Management of 
Deep Vein Thrombosis
in the Ambulatory Patient

Low-molecular-weight heparins (LMWHs) represent a new treatment option for DVT. This modality has altered the treatment of DVT from a disease that required hospitalization to one that can be treated out of the hospital in select patients. The purpose of this article is to review the pathogenesis, clinical presentation, and pharmacologic management of DVT, focusing on the outpatient management of this disorder using LMWH.

 

 

A thrombus, or fibrin clot, forms when the coagulation cascade is activated. In brief, activation of the coagulation cascade via the intrinsic and extrinsic pathway leads to activation of factor X, and activated factor X (Xa) stimulates the conversion of prothrombin to thrombin (IIa). In turn, thrombin catalyzes the conversion of fibrinogen to fibrin, which forms the foundation of a clot. Venous thrombosis usually occurs as a result of venous stasis, vascular injury, and/or hypercoagulability, otherwise known as Virchow's Triad.^1,3,4 The presence of one or more of these abnormalities can predispose to thrombosis.

 

Venous stasis occurs from conditions such as immobility, paralysis, or prolonged bed rest. With venous stasis, endothelial damage from hypoxia occurs from poor venous emptying, leading to thrombus formation. In addition, the pooling of blood in the vessels can lead to thrombus formation by the accumulation of clotting factors in the area of stasis.^1,5

 

Vascular injury can result from trauma or surgery. Vascular damage may expose collagen, which can also activate the coagulation cascade and stimulate platelet aggregation, thus leading to thrombus formation.^1,5 For example, surgery, such as total hip replacement, is a major risk factor for thrombosis.

 

The symptoms of DVT are often nonspecific. They occur as a consequence of venous outflow obstruction and inflammation. The usual symptoms include pain and tenderness, swelling, discoloration of the skin, and increased leg circumference. The Homans' sign, or pain in the calf on dorsiflexion of foot, or a palpable cord may be present as well. Patients with other conditions, such as cellulitis, muscle strain, or varicose veins, can present with similar symptoms. Therefore, objective tests must be performed to make a definitive diagnosis. Many reliable noninvasive tests, such as duplex ultrasonograpy, Doppler ultrasonography, and impedance plethys- mography, are available. The most accurate test for the diagnosis of DVT is venography, which is the gold standard. The higher expense and possible complications limit its routine use.

 

Complications of DVT include post-thrombotic syndrome, pulmonary embolism, DVT recurrence, and death.^1,2,9 Post-thrombotic syndrome is a chronic complication of DVT that occurs as a result of venous valve incompetence and hypertension. Symptoms consist of pain, swelling, and occasionally ulceration of the skin of the legs. The incidence of this syndrome is approximately 28% at 5 years after the initial DVT.² When part of the venous thrombus breaks off to form an embolus that passes to and obstructs the arteries of the lung, pulmonary embolism (PE) develops. Although PE rarely develops after calf vein or superficial vein thrombosis, it is often a complication of proximal DVT. Pulmonary emboli are detected in approximately 50% of patients with documented DVT.¹ Approximately 15% to 20% of patients with proximal DVT develop PE if untreated. Recurrence is another complication. Recurrent DVT occurs in 3% to 6% of patients at 3 months, 14% to 17% of patients after 2 years, and in approximately 30% of patients after 8 years.^2,8 Death, the most serious consequence of DVT, usually occurs as a result of PE. It is estimated that 600,000 patients develop PE each year and that 60,000 die of this complication.¹ An 8-year death rate of 30% was reported in one study.²

 

Treatment of DVT includes the initial use of heparin, either unfractionated heparin (UFH) or LMWH, and warfarin for chronic anticoagulation.^1,3,10 Because the onset of effect with warfarin is delayed, heparin is necessary for rapid antithrombotic effects followed by the administration of warfarin. The overall treatment of DVT with LMWH and warfarin is summarized in Figure 1.

 

Unfractionated Heparin. The cornerstone of treatment of DVT is heparin. Heparin is started immediately once the diagnosis is confirmed. UFH^1,3,11 is still considered the drug of choice because of its excellent antithrombotic effects and rapid onset of action. UFH works by binding to antithrombin III, a coagulation inhibitor that accelerates antithrombin III's ability to inhibit clotting factors IX, X, and II. It prevents the extension and formation of thrombus and permits the endogenous fibrinolytic system to lyse the thrombus that is already present. For DVT, weight-based dosing (80 units/kg intravenous [IV] bolus, followed by 18 units/kg continuous IV infusion­Raschke et al¹² used actual body weight) is preferred, because this method of dosing has been shown to be more effective in achieving therapeutic levels compared with empiric dosing.

 

There are some disadvantages to UFH, however. Because of its short half-life, UFH is generally administered as a continuous IV for the treatment of DVT. UFH binds nonspecifically to plasma proteins, macrophages, and endothelial cells, and leads to a variable anticoagulant response among patients. Intra-patient variability occurs as well, and dose requirements for UFH may vary in the acute treatment of DVT. Therefore, a specific test, the activated partial thromboplastin time (aPTT), must be monitored at least daily to ensure adequate anticoagulation,^4,5,10 making hospitalization necessary to properly manage patients on UFH. The usual aPTT goal is 1.5 to 2.5 times the control (patient's baseline value) or an aPTT range that corresponds to a heparin concentration of 0.2 to 0.4 U/mL by protamine titration. Because there are problems with the accurate measurement of aPTT as a result of varying reagent sensitivity,¹³ the latter method of using heparin concentrations is preferred.³

 

Adverse effects of heparin include bleeding and thrombocytopenia (immune and nonimmunemediated). The incidence of immune-mediated heparin-induced thrombocytopenia (HIT), which can lead to serious thrombosis, is estimated to be approximately 1% to 3%. To minimize serious complications of HIT, the platelet count must be monitored daily while on UFH, and UFH must be discontinued if HIT is suspected. With prolonged use, usually more than 3 months and at higher doses (>=10,000 units/day), osteoporosis is another concern.

 

 

Like UFH, LMWHs bind to anti-thrombin III and stimulate anti-thrombin III's ability to inhibit coagulation. Because of their small size, however, LMWHs have more activity against factor Xa than thrombin to a ratio ranging from 4:1 to 2:1 depending on the product. Although the clinical significance of this difference is unknown, it makes each LMWH unique, and these products may not be interchangeable. LMWHs also possess several pharmacokinetic advantages over UFH, which contribute to greater convenience. Because LMWHs bind less to plasma proteins, they have a better bioavailability and a more predictable anticoagulant response. The need for aPTT monitoring and dose adjustment is usually eliminated. Although UFH binds nonspecifically to macrophages and endothelial cells, LMWHs have a reduced binding to these cells, which results in a longer half-life, allowing for subcutaneous administration once or twice daily. In addition, LMWHs bind less to platelets and activate osteoclasts less, thereby possibly reducing the incidence of immune-mediated heparin-induced thrombocytopenia and osteoporosis. Because of the decreased incidence of HIT with LMWHs, the platelet count may be monitored every 3 to 5 days while on LMWH rather than daily, as with UFH.³

 

The development of LMWH has allowed for simplified, yet efficacious, treatment of DVT in the ambulatory population. Since there is no need for aPTT monitoring and a predictable anticoagulant response occurs with fixed doses, the use of LMWH in the outpatient treatment of uncomplicated DVT is feasible.^16,17 This method of treatment has been shown to be effective and makes the use of LMWH cost-effective in a subset of patients. In some centers, the use of LMWH for outpatient DVT treatment was feasible in 50% to 80% of patients.^18-20

 

Currently, only enoxaparin (Lovenox) is FDA-approved for the treatment of DVT in outpatients. For the outpatient treatment of DVT, enoxaparin 1 mg/kg subcutaneously every 12 hours must be used. In the clinical trials using enoxaparin, total body weight was used in dosing calculations. For those who are <50 kg, >80 kg, or with renal insufficiency, the optimal dose is unknown. Although recommendations to adjust doses based on antifactor Xa levels in such patients exist,¹³ reliable anti-Xa levels may not be readily available.

 

In addition to short-term heparin therapy, chronic anticoagulation is necessary to prevent recurrence.^1,3,9,21 The efficacy and relative ease of oral administration makes warfarin the drug of choice for chronic anticoagulation. Warfarin inhibits the production of the vitamin K­dependent clotting factors II, VII, IX, and X. Warfarin is never used alone in the initial treatment of DVT because it has a delayed onset of action. The antithrombotic effects of warfarin may not be apparent for 3 to 5 days.

 

Warfarin therapy should be started as soon as possible to minimize the use of heparin. In the past, warfarin was started after several days of heparin therapy. Since delaying warfarin administration increases hospital stay (or use of heparin) without improving the patient outcome,²² warfarin should be started on the first day of starting heparin, if possible. The goal is to achieve a therapeutic international normalized ratio (INR), a laboratory measure of warfarin response, in a timely manner. Large "loading" doses are unnecessary and may even be harmful, leading to supratherapeutic levels. Rather, the recommended initial dose is warfarin 5 mg, started on the first day of diagnosis after heparin therapy has been initiated. The INR should be monitored daily, and warfarin dose adjustments should be made based on the INR value. With daily dose titration, a therapeutic INR of 2 to 3 can usually be achieved in about 4 to 7 days. It is critical that therapeutic INRs are achieved, since the risk of bleeding with warfarin is greater at higher INRs, and the risk of thrombosis is higher at lower INRs. In addition to the expected risk of bleeding, other adverse effects of warfarin, albeit rare, include skin necrosis and purple toe syndrome. Purple toe syndrome is an idiosyncratic reaction to warfarin that results in a purplish or mottled discoloration of toes. It results from cholesterol microemboli and occurs usually 3 to 10 weeks after starting warfarin.

 

In DVT treatment, patients remain on heparin until warfarin dosing results in a therapeutic INR of 2 to 3 for a minimum of 2 days. Heparin and warfarin should be overlapped at least 4 days because of the delayed onset of warfarin's action. The duration of chronic anticoagulation with warfarin will vary depending on the characteristics of the patient.³ For patients who develop a DVT for the first time because of a reversible or time-limited risk factor, such as transient immobilization, trauma, surgical operation, or pharmacologic estrogen use, the recommended duration of treatment is 3 to 6 months. For those with heterozygous activated protein C resistance (a specific inherited disorder that predisposes to thrombosis) and a first-time DVT, 3 to 6 months of treatment with warfarin is recommended. In a patient with a first event and idiopathic etiology, at least 6 months of chronic anticoagulation is recommended. Patients with recurrence or patients with a first DVT and comorbid conditions such as active cancer or a hypercoagulable state (homozygous activated protein C resistance, antiphospholipid syndrome, or deficiencies of antithrombin III, protein C, or protein S) should receive warfarin for a minimum of 12 months. These patients often need lifelong therapy.

 

In clinical studies that evaluated the use of various LMWHs in the treatment of acute thromboembolism, the results have been consistent. Two unblinded randomized trials involving LMWHs evaluated their use in the treatment of DVT versus standard therapy with UFH in hospitalized patients. Simonneau and colleagues²³ compared UFH (500 units/kg/day), adjusted to maintain an aPTT 1.5 to 2.5 times control, to fixed, weight-based doses of subcutaneous enoxaparin (1 mg/kg every 12 hours) in 134 patients. Oral anticoagulation with warfarin was started on day 10 and continued for at least 3 months. The primary outcome measure was a change in the size of the initial thrombus, determined by repeat venography performed at baseline and 10 days later. Venography determined whether the clot size was reduced, enlarged, or stayed the same.²³ Overall, patients treated with enoxaparin demonstrated a significantly greater venographic improvement compared with patients treated with unfractionated heparin (P < 0.002). No major bleeding events occurred in either group.

 

A second study²⁴ evaluated dalteparin versus UFH in 204 patients, utilizing the same outcome measure as above, venographic improvement. UFH was administered as a 5,000-unit loading dose followed by a continuous infusion of 800 to 1,700 units/hour, adjusted to maintain the aPTT 1.5 to 3 times control. Patients randomized to dalteparin received 200 units/kg subcutaneously once daily. All patients received concurrent warfarin therapy. Venography was performed at baseline and following discontinuation of either UFH or dalteparin. UFH and dalteparin were found to be equally efficacious in stabilizing or decreasing clot size (P = 0.62). No patients in either group experienced symptomatic progression of the thrombus, pulmonary embolism, major bleeding, or death during hospitalization. These two studies demonstrated that LMWH is as effective and safe as UFH in the treatment of DVT.

 

The finding that LMWHs were efficacious in the initial treatment of DVT led investigators to evaluate their use using more clinically relevant outcome measures. A randomized, double-blind, placebo-controlled trial of 432 patients was designed to determine the efficacy of the LMWH tinzaparin compared with UFH in the inpatient treatment of acute DVT.²⁵ The outcome measures evaluated were recurrent thromboembolism, major bleeding, and mortality. Patients received either a continuous infusion of UFH (5,000-unit IV bolus dose followed by 40,320 units/24 hours or 29,760 units/24 hours--the lower dose in patients at high risk for bleeding) adjusted to maintain an aPTT of 1.5 to 2.5 times the reference standard or 175 units/kg of tinzaparin daily. Patients in the LMWH group experienced less recurrence of thromboembolism (P = 0.049), less bleeding (P = 0.006) during or immediately after the initial LMWH therapy, and lower mortality (P = 0.049) during this 3- month trial.

Gould and colleagues²⁶ performed a meta-analysis of 11 trials that evaluated the use of LMWHs in the treatment of acute DVT. Both inpatient and outpatient trials were included. Rates of recurrent thromboembolism and major bleeding were slightly less prevalent, overall, in patients treated with LMWH, although these differences were not statistically significant. Recurrent thromboembolism occurred in 5.4% of patients treated with UFH compared with 4.6% of patients treated with LMWH. Major bleeding episodes occurred in 1.9% of patients in UFH groups and in 1.1% of patients treated with LMWH. Death as a result of documented thromboembolic recurrence or bleeding was evaluated, and no difference was found between UFH and LMWH.

 

Ambulatory Setting. The determination of comparable efficacy of LMWH to UFH therapy in inpatient studies coupled with the convenience of once- or twice-daily administration without the need for dose adjustment prompted researchers to evaluate the use of LMWH in the ambulatory population. Two large, randomized trials evaluated the treatment of DVT with adjusted-dose UFH in the hospital setting compared with fixed, weight-based LMWH, either nadroparin or enoxaparin, administered primarily at home. These trials were designed to allow patients in the LMWH group to be treated at home without admission to the hospital or to be discharged early after a brief hospital stay. Patients were excluded from both studies if they had recurrent thromboembolism or concomitant pulmonary embolism. Major study outcomes of efficacy and safety in both studies were rates of recurrent thromboembolism and major bleeding, respectively. All patients, in both studies, received concomitant oral anticoagulation therapy with warfarin for a minimum of 3 months. Therapy with LMWH or UFH was discontinued when the target INR (2 to 3) was reached with warfarin and maintained for 2 consecutive days and following at least 5 days of treatment with heparin.

 

 

Levine and colleagues²⁸ treated 500 patients with either a 5,000- unit loading dose of UFH followed by 1,280 units/hour initially (adjusted to a target aPTT of 60 to 85 seconds, which corresponds to a therapeutic heparin concentration of 0.2 to 0.4 units/mL by protamine titration) or 1 mg/kg of enoxaparin subcutaneously every 12 hours. Patients randomized to enoxaparin were discharged home to self-administer enoxaparin following a demonstration of injection technique. Three months after randomization, 5.3% of patients assigned to enoxaparin had recurrent thromboembolism compared with 6.7% of patients treated with UFH. Major bleeding events occurred in 2% and 1.2% of patients treated with enoxaparin and heparin, respectively. Differences in rates of thromboembolic recurrence and major bleeding between LMWH and UFH were not statistically significant. The results of this study were similar to and consistent with the results of the study by Koopman and colleagues.²⁷ These two studies indicate that the outpatient treatment of DVT with LMWH is both safe and efficacious. (Table 3 summarizes the outcome data.)

 

Originally, hospitalization was required to monitor the dose of UFH and to monitor for potential development of pulmonary embolism. It has since been shown that the progression of an initial episode of DVT to fatal pulmonary embolism is unlikely, and, therefore, hospital admission is solely to monitor and adjust the dose of UFH.¹⁴ By treating patients at home, the use of LMWH can bring about significant cost savings. Although the initial cost of LMWH is significantly higher than UFH, the lack of anticoagulant monitoring and potential for outpatient treatment offsets this cost. Multiple cost analyses have demonstrated the cost-effectiveness of LMWH in comparison to UFH in both inpatients and outpatients. One study discussed earlier by Hull and colleagues,²⁹ which compared tinzaparin to UFH in the initial treatment of DVT in the hospital setting, was evaluated to determine if treatment with an LMWH could produce cost savings. Costs involved in the diagnosis, administration of treatment, and treatment of complications were included in the evaluation. Investigators determined that it costs approximately $40,000 less to treat 100 patients with DVT when initial treatment is with the LMWH, tinzaparin. Furthermore, it was determined that 37% of the patients could have potentially been treated as outpatients. Considering these criteria, cost savings per 100 patients increased to more than $91,000 with the use of LMWH. This economic benefit further makes home treatment appealing.

 

Although LMWHs are effective and cost-effective, the success of home-based DVT treatment with LMWH relies on proper patient selection.¹⁴ Not all patients diagnosed with acute DVT should be treated at home at this time, since some patients require admission to the hospital because they may be at high risk for recurrent thromboembolism or bleeding. Such patients require monitoring for progression of DVT to pulmonary embolism or for development of any hemorrhagic complication related to drug therapy, both of which can be fatal. No clear guidelines for patient selection are available. However, certain characteristics place a patient at an increased risk for developing complications, which may preclude the option of outpatient treatment. A history of recurrent DVT, concurrent pulmonary embolism, pregnancy, and coagulopathies, such as protein C or S deficiency, have all been correlated with an increased risk of developing recurrent thromboembolism. These patients may not be candidates for home treatment. Patients at an increased risk for bleeding may not be candidates as well. Those with active peptic ulcer disease, hemorrhagic stroke, recent trauma or surgery, concomitant NSAID use (no more than low-dose aspirin), bleeding disorders, and a history of falls are at high risk for bleeding complications. Patients with severe renal insufficiency, defined as creatinine clearance less than 30 mL/min, have reduced elimination of LMWH and are also at a greater risk of bleeding. The optimal dose of LMWH for morbidly obese patients is unknown and may increase the risk of complications. Admission to the hospital continues to be the treatment of choice for patients presenting with any of the above characteristics.

 

Since DVT can safely and effectively be treated at home in many patients, the pharmacist will need to play an active role in their education and management. A multidisciplinary team of physicians, nurses, and pharmacists is critical to achieving successful outcomes as more institutions adopt outpatient treatment protocols with the LMWH enoxaparin. The consequences of inadequate treatment of DVT can be fatal. One key role of the pharmacist is proper counseling of the patient. It is therefore imperative that the pharmacist ensures the patient has a thorough understanding of the need for treatment to encourage medication adherence. Persistence of pain or swelling, shortness of breath, chest pain, or rapid heart rate can indicate the patient is not responding to treatment, the thrombus may be enlarging, or a pulmonary embolism may be developing. Patients need to understand the seriousness of these findings and must seek medical care immediately. Information regarding a patient's ability to contact emergency personnel and proximity to treatment centers needs to be ascertained. Pharmacists should also demonstrate proper injection technique to the patient and/or caregiver. Instruct patients to inject the LMWH subcutaneously at the same time every day. The manufacturer of enoxaparin recommends injecting the drug at a 90-degree angle in the abdomen 2 inches away from the belly button unless the patient is very thin. In the thin patient, it should be injected at a 45-degree angle. For those using the exact amount of prefilled enoxaparin, available as 30-, 40-, 60-, 80-, and 100-mg syringes, the air in the syringe should not be expelled since there is the potential for drug loss. If, for example, 75 mg is to be used, the air and 5 mg extra may be expelled. LMWH should be stored at room temperature, and the syringes should be disposed in designated containers.

 

The treatment of DVT with LMWH has its risks; therefore, pharmacists should obtain a complete medical history to determine if any contraindications to therapy exist. Patients with a known allergy to any heparin preparation or a history of immune-mediated heparin-induced thrombocytopenia should not receive LMWH. Patients at risk for major bleeding episodes should not receive home-based therapy. All patients should be aware of the potential for major bleeding and instructed to look for signs of bleeding at the injection site, nose, urine, stool, and gums.

 

The use of LMWH, specifically enoxaparin, in the treatment of acute DVT in the ambulatory patient is a viable treatment option. It has been shown to be at least equally effective as UFH in the treatment of DVT. Pharmacists must ensure that the proper patient is selected and that the drug is administered properly. Pharmacists must also effectively counsel the patient on the proper use of these medications.

Questions 17 through 20 of the quiz are based on the following case:
A 50-year-old white male truck driver develops a first episode of DVT. He just completed a trip from New York City to Los Angeles. He has hypertension but no other medical problems. He currently takes atenolol 50 mg daily for hypertension. He smokes tobacco (1 pack daily). Weight, 70 kg; height, 5 feet 10 inches. He is very reliable and has good family support at home. He lives 5 miles from the hospital. He has a phone at home.

References

For a list of references, send a stamped, self-addressed envelope to: References Department, Pharmacy Times, 1065 Old Country Road, Westbury, NY 11590.