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Low-Molecular-Weight Heparins

by Diane B. Crutchfield, Pharm.D., C.G.P.

Geriatric Times January/February 2002 Vol. III Issue 1

Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1990s, their uses and indications have expanded. These agents provide advantages over unfractionated heparin (UFH), including an improved safety profile without loss of efficacy in the prevention and treatment of venous thromboembolism (VTE) (LaPointe et al., 2001). Three LMWHs are currently available in the United States: dalteparin (Fragmin), enoxaparin (Lovenox) and tinzaparin (Innohep).

Venous thromboembolism includes deep venous thrombosis (DVT) and pulmonary embolism (PE). Deep venous thrombosis is associated with more than 600,000 hospitalizations annually in the United States and results in more than 200,000 deaths caused by PEs. Both are prevalent after hip replacement or hip fracture surgery (Lopez, 2001). Risk factors that contribute to the development of either a distal or proximal DVT or PE in the long-term care resident include immobility, comorbid medical conditions, hip replacement surgery and falls resulting in the need for hip fracture surgery, among others.

In addition to their use for VTE, dalteparin and enoxaparin have been approved for treatment of acute coronary syndrome; enoxaparin has additional indications for use in the medically ill and for outpatient treatment of DVT. Each agent has specific indications approved by the U.S. Food and Drug Administration for use in prophylaxis and in treatment (Table 1).

Prophylaxis and Treatment

The prevalence of VTE in hospitalized patients and the resultant morbidity and potential mortality indicate the need for treatment prophylaxis. However, as pointed out in the sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy (Geerts et al., 2001), few patients receive prophylaxis despite the presence of risk factors without contraindications. Reasons for the lack of prophylaxis include: physicians believe the actual incidence of VTE among hospitalized patients is low; concern about bleeding complications resulting from the use of anticoagulants; and physician perception that the occurrence of VTE in their patient population is rare. General recommendations from the ACCP consensus conference included the development of a strategy for thromboprophylaxis for high-risk groups in all hospitals. Recommendations also included the use of LMWHs, in addition to low-dose UFH and/or warfarin (Coumadin).

Recommendations for acute treatment of DVT or PE include the use of LMWH, intravenous UFH or dose-adjusted subcutaneous heparin, with preference given to the use of LMWH. Treatment and dosage recommendations for all indications are summarized in Table 2. For most patients, heparin (UFH or LMWH) treatment should be continued for five days and oral anticoagulation should overlap for at least four to five days. Heparin and oral therapy can be started together and the heparin discontinued on day 5 or 6 if the international normalized ratio (INR) has been therapeutic for two consecutive days (Hyers et al., 1998).

Heparin is an effective antithrombotic agent for the treatment of PE and DVT, but it requires careful monitoring and dose adjustment. Standard heparin has a molecular weight that ranges from 5,000 daltons to 30,000 daltons (Hyers et al., 1998). The LMWHs are fragments of unfractionated heparin that are produced by either chemical or enzymatic depolymerization and have molecular weights from 1,000 daltons to 10,000 daltons (Rydberg et al., 1999).

Both UFH and LMWHs inactivate factor Xa by interacting with antithrombin. The UFH inactivates factors IIa and Xa, while LMWHs exert their anticoagulant effect by inhibiting factor Xa, but minimally affect thrombin (factor IIa). As a result, the activated partial thromboplastin time (aPTT), a measure of antithrombin (anti-factor IIa) activity, is not used to measure the activity of LMWH, which requires a specific anti-Xa assay (Yeager and Matheny, 1999).

The LMWHs have a much more predictable anticoagulant response, and routine monitoring is not needed. Monitoring is recommended for specific settings, including renal insufficiency; obesity; pediatric patients; and patients on prolonged therapy for pregnancy, malignancy or antiphospholipid antibody syndrome. The chromogenic anti-factor Xa method is recommended for determining the plasma concentration of LMWH. The acceptable range for twice-daily treatment of venous thromboembolism is 0.6 U/mL to 1.0 U/mL, with samples taken four hours after administration (Hassett, 1999).

Because of the risk of thrombocytopenia, platelet counts should be checked periodically and the LMWH discontinued if the platelet count falls below 100,000/mm3. Hematocrit, hemoglobin and stool for occult blood should also be monitored.

Drug interactions that should be monitored closely include the concurrent use of any agent that increases the risk of bleeding, such as oral anticoagulants, platelet inhibitors and thrombolytics.

Advantages of LMWH





Warnings

Because of the differences between agents, therapeutic interchange (unit for unit) is not recommended. The FDA has indicated that LMWHs should not be considered interchangeable for treatment or prevention of VTE (Lopez, 2001).

Low-molecular-weight herapins should not be used in patients with active bleeding or in patients with a history of heparin-induced thrombocytopenia. As with other anticoagulants, the risk of hemorrhage must be considered. Included in class labeling for LMWHs is a warning regarding the potential for occurrence of spinal or epidural hematomas, with an increased risk with the use of post-operative indwelling epidural catheters or with the concomitant use of additional drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs.

Pharmacoeconomics

Groce and Cooper (2001) pointed out that although the cost of LMWHs ranges from 10 to 20 times the cost of UFH, outpatient-based protocols have been used in clinical trials with cost-savings noted. A comparison of the use of enoxaparin in a long-term care facility (LTCF) compared to UFH to treat proximal DVT in a hospital setting demonstrated significant cost-savings for treatment in the LTCF. The LTCF cost was $1,421 less than UFH in the hospital (Witter et al., 2000).

The cost of these agents definitely poses a challenge for the skilled nursing facility on a prospective-payment reimbursement system. Health care providers must consider the overall health care cost-savings that can be realized by keeping a resident in the facility for treatment versus transferring them to an acute care setting for an indefinite period of time. Cost-savings related to a reduction in nursing time for administration of a subcutaneous dosage form, drug monitoring and dose adjustments, as well as a reduced risk of adverse drug reactions with LMWHs should also be considered in choosing an LMWH versus UFH.

Quality of life issues also affect a treatment decision. For example, most LTCF residents lose weight when hospitalized and are more prone to skin breakdown. Many experience an increase in confusion in the hospital as well. Therefore, it is beneficial to have the option of treating residents in the facility whenever possible.

Education and Safety

The Institute for Safe Medication Practices (2001) published an alert related to the use of LMWH. Three deaths were reported that resulted from the use of duplicate anticoagulant therapy. Two cases involved use of an LMWH in addition to UFH and one case of warfarin added to enoxaparin. Several communication errors occurred that contributed to these fatal outcomes. Errors can also lead to serious outcomes in the LTCF if care is not taken to educate staff and clarify all orders.

Nursing staff, as well as physicians, should be aware of the importance of not interchanging medications. Another concern in this setting is the commonly used physician order to continue previous medications when a resident returns to the LTCF from the hospital. Previous medications may include anticoagulants. Anticoagulant monitoring services available in the hospital setting are frequently not in place in LTCFs, although orders are received to continue the LMWH based on warfarin INR values. Clarification of these orders is necessary to avoid prolonged therapy and to avoid extended lengths of therapy.

Two new strengths of enoxaparin prefilled, graduated syringes will allow a reduction in volume of injection and simplify drug delivery in patients who require weight-based dosing. The 150 mg/mL concentration is available in 120 mg and 150 mg doses. Available dosage forms of the LMWHs are listed in Table 3.

Proper use of the LMWHs will provide improved quality of life for residents of LTCFs. This requires knowledge of proper administrtion techniques, dosing and duration of therapy, and monitoring to avoid potential errors and to maximize the benefits of this medication class.



Dr. Crutchfield is president of Pharmacy Consulting Care, an independent consultant pharmacy practice located in Knoxville, Tenn.


References

Geerts WH, Heit JA, Clagett GP et al. (2001), Prevention of venous thromboembolism. Chest 119 (1 suppl):132S-175S.

Groce J, Cooper JW JR (2001), The pharmacoeconomics of low-molecular-weight heparins: getting the most bang for the health care buck. The Consultant Pharmacist 16(suppl D):18-22.

Hassett AC (1999), Laboratory monitoring of anticoagulant therapy. Transfusion medicine update. Available at: www.itxm.org/TMU1998/tmu2-99.htm. Accessed Dec. 5, 2001.

Hyers TM, Agnelli G, Hull RD et al. (1998), Antithrombotic therapy for venous thromboembolic disease. Chest 114(5 suppl): 561S-578S.

Institute for Safe Medication Practices (2001), Hazard alert! Action needed to avert fatal errors from concomitant use of heparin products. ISMP Medication Safety Alert. Available at: www.ismp.org/MSAarticles/HeparinAlert.html. Accessed Nov. 23.

LaPointe KJ, Cappuzzo KA, Hamilton CW (2001), Low-molecular-weight heparins for deep vein thrombosis. U.S. Pharmacist HS3-HS23.

Levien TL, Baker DE (1999), Enoxaparin (Lovenox) treatment of DVT and PE. Online Pharmacists Letter. Detail number 150204.

Lopez LM (2001), Low-molecular-weight heparins are essentially the same for treatment and prevention of venous thromboembolism. Pharmacotherapy 21(6 pt 2):56S-61S, discussion 715-725.

Rydberg EJ, Westfall JM, Nicholas RA (1999), Low-molecular-weight heparin in preventing and treating DVT. Available at: www.aafp.org/afp/990315ap/1607.html. Accessed Nov. 23, 2001.

Witter MD, Gupchup GV, Dole EJ et al. (2000), Pharmacoeconomic assessment of enoxaparin in the skilled ward of a long-term care facility versus unfractionated heparin the hospital for treatment of proximal deep vein thrombosis. The Consultant Pharmacist 15(2):151-159.

Yeager BF, Matheny SC (1999), Low-molecular-weight heparin in outpatient treatment of DVT. Am Fam Physician Available at: www.aafp.org/afp/990215ap/945.html. Accessed Nov. 23, 2001.