Deep vein thrombosis (DVT) and pulmonary embolism (PE) are costly and common problems in the United States. The clinical consequences of DVT include fatal PE, thromboembolic pulmonary hypertension, varicosities, venous stasis changes, venous claudication, and recurrent DVT.1 It is estimated that each year, DVT affects 2 million Americans, and PE affects 600,000, with approximately 10% of those dying from this complication.2-4 Patients with thrombophilic risk factors (e.g, protein C or S deficiency, antithrombin III deficiency, antiphospholipid antibody syndrome, Leiden Factor V) and symptoms are at risk for recurrent DVTs and/or PEs. The primary goal of DVT treatment is to prevent the development of associated complications.
Traditional treatment of proximal DVT is administering unfractionated heparin (UFH) for 5 to 7 days with concomitant oral anticoagulation (warfarin) therapy. Daily International Normalized Ratio (INR) levels are drawn until therapeutic, at which time the heparin is discontinued. The patient must then remain on oral anticoagulation therapy for 3 to 6 months.2 UFH requires hospitalization for continuous intravenous infusion and requires close laboratory monitoring by the activated partial thromboplastin time (aPTT) test. When the aPTT is maintained at a therapeutic level, PE is usually no longer a risk, but when the aPTT is subtherapeutic or widely fluctuating, the risk for PE increases. The intensity of both initial heparin therapy and long-term warfarin therapy must be sufficient to prevent the recurrence of DVT. Both UFH and low molecular weight heparins (LMWH), when used in therapeutic doses, are 95% effective, and recurrence of DVT is unlikely. However, in patients who receive inadequate initial or long-term anticoagulant therapy, the risk of recurrent DVT increases by 20% to 50%.1,5 The risk of major bleeding from both UFH and LMWH is approximately 1% to 3% per year, and the risk of major bleeding from warfarin therapy is 1% to 2% per year.3
LMWH has already replaced UFH for many indications in Europe and Canada and is likely to become the new standard of treatment for DVT and PE in the United States as well.6 LMWH has been demonstrated to be comparable to UFH while overcoming many of its limitations. Studies indicate that LMWH is at least as safe as UFH with regard to major bleeding complications, and appears to be as effective as UFH in preventing thromboembolic recurrences.7,8
As with UFH, LMWH is administered for the first 5 to 7 days of treatment with concomitant oral anticoagulation therapy. The patient must have daily INR levels taken until therapeutic, at which time the LMWH is discontinued and the patient is maintained on oral anticoagulation for 3 to 6 months. The advantages of LMWH over UFH are that dosages are determined by body weight, administered once or twice daily by subcutaneous (SC) injection, achieve sustained effects without the need for laboratory monitoring or dosage adjustment, and can be administered in the outpatient setting.
Studies have shown that 37% to 80% of patients with proximal DVT can be managed safely and cost-effectively at home with LMWH, thereby decreasing the risk of nosocomial infection and other hospital hazards.5,9-13 Using LMWH could save an average of 5 to 6 hospital days for each patient treated, and could save $250 million annually in the United States.14
To appreciate the advantages of LMWH, a review of the pharmacokinetic limitations of UFH is helpful for comparison. UFH has a mean molecular weight of 15,000 daltons and an anti-factor Xa to anti-factor IIa ratio of 1:1.14 It inhibits thrombin and other serine proteases by binding to antithrombin III. The heparin-antithrombin complex exerts its major impact on factor Ua (thrombin) and factor Xa, which are neutralized equally. It has a short half-life of approximately 1 to 2 hours, which is why it must be administered by continuous intravenous infusion. Clearance does not appear to be affected by hepatic or renal disease.14
A significant disadvantage of UFH is its nonspecific binding to plasma proteins, platelets, and vascular endothelial cells. The bound heparin molecules become inactive, resulting in decreased bioavailability, marked variability in anticoagulant response, and a short plasma half-life. The nonspecific binding also explains the very high heparin requirements in some patients who demonstrate heparin resistance. Because of these limitations, the aPTT must be frequently measured and dosage adjustments made accordingly.2,14-16
The aPTT assay for monitoring heparin is sometimes an unreliable measure because it can be affected by many factors such as (1) varying responsiveness of different commercial aPTT reagents; (2) varying responsiveness between batches of the same commercial aPTT reagent; (3) the type of clot detection system used; and (4) elevated levels of factor VIII which can reduce the aPTT to heparin ratio.15
Another limitation of UFH is its affinity to bind to platelets. The immune-mediated form of heparin induced thrombocytopenia (HIT) is caused by an antibody to heparin and platelet factor 4 (PF4) complexes, which cause thrombocytopenia and endothelial injury. The clinical sequelae of HIT can result in devastating thrombotic complications.15 HIT has been reported with LMWH, but occurs less frequently than with the conventional UFH.
LMWHs demonstrate reduced activation of platelets and a lower affinity for PF4, which results in less neutralization of the anticoagulant effects of heparin. They do not increase microvascular permeability and are less likely to interfere with the interaction between platelets and vessel walls than UFH, resulting in lower incidences of bleeding.20 LMWH is cleared principally by the renal route, and the biologic half-life is increased in patients with renal failure.16
Other advantages of LMWH include a longer half-life and better subcutaneous absorption. These characteristics result in LMWH producing consistent effects when given subcutaneously, allowing them to be administered without laboratory monitoring.2'17"20 The improved absorption, predictable response, and consistent effects of LMWH provide more rapid protection against PE than UFH, as they eliminate the concerns ofsubtherapeutic aPTT levels, frequent dosage adjustments, and intense monitoring.
LMWHs are fragments of commercial grade standard heparin produced by either chemical or enzymatic depolymerization. They have different mean molecular weights that vary from 4,000 to 6,500 daltons.16 LMWH inhibits thrombin generation by blocking the conversion of factor X to its activated form. The pharmacokinetic advantages of LMWH include (1) greater bioavailability; (2) dose-independent clearance; (3) decreased affinity for binding to plasma proteins and vascular endothelial cells; and (4) a higher anti-factor Xa to anti-factor Ua ratio (which ranges between two and four depending on the formulation). These advantages make the anticoagulant response of LMWH more predictable than UFH.15
Commercially available LMWHs are made by different processes and differ both chemically and pharmacokinetically, which may result in differences in the anticoagulant effect. Each LMWH must be administered according to the recommendations specific to the particular preparation.18,21,23
The most commonly used LMWHs in the United States are enoxaparin sodium (Loyenox), tinzaparin sodium (Innohep), and dalteparin sodium (Fragmin). Enoxaparin has FDA approval for both treatment and prophylaxis of DVT, tinzaparin has FDA approval for DVT treatment only, and dalteparin has PDA approval for only DVT prophylaxis. The "off-label" use of dalteparin for outpatient DVT treatment is supported by published data,24-27 and authorities agree on the appropriateness of its use for this indication.17
* Economic Impact
Treatment of proximal DVT with LMWH has demonstrated decreased costs without compromising clinical outcomes or quality of life (QOL).2'17 A study by Hull et al5 reported a cost savings of $40,149 (U.S.) per 100 hospitalized patients with proximal DVT when using LMWH. The investigators also purported that if 37% of the study patients were treated at home, the total cost savings would increase from $40,149 to $91,332.
O'Brien et al28 performed an economic evaluation of outpatient treatment with LMWH for proximal vein thrombosis and found that costs (expressed in Canadian dollars) and lost productivity were significantly lower with LMWH than with the UFH group. Patients assigned to UFH spent an average of 6.7 days in the hospital compared to 0.9 days for persons assigned to LMWH. Patients receiving UFH had a mean of 6.79 days of lost productivity versus 3.14 days for patients receiving LMWH. Overall, the total cost per patient randomized to UFH was $5,323 versus $2,278 for LMWH, a societal cost savings per patient using LMWH of $3,045. The study concluded that outpatient treatment of proximal DVT with the use of LMWH reduced costs with no compromise in clinical efficacy or patient QOL except in the domain of social functioning, which favored the LMWH group.
* Outpatient Treatment of Proximal DVT With LMWH
The decision to treat a patient with DVT in the outpatient setting is made by the primary care provider. When the patient arrives at the emergency room (ER), the primary care provider can evaluate and discharge the patient, or the patient can be admitted over night and considered for outpatient treatment the following day.
Successful outpatient treatment of proximal DVT is dependent on a carefully designed treatment plan (see Tables: "Exclusion Criteria" and "Outpatient DVT Treatment Plan"). This treatment plan should include (1) careful patient selection and clear exclusion criteria; (2) coordination of services; (3) ability to provide close monitoring; (4) thorough patient and caregiver education; (5) daily patient contact; (6) laboratory monitoring; (7) drug administration; (8) ability of patient to obtain medication; and (9) careful and complete documentation.6,17
The patient or caregiver can be instructed on the administration of LMWH. If the patient is unable to self-inject, arrangements can be made for the LMWH to be administered in the health care provider's office, anticoagulation management service, clinic, or by a visiting nurse.
* Patient and Caregiver Education
Patient and caregiver education is the cornerstone of successful outpatient DVT therapy (see Table: "Patient and Caregiver Information"). Education should be reinforced with printed literature at a reading level and language appropriate for each individual patient. Education should also be reinforced at all subsequent visits, and the patient should be encouraged to ask questions.
One of the biggest obstacles to home DVT treatment is the relatively high acquisition cost of LMWH drugs. Although UFH is less costly, the overall treatment costs associated with LMWH are lower. Medicare does not cover LMWH for home therapy, but many managed care plans do. Issues of cost and coverage for outpatient treatment must be addressed before implementing a treatment plan. If faced with the choice of avoiding a hospitalization, some patients may be willing to pay the out-of-pocket cost for the LMWH.6
It is rare to find a cost-effective treatment that produces equivalent, if not better, outcomes as the traditional method. Treatment of proximal DVT with LMWH has demonstrated both these outcomes. Its predictable antithrombotic response based on body weight eliminates the need for laboratory monitoring and dosage adjustment. Its convenient once or twice daily SC administration allows it to be used in the outpatient setting. Although the initial cost of LMWH is higher than that of UFH, the cost savings achieved in decreasing hospital length of stay makes treatment with LMWH more economically advantageous.
Appropriate patient selection, a carefully designed treatment plan, thorough education, and daily patient contact are critical components for providing high quality outpatient care.
The authors are indebted to Jack Ansell, MD, David L.A. Green, MD, PhD, Susan Bowar-Ferres, RN, PhD, Linda Valentine, RN, MS, Barbara Delmore, RN, PhD, and Kathleen Leonard, RN, MA, ANP for their review of this manuscript, valuable comments and suggestions.
Treat DVT with Low Molecular Weight Heparin
General Purpose: To provide nurse practitioners with an overview on the use of low molecular weight heparin (LMWH) in the treatment of deep vein thrombosis (DVT). Learning Objectives: After reading the article and taking this test, you will be able to: 1. Identify patients who are appropriate candidates for home DVT therapy. 2. Discuss the actions, side effects, and nursing considerations for unfractionated heparin (UFH). 3. Discuss the actions, side effects, and nursing considerations for low molecular weight heparin (LMWH).
1. Ecklund M: Optimizing the flow of care for prevention and treatment of deep vein thrombosis and pulmonary embolus. AACN Clinical Issues 1995; 6 (4): 588-601.
2. Carroll P: Treating deep venous thrombosis at home with low-molecular-weight heparin. Home Healthcare Nurse January 2000; (suppl.): 3-13.
3. Hirsh J, Hoak J: Management of deep vein thrombosis and pulmonary embolism. Circulation 1996; 93 (12): 2212-2235.
4. Schraibman IG, Milne AA, Royle EM: Home versus in-patient treatment for deep vein thrombosis (Cochrane Review). In: The Cochrane Library, Issue 1, 2002. Oxford: Update Software.
5. Hull RD, Raskob GE, Rosenbloom D, et al: Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs. intravenous heparin. Arch Intern Med 1997; 157: 289-293.
6. Ansell JE,Hickey AD, Kleinschmidt KC, et al: Advancing the treatment of deep venous thrombosis and pulmonary embolism, [serial online]. 2000: 1-32. Available at: http://www.acforum.org/doc_educauon_advancing.pdf. Accessed April 1, 2002.
7. Gould MK, Dembitzer AD, Doyle RL, et al: Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. Ann Intern Med 1999;130:800-809.
8. Dolovich LR, Ginsberg JS, Douketis JD, et al: A meta-analysis comparing low-molecular weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000; 160: 181-188.
9. Hull RD, Pineo GF: Economic aspects of deep vein thrombosis therapy and outpatient management. Home Healthcare Consultant 2000; 7 (7): 22-29.
10. Koopman MM, Prandoni P, Piovella F, et al: Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334 (11): 682-687.
11. Wells PS, Kovacs MJ, Bormanis J, et al: Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin. Arch Intern Med 1998; 158: 1809-1812.
12. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326 (15): 975-981.
13. The Columbus investigators: Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337 (10): 657-661.
14. Hyers TM, Agnelli G, Hull RD, et al Antithrombotic therapy for venous thromboembolic disease. CHEST 2001; 119 (suppl. 1): 176S-194S.
15. Hirsh J, Warkentin TE, Shaughnessy SG, et al: Heparin and low-molecular-weight heparin: mechanism of action, pharmacokinetics, dosing, monitoring, efficacy and safety. CHEST 2001, 119 (suppl. 1): 64S-94S.
16. Hirsh J, Levine MN: Low molecular weight heparin. Blood 1992; 79 (1): 1-12.
17. Dunn AS, Coller B: Outpatient treatment of deep vein thrombosis: translating clinical trials into practice. Am J Med 1999; 106: 660-667.
18. Tapson VF, Hull RD: Management of venous thromboembolic disease. Clin Chest Med 1995; 16 (2): 281-294.
19. Schwarz T, Schmidt B, Beyer J, et al: Eligibility for home treatment of deep vein thrombosis: a prospective study in 202 consecutive patients. J Vase Surg 2001; 34 (6): 1065-1070.
20. Weite JI: Low-molecular-weight heparins. N Engl J Meet 1997; 337 (10): 688-698.
21. Campbell Betten K: The use of low molecular weight heparin in the initial management of patients with deep vein thrombosis. J Am Acad Nurse Pract 2000; 12 (7): 267-272.
22. Levine M, Gent M, Hirsh J, et al: A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. N Enggl J Med 1996; 334 (11): 677-681.
23. Fareed J, Hoppensteadt DA, Walenga JM: Current perspectives on low molecular weight heparins. Seminars in Thrombosis and Hemostasis 1993; 19 (suppl. 1): 1-11.
24. Lindmarker P, Holmstrom M: Use of low molecular weight heparin (dalteparin), once daily, for the treatment of deep vein thrombosis. A feasibility and health economic study in an outpatient setting. J Intern Md 1996; 240 (6): 395-401. e
25. Handeland GF, Abildgaard U, Holm HA, et al: Dose adjusted heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. Eur J Clin Pharmacol 1990; 39 (2): 107-112.
26. Bratt G, Aberg W, Johansson M, et al. Two daily subcutaneous injections of fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis. Thrombosis and Haemostasis 1990; 64: 506-510.
27. Holm HA, Ly B, Handeland GF, et al: Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low-molecular-weight heparin. Haemostasis 1986; 16 (suppl. 2): 30-37.
28. O'Brien B, Levine M, Willan A, et al: Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis. Arch Intern Med 1999, 159: 2298-3304.
29. Boling PA: American Academy of Home Care Physicians guidelines for deep vein thrombosis treatment. Home Health Care Consultant 2000; March (suppl.): 1-8.
30. McMahan Nagle B. Low molecular weight heparin. RN 1998, April: 40-42.
Cheryl Nadeau, RN, MS, FNP-CS, CACP Jerry Varrone, RIM, MS, FIMP
ABOUT THE AUTHORS
At the NYU Hospitals Center Anticoagulation Management Service, Cheryl Nadeau is a Family Nurse Practitioner, Certified Anticoagulation Care Provider and Jerry Varrone is a Family Nurse Practitioner.
Copyright Springhouse Corporation Oct 2003
Provided by ProQuest Information and Learning Company. All rights Reserved