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Dosing Differences and Rationale Among Low Molecular Weight Heparins (LMWH)

Summary:

  • The use of low molecular weight heparins (LMWH) offer many advantages over unfractionated heparin and are thus used to prevent and/or treat a number of cardiovascular related thrombotic complications.
  • LMWH differ on their ability to pharmacologically inhibit factors Xa and IIa of the coagulation cascade and are normally reflected by their individual anti-Xa:anti-IIa ratios as designated by the World Health Organization First International Low Molecular Weight Heparin Reference Standards.
  • Due to the differences in anti-Xa:anti-IIa activity ratios between the agents, their dosing is based on international units (IU; or anti-Xa activity) or IU per kg.  This nomenclature can be confusing to some clinicians and require additional mathematical calculations to appropriately dispense and administer.
  • However, enoxaparin is able to be dosed in mg or mg per kg because of its easy conversion (1 mg inhibits 100 anti-Xa units).  So instead of the dose being 100 anti-Xa units per kg for treatment doses of enoxaparin, clinicians can use 1 mg per kg (depending on indication and renal function).  This nomenclature is easier to remember and use in clinical practice.  It is important to note that this only works for enoxaparin.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed: October 2015

Explanation

  • Low molecular weight heparins (LMWH) are used for a variety of cardiovascular conditions and offer many advantages over traditional unfractionated heparin (UFH).  The three most commonly prescribed LMWH are enoxaparin (Lovenox), dalteparin (Fragmin) and tinzaparin (Innohep) of which enoxaparin is most commonly used in clinical practice.1-3  While the ultimate choice of which LMWH to use may be influenced by the approved indication, the ease of use and dosing are also important factors in clinician acceptance.  As such, if a medication is complicated to prescribe, dispense and/or administer, then healthcare systems and clinicians are likely to perceive an increase in risk for human error.  This is especially true if a medication's dose falls outside of the normal medical nomenclature recognized by most healthcare providers and if the drug requires more than one mathematical calculation to be performed prior to dispensing and/or administration.  While LMWH do offer many benefits over UFH, their dosing can appear complicated or confusing to many clinicians. 

    The dosing of all LWMHs is based on the amount of inhibition of Xa and IIa and is commonly reported as the anti-Xa:anti-IIa activity ratio.1-4  This ratio was established by the World Health Organization First International Low Molecular Weight Heparin Reference Standards and reflects the differences between the individual LMWHs.  As such, the LMWH are not interchangeable and require significantly different doses to elicit similar effects.  Specifically, enoxaparin is dosed in milligrams (mg) or mg per kilogram (kg) while dalteparin and tinzaparin are dosed in IU (international units) or IU per kg.1-3 To further complicate the issue, the IU actually designates anti-Xa activity.  Since most medications are dosed in micrograms (mcg), mg, or mg/kg, it stands to reason that clinicians may not be as familiar or comfortable with prescribing medications that deviate from this standard.  When considering the dose or a therapeutic interchange between the LMWHs, a clinician would first have to recognize what an IU or anti-Xa activity was and then know how to use that information to possibly perform a series of calculations to determine the volume of drug to be administered.  Most clinicians recognize that any time more steps are required for the correct prescribing, dispensing and administration of a drug, the greater the chance of error. 

                              Differences in LMWH Medications

    How, then, was enoxaparin able to be marketed using mg and mg per kg dosing, which is more readily recognized by all practicing healthcare providers?       
    The answer is found in the original designation of its pharmacological activity and its ability to be easily converted to traditional nomenclature.  As noted in the table below, the concentration of enoxaparin is 10,000 IU per 1 mL.  It just so happens that 10 mg of enoxaparin inhibits 1000 IU (or anti-Xa units) and thus works out to be 1 mg of enoxaparin inhibits 100 anti-Xa units.  As such, the treatment doses for enoxaparin are essentially 100 IU or 100 anti-Xa units per kg subcutaneously every 12 hours.  This can be converted to 1 mg per kg SC every 12 hours which is much easier for the clinician to recognize, remember, prescribe and even administer.  Unfortunately, dalteparin and tinzaparin are not as easily converted to a mg strength which can be further standardized with nomenclature that most clinicians recognize.  In addition, not only does a clinician have to calculate the number of IU to give based on the patient's weight, but the clinician will still have to convert that number if IU or anti-Xa units to a specific volume of medication to administer.

    Therefore, the easy conversion and representation of the anti-Xa activity of enoxaparin works in its favor in terms of ease of prescribing, dosing, dispensing and administration.  It is of significant importance that all healthcare providers recognize that LMWH are not interchangeable and the dosing used for one LMWH is clearly not the same for other LMWH.

    References:

    1. Enoxaparin (Lovenox) product package insert.  Sanofi-Aventis LLC.  Bridgewater, NJ. 2008.
    2. Dalteparin (Fragmin) product package insert.  Pfizer Inc. New York, NY.  April 2007.
    3. Tinzaparin (Innohep) product package insert.  DuPont Pharma.  Wilmington, DE.  July 2000.
    4. Kaul S, Shah PK.  Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin.  J Am Coll Cardiol  2000;35:1699-712.

MESH Terms & Keywords

  • Low Molecular Weight Heparin, LMWH, Parenteral Anticoagulants, Enoxaparin, Lovenox, Dalteparin, Fragmin, Tinzaparin, Innohep