA,Diletti R, An update on the use of anticoagulant therapy in ST-segment elevation myocardial infarction. Expert opinion on pharmacotherapy. 2018 Sep;     [PubMed]
Miranda S,Le Cam-Duchez V,Benichou J,Donnadieu N,Barbay V,Le Besnerais M,Delmas FX,Cuvelier A,Lévesque H,Benhamou Y,Armengol G, Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study. Thrombosis research. 2017 Jul;     [PubMed]
Xing J,Yin X,Chen D, Rivaroxaban versus enoxaparin for the prevention of recurrent venous thromboembolism in patients with cancer: A meta-analysis. Medicine. 2018 Aug;     [PubMed]
Nutescu EA,Burnett A,Fanikos J,Spinler S,Wittkowsky A, Pharmacology of anticoagulants used in the treatment of venous thromboembolism. Journal of thrombosis and thrombolysis. 2016 Jan;     [PubMed]
Levesque H,Verdier S,Cailleux N,Elie-Legrand MC,Gancel A,Basuyau JP,Borg JY,Moore N,Courtois H, Low molecular weight heparins and hypoaldosteronism. BMJ (Clinical research ed.). 1990 Jun 2;     [PubMed]
Tahaineh L,Edaily SM,Gharaibeh SF, Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clinical pharmacology : advances and applications. 2018;     [PubMed]
Ahuja T,Mousavi KM,Klejmont L,Desai S, Enoxaparin Dosing and AntiXa Monitoring in Specialty Populations: A Case Series of Renal-Impaired, Extremes of Body Weight, Pregnant, and Pediatric Patients. P     [PubMed]

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