REPORT

Antithrombotic Therapy for the Treatment of Venous Thromboembolism Edith A. Nutescu, PharmD

enous thromboembolism (VTE), a disease encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is responsible for 300 000 to 600 000 hospitalizations in the United States each year,1 with 60 000 deaths annually attributed to PE alone.2 Preventive antithrombotic agents can reduce morbidity and mortality associated with VTE but are frequently underemployed; therefore, the prevalence of VTE remains high in hospitalized and surgical patients.3 The costs of treatment associated with VTE are high and have been estimated to range around $1.5 billion per year.4 Patients with VTE can often present with asymptomatic disease leading to fatal PE if treatment is not initiated in a timely manner.5 Unrecognized and untreated DVT may predispose patients to recurrent VTE episodes and result in long-term complications such as the postphlebitic syndrome.6 Anticoagulation is an essential component of care for patients with DVT and PE. Inadequate treatment has been associated with a 47% symptomatic recurrence of the disease within 3 months. In contrast, less than 5% of patients who receive adequate treatment will develop a recurrent event.7 Traditional anticoagulants employed in the treatment of VTE include unfractionated heparin (UFH) and warfarin. Developed in the 1980s, low-molecular-weight heparins (LMWHs) represent a significant advance over traditional anticoagulants and are now considered the standard of care for VTE treatment.8 In addition to LMWHs, a number of new antithrombotic agents, including the synthetic factor Xa inhibitors and the direct thrombin inhibitors, are emerging and may offer additional benefits over cur-

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rent therapies once their role in practice has been defined.9 Etiology and Pathophysiology of VTE

The natural physiology of VTE can be explained by 3 factors collectively known as Virchow’s triad: venous stasis, vascular injury, and hypercoagulability (Figure).2,10 Venous stasis is marked by altered or decreased blood flow to the deep veins in the lower limbs. This can lead to local endothelial damage of the venous valves secondary to hypoxia and the local concentration of activated clotting factors. Vascular injury can occur secondary to mechanical or chemical trauma that evokes an inflammatory response and local activation of the coagulation cascade. Hypercoagulability may develop in individuals who are predisposed to this disorder as a result of acquired or inherited risk factors.10,11 Several factors can affect each of the components of Virchow’s triad, placing patients at risk for thrombosis.11,12 Venous stasis can result from prolonged immobility, increased age, obesity, pregnancy, malignant disease, varicose veins, and congestive heart failure. Sources of vascular injury include surgery, bone fracture, venipuncture, and chemical irritation. Inherited hypercoagulable states (thrombophilic disorders) potentiating the risk of VTE include activated protein C resistance (factor V Leiden mutation), the presence of prothrombin variant 20210A, elevation in coagulation factor VIII or XI, and deficiencies in protein C, protein S, and antithrombin. Acquired risk factors, including the presence of lupus anticoagulant and antiphospholipid antibodies, cancer, and estrogen and selective estrogen receptor modulator use, can also contribute to

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REPORT Figure. Venous Thromboembolism Pathogenesis

Virchow’s Triad

Vascular injury

Venous stasis

Hypercoagulability

Very high risk Medium/high risk Low/medium risk Source: Adapted from Hirsh J et al. Circulation. 1996;93:2212-2245.

hypercoagulability.6,13,14 These risk factors are additive in nature, and the risk of developing VTE increases in direct proportion to the number of risk factors (Table 1).14 Treatment of VTE

Anticoagulation is the key therapeutic component in treating patients with VTE. PE and DVT are treated using similar anticoagulant drugs and physical methods.

Table 1. Risk of Developing VTE (Additive Nature of Risk Factors) No. DVT Risk Factors

Confirmed DVT (%)

0

11

1

24

2

36

Thrombolytic Therapy

Thrombolytic therapy (streptokinase, urokinase, tissue plasminogen activator) is currently reserved for patients with massive PE, cardiorespiratory compromise, and low risk of bleeding. Unlike the heparins and warfarin, these agents lyse the clot. However, in patients with PE, evidence suggests that clot dissolution may not be complete, and the risk of bleeding is increased. In addition, there is no evidence that these agents reduce short-term mortality.8,16

3

50

Physical Methods

≥4

100

Physical methods of VTE prevention and treatment include inferior vena cava filters and various mechanical and surgical methods to extract the thromboemboli. Inferior

Source: Adapted from Wheeler HB et al. Arch Surg. 1982;117:1206-1209. VTE indicates venous thromboembolism; DVT, deep vein thrombosis.

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Anticoagulation treatment for VTE can be divided into an initial or acute phase (> 5 days) followed by a period of chronic anticoagulation (> 3 months). Current anticoagulant alternatives for the initial and chronic treatment phases include UFH, LMWH, and warfarin. UFH and warfarin have been the cornerstone agents traditionally used for VTE treatment. Over the past decade, LMWHs have been gradually replacing the traditional anticoagulants and are now considered a standard of care for VTE treatment. Less frequently used options include thrombolytic agents and various physical methods.8 Emerging anticoagulant options for both the acute and chronic phases of VTE treatment include synthetic factor-Xa inhibitors such as fondaparinux and idraparinux and the oral direct thrombin inhibitor (DTI) ximelagatran.9,15 The goal of treatment in patients with VTE is to prevent thrombus extension, embolization to the lungs, death due to PE, and the development of complications such as recurrent thromboembolic events and the postthrombotic syndrome. The ideal anticoagulant therapy would of course achieve these goals with minimal adverse effects and patient inconvenience.2,8 The American College of Chest Physicians (ACCP) provides evidence-based recommendations for the use of various antithrombotic agents in the treatment of VTE (Table 2).

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Antithrombotic Therapy for the Treatment of Venous Thromboembolism vena cava filters can be used in patients in whom anticoagulation is contraindicated and in patients with or at high risk of proximal DVT. Filters reduce the rate of PE, although this benefit is offset by a higher recurrence in DVT. Therefore, anticoagulation needs to be resumed as soon as possible after filter insertions. Pulmonary embolectomy is reserved for emergency situations, such as in patients with massive PE in whom other measures of treatment have failed.8,16 Unfractionated Heparin

Heparin has been the mainstay anticoagulant for initial VTE treatment for several decades. Discovered in the early 20th century, UFH is a heterogeneous mixture of glycosaminoglycans commercially isolated from porcine or bovine mucosa.17 UFH exerts its anticoagulant effect via a plasma cofactor—antithrombin (AT). UFH binds to AT via a unique 5-saccharide sequence, causing a conformational change in AT. AT in turn inhibits thrombin (factor IIa) and factor Xa. Only larger saccharide chains (> 18 units) are able to catalyze thrombin inhibition. The smaller heparin molecules (< 18 units) containing the highaffinity pentasaccharide sequence accelerate inactivation of factor Xa but are unable to inactivate thrombin. UFH is a heterogeneous mixture of chains with molecular weights ranging from 3000 to 30 000 daltons, with only one third of molecules exhibiting anticoagulant activity. Heparin has a short half-life and must be administered parenterally.18 Heparin’s nonspecific binding to a number of plasma and cellular proteins results in decreased bioavailability and substantial interpatient variability in anticoagulant response. Therefore, when given in therapeutic doses, UFH requires frequent laboratory monitoring to assess the level of anticoagulation, as measured by activated partial thromboplastin time (aPTT).18 UFH dosed to achieve aPTT > 1.5 has been demonstrated to be effective in the initial treatment of VTE. Attaining an adequate level of anticoagulation quickly after starting heparin therapy is crucial, as the risk of VTE recurrence is significantly higher in patients with aPTT ratios < 1.5 during the first few

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Table 2. ACCP Consensus Conference Recommendations for Current Treatment of VTE ■ ACCP recommends initial treatment with LMWH, IV UFH, or adjusted-dose SC UFH followed by at least 3 months of oral anticoagulation therapy. (ACCP Grade 1A recommendation) ■ LMWHs are preferred agents due to the benefits of convenient dosing, the transition to outpatient treatment, slightly less recurrent VTE, and a potential survival benefit in cancer patients. (ACCP Grade 2B recommendation)

Source: Adapted from Hyers TM et al. Chest. 2001;119(suppl 1):176S-193S. ACCP indicates American College of Chest Physicians; VTE, venous thromboembolism; LMWH, low-molecular-weight heparins; SC, subcutaneous; UFH, unfractionated heparin.

days of therapy. Therefore, an adequate bolus dose of UFH should be given, and frequent aPTT monitoring, every 6 hours, is indicated during the first 24 hours of infusion. The initial phase of heparin therapy needs to be followed by long-term anticoagulation with warfarin. Warfarin can be started on the first day of UFH therapy and should be continued for ≥ 3 to 6 months. Heparin therapy must be continued for ≥5 days and until concurrent use with warfarin has achieved an international normalized ratio (INR) of 2 to 3 for ≥48 hours. In patients with more complicated DVT or major PE, UFH can be continued for ~10 days.16 Warfarin

The initial treatment phase of VTE with UFH or LMWH is continued with treatment with oral anticoagulants. These agents interfere with the metabolism of vitamin K, inhibiting the synthesis of biologically active coagulation factors II, VII, IX, and X. Warfarin, discovered in the early 1940s, is the most widely used oral anticoagulant in North America. Warfarin’s efficacy is influenced by significant interindividual variations, such as dietary fluctuations in vitamin K, drug interactions, and genetic factors. Warfarin has a narrow therapeutic index, indicating a relatively small margin between safety and toxicity. Frequent laboratory

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REPORT monitoring of warfarin’s anticoagulant effect via the INR is required to allow for dose adjustments that aid in attaining efficacy without compromising safety. Due to the slow onset of effect of warfarin, a stable anticoagulant response may not be achieved until ≥5 days after the initiation of treatment or any change in dose. Patient response to warfarin is highly variable. Although the average daily dose to maintain patients within the appropriate therapeutic range is 4 to 5 mg, dosing requirements range from 20 mg-day to reach a similar end point.19 Adjusted-dose warfarin at an INR goal 2.5, range 2.0 to 3.0, is the standard for the treatment of VTE. Higher INR levels tend to increase the incidence of bleeding without additional benefit in reducing VTE. Warfarin should be initiated in conjunction with UFH or LMWH once the diagnosis of VTE is confirmed. Heparin or LMWH should be continued concomitantly with warfarin for ≥5 days, until INR is >2.0 for 48 hours. Warfarin therapy should then be continued for at least 3 to 6 months. Higher risk patients, such as those with recurrent VTE, hypercoagulable states, or cancer, should receive chronic anticoagulation therapy.8 Warfarin is contraindicated during pregnancy (especially during weeks 6-12) because it crosses the placenta and can cause fetal malformations and spontaneous abortion. The long-term therapy of choice in pregnant patients with VTE is subcutaneous LMWH or UFH given in treatment doses.8,16 Factor Xa Inhibitors

Similar to thrombin, factor Xa can be inhibited directly or indirectly. The direct inhibitors bind to factor Xa directly, thus blocking its activity. Direct factor Xa inhibitors in development include tick anticoagulant peptide, YM-60828, and the orally active agent, DX-9065A.20-22 Indirect factor Xa inhibitors, such as fondaparinux, have a higher affinity for AT than the naturally occurring pentasaccharides, with a greater inhibitory activity against factor Xa than heparin or LMWH.23 Fondaparinux is a synthetic version for the pentasaccharide sequence of heparin that leads to AT-mediated factor Xa inactivation.20 Unlike the heparins, fondaparinux does

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not affect platelet function and does not react with heparin-PF4 antibodies, thus lessening the risk of heparin induced thrombocytopenia (HIT).24,25 Fondaparinux was approved by the Food and Drug Administration (FDA) in December 2001 for the prophylaxis of DVT in patients with hip fracture and in those undergoing hip or knee replacement surgery. Fondaparinux is administered by subcutaneous (SC) injection, and due to its predictable pharmacokinetic profile and no variations in dose response, it does not require monitoring of its anticoagulant effect. Fondaparinux has a long half-life (17-21 hours), allowing once-daily administration. To date, fondaparinux has been evaluated in 4 large clinical trials in the setting of major orthopedic surgery, demonstrating significantly lower VTE rates compared with LMWH. The incidence of clinically significant bleeding complications with fondaparinux is comparable to LMWH.26-29 In the treatment of VTE, fondaparinux compared favorably with dalteparin in a phase II study.30 Two phase III trials for treatment of DVT and PE have recently completed patient enrollment and will provide further knowledge on the role of fondaparinux for these indications.15 Direct Thrombin Inhibitors

DTIs bind with thrombin to prevent an interaction between the enzyme and substrates. Advantages of DTIs include a targeted specificity for thrombin, the ability to inactivate clot-bound thrombin, and an absence of plasma protein and platelet interactions that can lead to complications such as HIT. Unlike heparin, DTIs do not require antithrombin as a cofactor and do not bind to plasma proteins. Therefore, they produce a more predictable anticoagulant effect, and variability of patient response is relatively low compared with other drug classes.31 DTIs include recombinant hirudin (ie, lepirudin) and smaller synthetic derivatives such as hirulog or bivalirudin. Argatroban belongs to a family of small DTIs that bind noncovalently to the enzyme’s active site. 31 Similar agents

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Antithrombotic Therapy for the Treatment of Venous Thromboembolism include napsagatran, melagatran, and melagatran’s parent molecule, ximelagatran. Ximelagatran is a novel oral DTI currently under development. 32 Clinical evidence suggests that ximelagatran has a wider therapeutic index than warfarin, displays a low interindividual variability, and has a linear pharmacokinetic and pharmacodynamic profile; therefore, it may not require monitoring of its anticoagulant effect.33,34 Ximelagatran is in advanced phases of clinical evaluation for thromboprophylaxis in patients undergoing major orthopedic surgery and general surgery, stroke prevention in atrial fibrillation, and in the treatment of VTE.9 Low-Molecular-Weight Heparins

Since their development in the 1980s, LMWHs have increasingly replaced UFH not only for treatment of VTE but also for prophylaxis. LMWHs offer several advantages over UFH and are currently regarded as the drugs of choice for the treatment of DVT with or without PE.8 LMWHs are derived by chemical or enzymatic depolymerization of UFH, resulting in shorter heparin chains of 3800 to 5000 daltons. Because different methods of depolymerization are used to produce the various LMWHs, the pharmacokinetic and anticoagulant profiles of these agents are distinct, which precludes using them interchangeably. Several organizations, such as the FDA, ACCP, American College of Cardiology, and the American Heart Association, have published statements supporting consideration of the LMWHs as separate pharmacologic entities.35 Therefore, treatment decisions and agent selection should be based on the available efficacy and safety data for each of the LMWHs. Several LMWHs have received FDA approval for use in thromboembolic disorders, including ardeparin, dalteparin, enoxaparin, and tinzaparin. Of the 4 LMWHs approved in the United States, only 3 are currently commercially available: dalteparin, enoxaparin, and tinzaparin.35 LMWHs inactivate thrombin to a lesser extent than UFH because the smaller molecular fragments cannot bind both thrombin and AT simultaneously. LMWHs have an enhanced affinity for inhibiting factor Xa,

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compared with their activity against thrombin. Factor Xa:IIa ratios for LMWHs are agent-specific and range from 4:1 to 2:1. LMWHs have substantially improved pharmacodynamic and pharmacokinetic properties as compared with UFH. LMWHs display a lesser extent of binding to plasma and cellular proteins than UFH, resulting in a more predictable anticoagulant response. Consequently, routine monitoring of the intensity of anticoagulation and dose adjustments are not required. In addition, LMWHs have longer plasma half-lives, allowing once- or twice-daily administration, improved SC bioavailability, and dose-independent clearance. Thrombotic complications, including the risk of HIT, occur to a much lesser extent with LMWHs than with UFH. However, LMWHs cross-react with UFH and should not be given as alternative anticoagulants in patients with HIT.17,18 Table 3 reviews the ACCP algorithm for anticoagulation with LMWH in patients with VTE.

Table 3. ACCP Guidelines for Treatment of VTE Using LMWH Disease Suspected ■ Obtain baseline aPTT, PT, CBC ■ Check for contraindications to heparin therapy ■ Give UFH/LMWH and order imaging study Disease Confirmed ■ Start LMWH* ■ Start warfarin on day 1 at 5mg and adjust subsequent daily dose according to INR ■ Check platelet count between days 3 to 5 ■ Stop LMWH after at least 4 to 5 days of combined therapy when INR >2.0 for 2 consecutive days ■ Anticoagulate with warfarin for ≥ 3 months (goal INR 2.5; range 2.0 to 3.0)

*LMWH can be a choice of: dalteparin 200 IU/kg SC qd or 100 IU/kg SC every 12 hours; maximum daily dose 18 000IU (not FDA appproved in the United States); enoxaparin 1 mg/kg SC every 12 hours or 1.5 mg/kg SC daily (FDA approved for both inpatient and outpatient treatment of DVT with or without PE); tinzaparin 175 IU/kg SC daily (FDA approved treatment of DVT with or without PE). Source: Adapted from Hyers TM et al. Chest. 2001;119(suppl 1):176S-193S. ACCP indicates the American College of Chest Physicians; VTE indicates venous thromboembolism; LMWH, low-molecular-weight heparins; aPTT, activated partial thromboplastin time; PT, prothrombin time; CBC, complete blood count; UFH, unfractionated heparin; INR, international normalized ratio.

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REPORT Clinical Efficacy of LMWHs in the Treatment of VTE

The use of LMWHs in the inpatient treatment of DVT and PE has been well established. Several clinical trials have confirmed their efficacy and safety over UFH. All 3 LMWHs have been evaluated for treatment of VTE, and clinical studies support the use of dalteparin, enoxaparin, and tinzaparin.36-44 Randomized clinical trials have typically included a UFH control arm and defined efficacy based on relative rates of objectively confirmed, symptomatic recurrent venous thrombosis or PE, with a minimum follow-up period of 3 months. Patients with existing bleeding risks, pregnancy, renal impairment (creatinine clearance < 30 mL/min), or thrombocytopenia generally have been excluded from clinical trials. Although clinical trials have compared various LMWHs to UFH, individual LMWHs have not been directly compared in the treatment of DVT/PE. Therefore, the results of specific clinical trials only apply to the LMWH evaluated and should not be generalized to the drug class.35 Specific dosing guidelines for VTE treatment for the LMWHs are summarized in Table 3. Dalteparin

Dalteparin and UFH have been directly compared in 3 randomized, controlled trials of patients with established DVT.38-40 The individual studies did not differ in terms of rates of recurrent thromboembolic events or major bleeding complications. Subsequent pooling of the individual trial

Table 4. The Incidence of Symptomatic VTE: Pooled Data from Comparative Studies of LMWH and UFH Symptomatic VTE LMWH

No. LMWH (%)

No. UFH (%)

P Value

RRR

8/339 (2.4)

.07

−110

Dalteparin

16/322 (5)

Enoxaparin

13/314 (4.1)

20/320 (6.3)

.23

35

Tinzaparin

6/213 (2.8)

15/219 (6.9)

.07

59

Source: Adapted from Turkstra F et al. Thromb Haemost. 1997;78:489-496. VTE indicates venous thromboembolism; LMWH, low-molecular-weight heparins; UFH, unfractionated heparins; RRR, relative risk reduction.

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results, however, suggest a trend toward increased symptomatic VTE in patients treated with dalteparin, 5.0% versus 2.4% in patients treated with UFH (P = .07)41 (Table 4). The pooled failure rate in patients treated with UFH was notably lower than that reported in previous trials of UFH. Another potential reason for the differences in outcomes may be related to the fact that the maximum allowed daily dose of dalteparin was 18 000 IU, leading to a “potential” underdosing of the agent in patients weighing > 90 kg. Enoxaparin

Simonneau and colleagues compared enoxaparin (1 mg/kg twice daily) with continuous infusion IV UFH in 134 patients with proximal DVT. The incidence of overall recurrent thromboembolic events was significantly higher in the UFH group (10.4%) than in the enoxaparin group (1.5%), P < .002. No serious bleeding complications occurred in either group.36 A multicenter trial of 900 patients with acute DVT, which included patients with or without PE, compared once-daily administration of enoxaparin (1.5 mg/kg/dose) with twice-daily (1 mg/kg/dose) enoxaparin, and adjusted-dose UFH.37 Recurrent VTE was identified in 4.4% of patients who received enoxaparin once daily, in 2.9% patients who received enoxaparin twice daily, and in 4.3% of patients who received UFH. The differences were not statistically significant. The incidence of bleeding complications also did not differ among the groups. Although overall recurrent symptomatic thrombosis rates were similar across the 3 treatment groups, secondary stratification analyses revealed an increased incidence of clinical failure in patients with the comorbid conditions of obesity or cancer treated with once-daily enoxaparin. These results indicate that further prospective study may be warranted before once-daily regimens of enoxaparin can be recommended in high-risk patients, such as those who are overweight or those who have cancer.37 Tinzaparin

In the 3 trials that have compared tinzaparin with UFH in the treatment of VTE,42-44

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Antithrombotic Therapy for the Treatment of Venous Thromboembolism tinzaparin was dosed on at 175 IU/kg oncedaily. In 2 trials, subjects included patients with confirmed PE, with or without associated proximal DVT, excluding those patients suspected of having massive embolism, based on hemodynamically unstable presentations.43,44 Hull and colleagues compared tinzaparin to UFH in 432 patients with proximal DVT.42 Six of 213 patients who received tinzaparin (2.8%) and 15 of 219 patients who received UFH (6.9%) had new episodes of VTE (P = .07). In the initial treatment course, major bleeding was more common in patients treated with UFH (5.0%) than in those treated with tinzaparin (0.5%; P = .006).42 In a secondary analysis, a trend toward a reduction in overall mortality during a 3-month follow-up period favoring patients treated with tinzaparin was demonstrated (4.7% in tinzaparin group vs 9.6% in UFH group; P = .062). Another study randomly assigned 612 patients with symptomatic PE (not requiring thrombolytic therapy or embolectomy) to once-daily tinzaparin or adjusted-dose IV UFH.43 Treatment was continued for at least 5 days and until an INR of 2.0 or above (based on concomitant warfarin therapy) was achieved. Patients were evaluated at days 8 and 90 with respect to a combined end point of recurrent thromboembolism, major bleeding, or death. After 3 months (day 90), 22 patients assigned to UFH (7.1%) and 18 patients assigned to tinzaparin (5.9%) had reached at least 1 end point (P = .54). There were no differences between the groups when the end points of recurrent VTE, death, or major bleeding complications were analyzed separately. In a related trial, Hull and colleagues examined 200 patients with underlying proximal DVT and concomitant PE.44 Over a 3-month follow-up period, none of the 97 patients who received tinzaparin had a new episode of VTE as compared with 7 (6.8%) of 103 patients who received UFH (P = .01). The 2 groups did not differ in bleeding complications. Meta-analyses of LMWHs in the treatment of VTE have shown that LMWHs are at least as effective or better than UFH in preventing recurrent thromboembolic events, with evidence of a consistent and statistically significant decrease in overall mortality favoring

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LMWH treatment.45,46 A recent meta-analysis, limited to doses of LMWHs currently recommended for clinical use, reported a decrease in recurrent VTE events, major bleeding, and mortality by 34%, 44%, and 32%, respectively.47 LMWH in the Outpatient Treatment of DVT

Emerging data suggest that certain patients with DVT can safely be treated in the outpatient setting. Outpatient therapy allows for a more convenient and more economical way of managing patients with VTE.8 Two recent studies have been published evaluating the out-of-hospital use of LMWHs for the initial treatment of DVT.48,49 In the study conducted by Levine et al,48 patients with objectively diagnosed proximal DVT were randomly assigned to intravenous (IV) UFH in the hospital or enoxaparin 1 mg/kg (100 anti-Xa U/kg) SC twice daily, administered primarily at home. Patients on LMWH were either treated at home without admission or hospitalized patients were discharged early. Of the 247 patients randomized to receive LMWH, 120 were not hospitalized at all (49%). The 127 patients who were admitted spent an average of 2.2 days in the hospital. Of the 247 LMWH patients, 13 (5.3%) developed recurrent thromboembolism versus 17 (6.7%) of 253 patients receiving IV UFH (P = .57). Major bleeding occurred in 5 (2%) patients on LMWH versus 3 (1.2%) patients in the IV UFH group. The overall mortality was 17 (6.7%) patients in the IV UFH group and 11 (4.4%) patients in the LMWH group. After randomization, the mean hospital stay was 1.1 days in the LMWH group versus 6.5 days in the IV UFH group. A second study by Koopman et al49 randomized patients with DVT to IV UFH in the hospital or nadroparin SC twice-daily dosing based on a weight-adjusted regimen. Patients 70 kg received 18 400 anti-Xa U/kg. The protocol allowed patients in the LMWH group to be sent home immediately and treated as outpatients or hospitalized patients to be discharged early. Recurrent thromboembolism was docu-

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REPORT mented in 14 (6.9%) of 202 patients on LMWH versus 17 (8.6%) of 198 patients receiving IV UFH (P > .5). One patient (0.5%) in the LMWH group developed major bleeding compared with 4 (2%) patients in the IV UFH group. During the 6-month follow-up period, 16 patients (8.1%) in the IV UFH group died versus 14 patients (6.9%) in the LMWH group. In the LMWH group, 36% of patients were never admitted to the hospital and 40% were discharged early, resulting in a mean reduction in hospital stay of 67%. The results of these 2 studies indicate that LMWH administered to eligible patients with DVT on an out-of-hospital basis is as effective and safe as IV UFH administered in the hospital. Feasibility of Outpatient DVT Treatment Programs

Because a fairly high percentage of patients were excluded from the outpatient DVT treatment trials, the feasibility of implementing such programs in the real world has been questioned. Two studies explored the feasibility of this approach outside of a clinical trial setting.50,51 Harrison et al50 performed a prospective cohort study of consecutive patients presenting to 2 thromboembolism clinics. Of 113 patients diagnosed with DVT, 24 were excluded because of hospital admission, loss to follow-up, or inability to obtain LMWH at home because of insurance. The remaining 89 patients were treated at home with SC dalteparin 100 U/kg every 12 hours (72% of patients) or tinzaparin 175 U/kg daily (28% of patients). LMWH was given for a minimum of 5 days and until the INR was therapeutic. Warfarin was started early in the course of LMWH treatment and continued for a minimum of 3 months. Three quarters of the patients (n = 67) gave themselves injections or received them from a family member; the remaining 22 (25%) patients required assistance from nurses. Of the 89 patients, 1 died of PE and significant bleeding 4 hours after the first LMWH injection, 8 died of nonthromboembolic causes, 1 had a minor bleeding episode, and 5 patients with cancer had recurrent DVT. A total of 91% of patients preferred outpatient treatment, and 70%

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were comfortable with self-injection. The results support feasibility of such a model for most patients and demonstrate a high degree of patient satisfaction. A second study51 sought to determine whether expanding patient eligibility for outpatient treatment of DVT and PE affects safety and effectiveness of treatment and whether patient self-injection compared with injections administered by a homecare nurse affected outcomes. All patients with DVT and PE were treated as outpatients, except those with massive PE, high risk for major bleeding or an active bleed, or phlegmasia and patients hospitalized for reasons that prevented discharge. Both models involved nurse managers who provided daily patient contact. In 1 model, patients were taught to self-inject, and in the other model, injections were administered by homecare nurses. Most patients were treated with dalteparin 200 U/kg SC every 24 hours, for a minimum of 5 days. Warfarin therapy was started early and continued for at least 3 months. Of 233 consecutive patients, 194 (83%) were deemed eligible and treated as outpatients. Of the 39 patients who did not receive home therapy, 20 had concomitant medical problems responsible for their admission or were already inpatients, 6 had massive PE, 6 refused to pay for dalteparin therapy, 4 had active bleeding, and 3 had phlegmasia requiring treatment with IV narcotics. More than 184 (95%) of the 194 patients were treated entirely at home. The difference (P > .99) in the rate of recurrent VTE events between patients who were injected by homecare nurses (3/95 [3.2%]) and those who injected themselves (4/99 [4.0%]) was not significant. The overall recurrent event rate was 3.6%. Similarly, there was no significant difference in rates of major hemorrhage, minor hemorrhage, and death. The overall rate of major hemorrhage was 2.0%. This study demonstrated that more than 80% of patients could be treated at home and that patients can safely and effectively perform home self-injection. These 2 studies demonstrated that outpatient treatment programs can be safely and effectively implemented in real-world settings.

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Antithrombotic Therapy for the Treatment of Venous Thromboembolism Patient Considerations for Outpatient Treatment of DVT with LMWH

The use of out-of-hospital LMWH has created a number of logistical problems. Many of the exclusion criteria from the clinical trials apply in clinical practice as well. Exclusion criteria for the outpatient treatment of VTE include proximal DVT with vascular compromise, PE with hemodynamic instability, patients at high risk of bleeding, patients with significant comorbid conditions requiring hospitalizations, geographic inaccessibility, noncompliant patients, and patients with a previous history of HIT.52 Patients with a primary diagnosis of DVT (reason for admission is a confirmed DVT) are better candidates for outpatient treatment with LMWH. For ~40% to 50% of patients with primary DVT, outpatient treatment with LMWH has been shown to be safe and effective. Patients with a secondary diagnosis of DVT (DVT developed during hospitalization after admission for another medical condition) may be less suitable for outpatient DVT treatment with LMWH due to underlying medical conditions. Patients with secondary DVT have a gross mortality rate of 43%, compared with a gross mortality rate of 3% for primary DVT.53 Before outpatient DVT treatment programs are implemented, certain requirements must be met, such as appropriate clinical space, adequate staffing for patient education and care, a smooth transition from hospital to clinic, delivery of LMWH to the patient, ensuring that INRs are measured daily, appropriate warfarin dose is administered to patients, and adequate funding. Payment for LMWH, especially in patients with no third-party insurance, remains a challenging and unresolved issue. The need for transition clinics to enable proper conversion of treatment with LMWH to warfarin is evident.52,53 Depending on available resources at each specific site, there are 6 different models reported in the literature for establishing an outpatient DVT treatment program: anticoagulation clinic, homecare, ambulatory-care clinic, emergency department, 1-visit and self-injection, and physician’s office.53 After evaluating the 6 existing treatment models, the model that best suits the specific institutional require-

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ments needs to be implemented. Determination of a core group of clinicians who will assume responsibility for the program is critical for its success (eg, who will gather details on patient recruitment and follow-up). A well-designed, detailed protocol is also required. The protocol should include criteria for patient selection, drug selection, patient and caregiver education, monitoring, and LMWH dose preparation.54 Warfarin monitoring and continuity of care are frequently overlooked and can lead to increased time to reach therapeutic INR and extended use of LMWHs.52,53 Pharmacoeconomic Considerations

LMWHs have revolutionized the management of VTE, but the high cost of these drugs appears to be a major impediment to implementing outpatient treatment programs. Acquisition cost is not the only factor that needs to be considered when evaluating costeffectiveness of these agents for DVT treatment. Overall treatment costs are best analyzed through pharmacoeconomic modeling.55 Cost comparisons must be individualized based on each institution’s specific needs. Although acquisition cost of LMWHs can be quite high for patients with DVT, the savings attained by not using hospital facilities for selected patients can be far higher.54,55 Based on a randomized prospective clinical trial, Hull et al56 performed a cost-effectiveness analysis comparing the treatment of proximal DVT in 432 patients receiving oncedaily fixed-dose SC LMWH or adjusted-dose IV UFH. Table 5 shows the total cost and effects per 100 patients of the 2 alternative approaches for the treatment of proximal DVT. This economic analysis found that LMWH is at least as safe and effective as IV UFH and is less costly. The use of LMWH was associated with cost savings of $40 149 in the treatment of 100 patients with proximal DVT. A total of 70 of the 231 patients who were treated with LMWH had uncomplicated proximal DVT and could have been treated as outpatients. (In the cost analysis, it was defined a priori that treatment could be given on an outpatient basis to patients without comorbid conditions.) If 37% of the patients were treated as outpatients, then the total cost per 100 patients who received LMWH would have

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REPORT been $284 504. The potential use of outpatient therapy with LMWH in 37% of the patients increased the cost savings from $40 149 to $91 332 in the treatment of 100 patients with proximal DVT. This cost analysis demonstrates that the outpatient management of acute proximal DVT with the use of LMWH is more cost effective than treatment using IV UFH in the hospital. Several additional studies have demonstrated the cost-effectiveness of LMWHs for the treatment of outpatient DVT. An economic evaluation in a large HMO program resulted in cost savings of $2828 for each patient treated at home with LMWH.57 Similarly, another study documented a mean difference in cost of $2583 per patient favoring the LMWH group.58 These savings are consistent with data from non–managed care settings that estimated savings of $2750 per patient treated in the outpatient setting.59 These data clearly suggest that the economic evidence is in favor of outpatient treatment with LMWH. In addition, evidence suggests that even inpatient treatment of VTE with LMWH as opposed to UFH is able to reduce treatment costs.60 In today’s cost-conscious environment, treating VTE patients with LMWH seems economically logical. Formulary Considerations

At this time there is no evidence that 1 LMWH is more efficacious or safer than another, given the lack of comparative trials

between agents for treatment of VTE. As we gain more experience with these agents, the optimal choice may become more obvious. At this point, treatment choices should be made based on safety and efficacy data for each available formulation, ease of administration, and cost. Clinical trial data cannot be applied from 1 preparation to another, as these agents are slightly different in their method of preparation and pharmacokinetic and pharmacodynamic profiles.61 Summary

VTE is a major but often-overlooked healthcare problem resulting in significant morbidity, mortality, and resource expenditures. The efficacy of anticoagulation therapy has been well documented in patients with VTE. The availability of LMWHs has advanced treatment of VTE by allowing for effective anticoagulation without the need for dose adjustments and routine monitoring. In addition, patients with uncomplicated DVT can be safely treated in the outpatient setting, allowing for shorter hospital stays and cost savings. LMWHs have been replacing traditional anticoagulants and are now considered the antithrombotic agents of choice in the initial treatment of VTE. Research on additional novel anticoagulants such as DTIs and factor Xa inhibitors is promising. These agents may offer potential benefits over current therapies, but their exact role in clinical practice remains to be determined pending addition-

Table 5. Total Costs and Effects per 100 Patients of the Alternative Approaches for Antithrombotic Therapy for Proximal DVT Major Recurrent Approach IV UFH LMWH

Bleeding

Cost ($US)

VTE

Death

Complications

7 3

10 5

5 3

375 836 335 687 40 149* 91 332†

*Cost savings per 100 patients treated with LMWH. †Cost savings per 100 patients treated with LMWH and discharged on day 2. Source: Adapted from Hull R et al. Arch Intern Med. 1997;157:289-292. DVT indicates deep vein thrombosis; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin.

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Antithrombotic Therapy for the Treatment of Venous Thromboembolism al ongoing clinical studies. Benefit-to-risk analyses will be necessary for determining how effective novel therapies will compare with established regimens.

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