Low-Molecular-Weight Heparin in Preventing and Treating DVT

ERIC J. RYDBERG, M.D., JOHN M. WESTFALL, M.D., M.P.H., and RICHARD A. NICHOLAS, M.D.

University of Colorado Health Sciences Center

Denver, Colorado

Low-molecular-weight heparin is a relatively recent addition to the list of therapies for prophylaxis and treatment of deep venous thrombosis (DVT). As a prophylactic, low-molecular-weight heparin is as effective as standard heparin or warfarin and does not require monitoring of the activated partial thromboplastin time or the International Normalized Ratio. Traditionally, treatment for DVT required patients to be hospitalized for administration of intravenous heparin. With subcutaneous injections of low-molecular-weight heparin, treatment of DVT can be initiated or completed in the outpatient setting with no increased risk of recurrent thromboembolism or bleeding complications. Low-molecular-weight heparin is an attractive option for use in patients with a first episode of DVT, no risk factors for bleeding and the ability to administer injections with or without the help of a visiting nurse or family member.

Deep venous thrombosis (DVT) is a relatively common disease that is often encountered by family physicians. Epidemiologic data suggest that the annual incidence of a first episode of DVT ranges from 60 to 180 cases per 100,000 people, or more than 300,000 new cases annually in the United States.¹ The cost burden of this disease is quite high, since most patients with DVT require one or more diagnostic tests, treatment with intravenous heparin and a three- to seven-day hospital stay.² Low-molecular-weight heparin, which is administered by subcutaneous injection, offers the option of treatment on an outpatient basis for patients with DVT. Low-molecular-weight heparin can also be used effectively in patients requiring prophylaxis for DVT after general or orthopedic surgery.

Advantages of Low-Molecular-Weight Heparin

Advantages of low-molecular-weight heparin over standard heparin include predictable blood levels, lower likelihood of bleeding and no reports of thrombocytopenia or osteoporosis.

The clinical advantages of low-molecular-weight heparin include predictability, dose-dependent plasma levels, a long half-life and less bleeding for a given antithrombotic effect.³ Furthermore, immune-mediated thrombocytopenia is not associated with short-term use of low-molecular-weight heparin,³ and the risk of heparin-induced osteoporosis may be lower than the risk with the use of standard heparin. Low-molecular-weight heparin is administered according to body weight once or twice daily, both during the high-risk period when prophylaxis for DVT is recommended and also when waiting for oral anticoagulation to take effect in the treatment of DVT. The activated partial thromboplastin time (aPTT) does not need to be monitored, and the dosage does not need to be adjusted. Since low-molecular-weight heparin is given subcutaneously, outpatient administration by the patient, with or without the assistance of a visiting nurse or family member, is both possible and cost-effective.

Properties of Low-Molecular-Weight Heparin

Low-molecular-weight heparin is a relatively new class of anticoagulant that has been used in Europe and is now being used more often in the United States following reports of randomized, controlled trials demonstrating its efficacy and safety.

Low-molecular-weight heparin is derived from standard heparin through either chemical or enzymatic depolymerization. Whereas standard heparin has a molecular weight of 5,000 to 30,000 daltons, low-molecular-weight heparin ranges from 1,000 to 10,000 daltons, resulting in properties that are distinct from those of traditional heparin. Low-molecular-weight heparin binds less strongly to protein, has enhanced bioavailability, interacts less with platelets and yields a very predictable dose response, eliminating the need to monitor the aPPT. Low-molecular-weight heparin, like standard heparin, binds to antithrombin III; however, low-molecular-weight heparin inhibits thrombin to a lesser degree (and Factor Xa to a greater degree) than standard heparin.⁴

Prophylaxis of DVT

Patients with a first episode of proximal deep venous thrombosis who have no risk factors for bleeding are good candidates for therapy with low-molecular-weight heparin.

The symptoms, signs, risk factors and diagnosis of DVT are reviewed elsewhere.⁵ Low-molecular-weight heparin helps prevent DVT in a variety of clinical situations, including patients undergoing general surgery, or hip or knee replacements. Given the high incidence of DVT after such procedures, prophylaxis is strongly recommended. Although a surgeon often consults in such cases, family physicians should be aware of the need for prophylaxis for DVT and should ensure that adequate therapy is provided, when appropriate. The Fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy has recently published a review of the complex data on prophylactic treatment for DVT, which is summarized below.⁶

Prophylaxis for General Surgery
Patients undergoing general surgery have a 16 percent risk of DVT and a 1.6 percent incidence of pulmonary embolus when they do not receive prophylactic treatment for DVT.⁶ Low-molecular-weight heparin is as effective as low-dose subcutaneous heparin, decreasing the incidence of DVT to 5 to 8 percent following general surgery, and slightly reducing bleeding complications. Although low-molecular-weight heparin costs approximately 10 times more per dose than low-dose subcutaneous heparin, it can be given once daily, which may offset some of the higher cost. While noninvasive methods of preventing DVT (i.e., use of elastic compression stockings or intermittent pneumatic stockings) are adequate in low- and moderate-risk surgical patients, low-molecular-weight heparin is an excellent therapeutic choice in high-risk patients (i.e., patients over 40 years of age, patients undergoing major surgery, patients with concurrent risk factors for DVT).⁶ Prophylactic low-molecular-weight heparin should be given subcutaneously once or twice daily until the patient is ambulating well.

Prophylaxis for Orthopedic Surgery
In patients not receiving prophylaxis for DVT who are undergoing elective hip or knee replacement or hip fracture surgery, the risk of postoperative DVT is at least 40 percent, and the risk of pulmonary embolus ranges from 1.8 to 30 percent.⁶ Low-molecular-weight heparin is safe and effective following surgery for hip replacement. It has been shown in a recent meta-analysis⁷ to be superior to low-dose subcutaneous heparin, and its use resulted in significantly fewer hemorrhagic complications.⁸

Standard treatment of deep venous thrombosis with intravenous heparin administered in the hospital offers no advantages over low-molecular-weight heparin administered in the outpatient setting.

Studies comparing low-molecular-weight heparin with low-dose warfarin (Coumadin) therapy (maintaining an International Normalized Ratio [INR] between 2.0 and 3.0) showed that low-molecular-weight heparin is slightly more effective, although the difference is quite small.^9,10 Thus, the decision to use low-molecular-weight heparin or warfarin should be based on convenience and cost. Low-molecular-weight heparin is given subcutaneously twice daily, and laboratory monitoring is not required. Treatment with either warfarin or low-molecular-weight heparin should be continued for a minimum of seven days postoperatively.

DVT is especially hard to prevent following knee replacement surgery, and low-dose standard heparin provides marginal benefit.¹¹ Again, low-molecular-weight heparin is safe and effective. Five studies comparing low-molecular-weight heparin with low-dose warfarin demonstrate better efficacy with low-molecular-weight heparin.⁶ Intermittent pneumatic compression stockings are also quite effective in preventing DVT following knee replacement surgery¹²; however, the number of patients studied in this trial was small compared with the number of patients in the low-molecular-weight heparin trials. No trials to date have compared the use of intermittent pneumatic compression stockings with low-molecular-weight heparin therapy and, currently, either offers adequate prophylaxis. In high-risk patients, low-molecular-weight heparin and compression stockings may be used simultaneously.

TABLE 1 Controlled Trials Comparing Intravenous Heparin with Subcutaneous LMW Heparin in Proximal DVT Study Number of patients Outcome Prandoni, et al.13 170 No difference in rates of symptomatic extension, recurrence, pulmonary embolus or severe bleeding Hull, et al.14 432 No difference in rates of recurrence, pulmonary embolus, or major or minor bleeding Simonneau, et al.15 134 Less enlargement of thrombus in patients treated with LMW heparin, fewer thromboembolic events in patients treated with LMW heparin, no difference in rates of major bleeding Lindmarker, et al.16 204 No difference in Marder score (venographic assessment of clot size) Levine, et al.17 400 No difference in rates of recurrent thromboembolism or major bleeding Koopman, et al.18 400 No difference in rates of recurrent thromboembolism or major bleeding LMW=low-molecular-weight; DVT=deep venous thrombosis. Information from references 13 through 18.

TABLE 2 Low-Molecular-Weight Heparins Heparin Availability Prophylactic dosing Ardeparin (Normiflo) 5,000 U in 0.5 mL; 10,000 U in 0.5 mL 50 U per kg SC on the evening of the day of surgery or the following morning, then every 12 hours for 14 days or until ambulatory Dalteparin (Fragmin) 16 mg per 0.2 mL; 32 mg per 0.2 mL 2,500 IU SC 1 to 2 hours before surgery, then 2,500 IU every day for 5 to 10 days     High-risk patients: 5,000 IU SC the evening before surgery, then 5,000 IU every day for 5 to 10 days Danaparoid (Orgaran) 750 U per 0.6 mL 750 U SC 1 to 4 hours before surgery, then 750 U every 12 hours for 7 to 10 days Enoxaparin (Lovenox) 30 mg per 0.3 mL; 40 mg per 0.4 mL 30 mg SC every 12 hours or 40 mg every day for 7 to 10 days, depending on the type of surgery (hip, knee, abdomen); therapy should begin postoperatively (see prescribing information for more details) SC=subcutaneously.

Treatment of DVT

Traditionally, a patient diagnosed with DVT has been hospitalized for treatment, which includes intravenous heparin and monitoring of the aPTT. The patient remains hospitalized until warfarin is administered to achieve an INR between 2.0 and 3.0. Such management usually results in a three- to seven-day hospital stay.²

TABLE 3 Subsets of Patients Excluded from Controlled Trials of LMW Heparin in DVT* • Previous history of DVT: --Ipsilaterally15 --Ipsilaterally in the past two years12 --Two or more episodes, either extremity16 --Any venous thromboembolism in the past two years17 • Pregnancy12-17 • Renal or hepatic insufficiency13,15 • Active bleeding13-16 • Surgery in the previous five15 to seven14 days • Protein C,13,16 antithrombin III or protein S deficiency16 (hypercoagulable state) • Inability to undergo outpatient treatment16 • Noncompliance16 • Other relative contraindications: --Thrombocytopenia --Coagulopathy --Active peptic ulcer disease LMW=low-molecular-weight; DVT=deep venous thrombosis. *--Currently evidence is insufficient to support the routine use of low-molecular-weight heparin in the treatment of DVT in these patients. Information from references 12 through 17.

Recent randomized, controlled trials demonstrate the efficacy of low-molecular-weight heparin in the treatment of DVT, both in the hospital^13-16 and in an outpatient setting.^17,18 Results of each of these studies demonstrated no advantage to standard intravenous heparin over low-molecular-weight heparin in terms of recurrent thromboembolism or major bleeding complications (Table 1). Patients who received twice-daily injections of low-molecular-weight heparin spent fewer days in the hospital and, in the studies where low-molecular-weight heparin was administered in the outpatient setting, many patients did not require hospitalization at all.^17,18 Furthermore, social functioning and physical activity were better in the group receiving low-molecular-weight heparin.¹⁸ The dosage of low-molecular-weight heparin depends on the specific agent used (Table 2).

Cost analysis was incomplete in these trials; however, elimination of even a single hospital day by use of low-molecular-weight heparin would be likely to yield a savings. In our community, the cost of low-molecular-weight heparin ranges from approximately $100 to $150 per day. The average cost of treating a patient with uncomplicated DVT is reduced by approximately $5,000 to $8,000 when using low-molecular-weight heparin instead of standard heparin therapy. It is likely that additional studies will yield important information on the cost savings of treatment with low-molecular-weight heparin.

Patients with a first episode of proximal DVT and no risk factors for bleeding complications (e.g., active peptic ulcer disease, thrombocytopenia, liver disease, other coagulopathy) are good candidates for initial therapy with low-molecular-weight heparin. The Physicians' Desk Reference¹⁹ does not yet list low-molecular-weight heparin as an indicated use in the treatment of DVT; hence, this suggested treatment represents an off-label use. Because several subsets of patients were excluded from the low-molecular-weight heparin trials, treatment with low-molecular-weight heparin in these patients cannot be recommended at this time (Table 3).

Several recent articles have reported the safety and efficacy of low-molecular-weight heparin in the treatment of pulmonary embolism.^20,21 Because pulmonary embolism is sometimes suspected in patients with DVT, appropriate treatment is essential. Treatment with low-molecular-weight heparin may still be considered in patients with DVT and suspected pulmonary embolus. Physicians should become familiar with the absolute and relative contraindications of the specific brand of low-molecular-weight heparin they choose to use.

Appropriate patients may be taught to self-administer low-molecular-weight heparin or, if needed, a visiting nurse or a family member can give the injections. Warfarin is started on the first or second day of therapy with low-molecular-weight heparin and, once the INR is between 2.0 and 3.0, the low-molecular-weight heparin is discontinued (Figure 1).

As with any illness, patients benefit from education about the potential consequences of both their disease and its treatment. Close physician follow-up is advised when treating patients with low-molecular-weight heparin.

Treatment of Deep Venous Thrombosis FIGURE 1. Algorithm for the management of DVT. (DVT=deep venous thrombosis; INR=International Normalized Ratio; LMW=low-molecular-weight; SC=subcutaneously)

Obstacles to Treatment
Physician resistance to use of low-molecular-weight heparin in the treatment of proximal DVT is high. Intravenous heparin has been used since the 1940s, and physicians recognize the serious complications of treatment failure in patients with DVT. The availability and packaging of low-molecular-weight heparin provide other minor obstacles to treatment. Because low-molecular-weight heparin has been used primarily in the hospital setting, it may not be readily available through outpatient pharmacies. In addition, low-molecular-weight heparin is marketed in prepackaged syringes that contain the dosage usually adminstered for the prophylactic treatment of DVT. Consequently, several prepackaged syringes must be combined to form the larger doses needed for treatment of DVT. This step requires additional supplies and assistance from the pharmacist or home-health nurse. As low-molecular-weight heparin becomes more widely used in the outpatient treatment of DVT, physicians can encourage their local pharmacies to stock it, thus making larger vials available from which the appropriate dose can be drawn into a syringe.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

---

The Authors

ERIC J. RYDBERG, M.D.,
is currently in private practice in Denver. Dr. Rydberg earned a medical degree from the University of Colorado School of Medicine, Denver, where he also completed a residency in family medicine.

JOHN M. WESTFALL, M.D., M.P.H.,
is assistant professor of family medicine at the University of Colorado Health Sciences Center and a member of the faculty at the Rose Family Medicine Residency. Dr. Westfall earned his medical degree from the University of Kansas School of Medicine, Wichita, and completed a residency in family medicine at the University of Colorado Health Sciences Center.

RICHARD A. NICHOLAS, M.D.,
is an associate professor of family medicine at the University of Colorado Health Sciences Center and residency director at the Rose Family Medicine Residency. He received a medical degree from the University of Colorado School of Medicine and completed a residency in family medicine at Mercy Medical Center, Denver.

Address correspondence to Eric J. Rydberg, M.D., University of Colorado Health Sciences Center, Rose Family Medicine Residency, 2149 S. Holly St., Denver, CO 80222. Reprints are not available from the authors.

REFERENCES

1. Carter CJ. The natural history and epidemiology of venous thrombosis. Prog Cardiovasc Dis 1994;36: 423-38.
2. Hirsh J. Heparin. N Engl J Med 1991;324:1565-74.
3. Warkentin TE, Levine MN, Hirsch J, Horsewood P, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-5.
4. Hirsch J, Raschke R, Warkentin TE, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1995;108(4 suppl):
   258-75.
5. Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996;335:1816-28.
6. Clagett GP, Anderson FA Jr, Heit J, Levine M, Wheeler HB. Prevention of venous thromboembolism. Chest 1995;108(4 suppl):312-34.
7. Nurmohamed MT, Rosendaal FR, Buller HR, Dekker E, Hommes DW, Vandenbroucke JP, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-6.
8. Levine MN, Hirsch J, Gent M, Turpie AG, Leclerc J, Powers PJ, et al. Prevention of deep vein thrombosis after elective hip surgery. Ann Intern Med 1991; 114:545-51.
9. Mohr DN, Silverstein MD, Murtaugh PA, Harrison JM. Prophylactic agents for venous thrombosis in elective hip surgery. Arch Intern Med 1993;153:2221-8.
10. Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994;271:1780-5 [Published erratum in JAMA 1995;273:288].
11. Spiro TE, Colwell CW, Bona RD, Trowbridge AA, Wise GR, Furman KW, et al. A clinical trial comparing the efficacy and safety of enoxaparin (a low-molecular-weight heparin) and unfractionated heparin for the prevention of deep venous thrombosis after elective knee replacement surgery. Blood 1993;82 (suppl):1624A.
12. Lynch JA, Baker PL, Polly RE, Lepse PS, Wallace BE, Roudybush D, et al. Mechanical measures in the prophylaxis of postoperative thromboembolism in total knee arthroplasty. Clin Orthop 1990;260:24-9.
13. Prandoni P, Lensing AW, Buller HR, Carta M, Cogo A, Vigo M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992;339:441-5.
14. Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975-82.
15. Simonneau G, Charbonnier B, Decousus H, Planchon B, Ninet J, Sie P, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993;153:1541-6.
16. Lindmarker P, Holmstrom M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994;72:186-90.
17. Levine M, Gent M, Hirsch J, Leclerc J, Anderson D, Weitz 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 Engl J Med 1996; 334:677-81.
18. Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, 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;334:682-7 [Published erratum in N Engl J Med 1997;337:1251].
19. Physicians' desk reference. 51st ed. Montvale, N.J.: Medical Economics, 1997:2188.
20. Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997;337: 663-9.
21. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. The Columbus Investigators. N Engl J Med 1997;337:657-62.

Copyright © 1999 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.