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
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
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
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.
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
Recent randomized, controlled trials demonstrate the efficacy of low-molecular-weight heparin in the treatment of DVT, both in the hospital13–16 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).
|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|
|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)|
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).
|Previous history of DVT:|
|Ipsilaterally in the past two years12|
|Two or more episodes, either extremity16|
|Any venous thromboembolism in the past two years17|
|Renal or hepatic insufficiency13,15|
|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|
|Other relative contraindications:|
|Active peptic ulcer disease|
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.
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.