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(Circulation. 2004;110:I-10 – I-18.)
© 2004 American Heart Association, Inc.

Treatment of Venous Thromboembolism

Long-Term Management of Patients After Venous Thromboembolism

Clive Kearon, MB, MRCPI, FRCPC, PhD

From the Department of Medicine, McMaster University, McMaster Clinic, Henderson General Hospital, Hamilton, Ontario, Canada.

Correspondence to Dr Clive Kearon, McMaster University, McMaster Clinic, Henderson General Hospital, Hamilton Health Sciences, 711 Concession St, Hamilton, Ontario, Canada L8V 1C3. E-mail kearonc{at}mcmaster.ca

	Abstract

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Long-term treatment of venous thromboembolism (VTE) focuses mainly on the duration of anticoagulant therapy, usually with vitamin K (VK) antagonists. The duration of therapy should be individualized based on the risk of recurrent VTE if treatment were stopped and the risk of bleeding if treatment were continued. The risk of recurrence is low if thrombosis was provoked by a major reversible risk factor such as surgery; 3 months of treatment is usually adequate for such patients. The risk of recurrence is high if thrombosis was unprovoked ("idiopathic") or associated with an irreversible risk factor such as cancer; anticoagulant treatment for at least 6 months, and often indefinitely, is indicated for such patients. Risk of recurrence is intermediate if thrombosis was associated with a minor transient risk factor; such patients can be treated for 3 to 6 months. Within each of these categories, presentation as pulmonary embolism, >1 previous VTE, an underlying malignancy, an antiphospholipid antibody, or selected hereditary thrombophilic states favor more prolonged therapy, whereas isolated distal deep vein thrombosis, high risk of bleeding, and patient preference favor shorter treatment. The optimal intensity of anticoagulant therapy with VK antagonists corresponds to a target international normalized ratio of 2.5 (range, 2.0 to 3.0). Long-term treatment with low-molecular-weight heparin is an alternative to VK-antagonist therapy and is usually preferable in patients with active cancer. Oral direct thrombin inhibitors also appear suitable for long-term prevention of recurrent VTE but await regulatory approval and comparison with VK antagonists.

Key Words: deep vein thrombosis • pulmonary embolism • anticoagulant therapy • warfarin

	Introduction

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
After an episode of venous thromboembolism (VTE), treatment should be continued until the benefits of anticoagulation therapy no longer clearly outweigh the risks. For some patients, the benefit of continuing therapy never decreases to the point that anticoagulation should be stopped. The optimal duration of anticoagulation, therefore, should be individualized. Foremost, this assessment weighs the risk of recurrent VTE if anticoagulation is stopped against the risk of bleeding if treatment is continued. If it is concluded that the net benefit of continuing anticoagulant therapy is small or uncertain, then patient preference and cost of therapy become important factors, particularly if indefinite therapy is considered.

This review focuses principally on the optimal duration and intensity of vitamin K (VK) antagonist therapy for VTE. Secondarily, treatment of VTE with low-molecular-weight heparin (LMWH) as an alternative to VK antagonists and the role of graduated compression stockings to prevent the postthrombotic syndrome are addressed.

	Risk of Recurrent VTE After Stopping Anticoagulant Therapy

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Reversibility of Risk Factors for VTE
Perhaps the most important factor in assessing risk of recurrent VTE is the relationship of the initial episode of thrombosis to risk factors. When a major reversible risk factor such as surgery can be identified as the sole explanation for VTE, then the risk of recurrence is relatively low (ie, 3% in the first year).^1,2,4–7

In contrast, the risk is high (10% in the first year) in patients with unprovoked ("idiopathic") VTE and in those with persistent, irreversible, or other risk factors (Table 1).^1–7,37,38 Patients in whom thrombosis was provoked by a reversible risk factor, such as leg trauma, estrogen therapy, or prolonged air travel (eg, a flight >10 hours long), have an intermediate risk for recurrent VTE after stopping anticoagulant therapy (5% in the first year).^7,25,39

View this table: [in this window] [in a new window]   TABLE 1. Risk of Recurrent VTE After Stopping Anticoagulant Therapy

Thrombophilia
Hereditary and acquired biochemical states associated with VTE ("thrombophilia") are heterogeneous, both in terms of the frequency with which they occur in the normal population and the strength of their association with thrombosis (Table 1).^40–43

Antiphospholipid Antibodies
Antiphospholipid antibodies (anticardiolipin antibody^8,22 or lupus anticoagulant⁸) are associated with a 2-fold or greater risk of recurrent thrombosis after stopping anticoagulant therapy.^8,22 One study also found that after a first episode of VTE, an anticardiolipin antibody was associated with a higher mortality during long-term follow-up because of an excess of venous and arterial thrombotic events. Continuing anticoagulant therapy appeared to reduce this risk.²²

Factor V Leiden and the G20210A Prothrombin Gene Mutation
Individuals with heterozygous forms of either the factor V Leiden or the G20210A prothrombin gene mutation do not appear to harbor a clinically important risk for recurrent VTE.^7,8,17,38,39

Patients heterozygous for both of these mutations^9,15,18,19 or homozygous for the factor V Leiden mutation¹⁴ appear to be at increased risk of recurrent VTE (Table 1).

Deficiency of Protein C, Protein S, or Antithrombin
There is little prospective information on the risk of recurrent VTE in patients with antithrombin, protein C, or protein S deficiency. In patients with 1 of these abnormalities or a lupus anticoagulant, a prospective study identified a hazard ratio of 1.4 for recurrent VTE.¹⁰ In another study, relative risks for recurrent VTE were 1.0 for protein S, 1.8 for protein C, and 2.6 for antithrombin deficiency.⁷ A third study found no increase in recurrence among 15 patients with any of these deficiencies.⁹ In a retrospective family cohort study, the presence of 1 of these abnormalities was associated with a 10% cumulative frequency of recurrent VTE in the first year after diagnosis and a 23% frequency by 5 years.⁴⁴ Therefore, although there is uncertainty, these abnormalities do not appear to be clinically important risk factors for recurrent VTE.

Elevated Factor VIII Levels
Although a markedly elevated plasma level of factor VIII appears related to recurrent thrombosis, prospective validation is lacking (Table 1).^20,21

Hyperhomocysteinemia
Hyperhomocysteinemia, which can be hereditary or acquired,⁴⁵ was associated with a 2.7-fold increased risk of recurrent VTE in a study of patients with unprovoked VTE.²³ Lowering plasma homocysteine levels with vitamin therapy did not convincingly reduce the frequency of recurrent VTE.⁴⁶

Cancer
Cancer is associated with 3-fold increased risk of recurrent VTE both during^{26,29,47–49} and after^6,10,25,29 anticoagulant therapy. Among patients with cancer, the risk of recurrence is 3-fold higher in those with metastatic disease than in those with localized tumors (Table 1).²⁶ In patients with cancer, the risk of recurrent VTE after stopping anticoagulant therapy is as high as 10% to 20% in the first year, particularly in cases of progressive or metastatic disease, in those with poor mobility, or those receiving ongoing chemotherapy.^4,6,25 The risk of recurrence is uncertain but probably lower when the cancer is responsive to therapy, or if the initial VTE was provoked by other reversible risk factors such as surgery or chemotherapy.

Pulmonary Embolism Versus Deep Vein Thrombosis
Patients with pulmonary embolism (PE) appear to have the same risk of recurrent VTE as those with proximal deep vein thrombosis (DVT).^3,25,32,50 However, after an initial PE, 60% of recurrent episodes of VTE are also PE, whereas only 20% of recurrent episodes of VTE are PE after an initial DVT.^{30,32,50–52} This pattern of recurrence—with 3-fold higher risk of PE after an initial PE than after an initial DVT—appears persistent.^32,51 Approximately 10% of symptomatic PEs are rapidly fatal^53–55 and another 5% of those in whom PE is diagnosed and treated also die of it.^{32,51,56–59} Thus, after 3 months of treatment for DVT or PE, recurrent VTE presenting as PE has a case fatality rate of 15%. The risk of dying from acute DVT, because of early subsequent PE or other complications (eg, bleeding, precipitation of myocardial infarction), is closer to 2% or less.^{10,32,51,57,60} Based on these estimates, the case fatality rate associated with late recurrent VTE preceded by PE is 10%, whereas it is 5% after a preceding DVT. An overview of randomized trials involving patients with DVT who had completed 3 months of treatment noted a 5.1% case-fatality rate for recurrent VTE, consistent with the foregoing estimate.⁵⁰ Hence, although the risk of recurrence is approximately the same after PE and proximal DVT, the case fatality rate associated with recurrence is 2-fold higher after PE than DVT.

Patients with VTE and chronic thromboembolic pulmonary hypertension should generally be treated indefinitely because they may have a history of recurrent PE and cannot tolerate additional episodes.⁶¹

Residual Deep Vein Thrombosis
It is uncertain whether residual DVT is an independent predictor of recurrent VTE. Piovella et al found that residual proximal DVT on ultrasound after 3 months of treatment was associated with a >3-fold increase in recurrent thrombosis, with three-quarters of DVT occurring in the same leg.²⁹ Prandoni et al reported a >2-fold increase in the frequency of recurrent VTE when DVT persisted on ultrasound imaging.⁶² However, it is unclear whether this association persists after adjustment for the time elapsed after initial DVT. Agnelli et al reported a statistically significant 1.4-fold increase in recurrent VTE among patients with PE who had concomitant DVT 3 months after initial treatment.³⁰ In contrast, 2 other studies of patients with unprovoked VTE found that residual proximal DVT after 3 months of treatment did not predict recurrent VTE during anticoagulant therapy (hazard ratio 0.9; target international normalized ratio [INR] 1.5 to 1.9 for half of the patients)⁶³ or after treatment was stopped (hazard ratio 1.3).⁸ Similarly, abnormal impedance plethysmography after 1 month of treatment (suggesting persistent proximal vein obstruction) was not predictive of recurrence when treatment was stopped at 3 months (relative risk 1.3).² Furthermore, with the exception of early recurrence associated with inadequate initial treatment (eg, 6 weeks),³¹ recurrent DVT is equally distributed between the initially affected and unaffected legs.^9,31,62 Current evidence therefore suggests that residual DVT may be weakly associated with recurrent VTE (<2-fold increase), but venous obstruction is not the underlying mechanism.

Multiple Previous Episodes of VTE
Intuitively, one would expect that patients with >1 VTE might have a higher risk of recurrence than those with a single VTE, particularly if the interval between episodes is short (<5 years). Schulman et al, however, found a similar risk of recurrence after 6 months of treatment for a first or a second episode of VTE during 2 years of follow-up.^3,35 Even so, a large epidemiologic study of linked hospital discharge records from California³³ and follow-up of patients who, in a recent trial stopped anticoagulant therapy after 6 months³⁶ found statistically significant 50%³³ and 75%³⁶ higher ratios of recurrent VTE after a second or subsequent episode of VTE than after an initial episode.

Vena Caval Filters
In a randomized trial of routine placement of vena caval filters as an adjunct to anticoagulant therapy in patients with proximal DVT, filters reduced the frequency of PE during the first 12 days, but almost doubled the risk of recurrent DVT over 2 years.³⁴ Despite this increase of recurrent DVT, PE did not appear to be more frequent. Epidemiologic data support this observation and suggest that caval filters act as an independent risk factor for recurrent DVT (odds ratio 1.8), but are not a risk factor for PE (odds ratio 1.0).³² The increase in DVT associated with filter placement was largely confined to patients initially presenting with PE.³³ These findings support starting anticoagulant therapy in patients with filters when safe (eg, once the bleeding risk resolves), and then favor more prolonged, but not necessarily indefinite, treatment (Table 1).

D-dimer Levels After Stopping Treatment
Laboratory evidence of activation of the coagulation system after withdrawal of anticoagulants appears related to the risk of recurrent VTE. In 2 studies, a low or negative D-dimer level 1 month after stopping anticoagulant therapy was associated with a much lower rate of recurrent VTE during follow-up (18 and 38 months)^9,24 and occurred in one third²⁴ and more than half⁹ of patients. D-dimer levels predicted recurrence in patients with and without hereditary thrombophilia or provoking risk factors for VTE. Assay standardization and prospective validation are required before D-dimer testing can be recommended as a guide to duration of anticoagulant therapy.

Other Factors
The influence of a number of other factors on the risk of recurrent VTE is summarized in Table 1.

	Risk of Bleeding During Anticoagulant Therapy

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
After the first 3 to 6 months of treatment, long-term anticoagulation targeted to an INR of 2.0 to 3.0 is associated with an average rate of major bleeding of 2% per year in patients with VTE^64–66 (an increase of 2- to 3-fold, or an absolute increase of 1% to 1.5% per year).^8,35,63,67 Approximately 10% of major bleeds occurring on long-term anticoagulant therapy for VTE are fatal,⁶⁸ yielding a 0.2% annual rate of fatal bleeding in such patients.

The risk of bleeding in individual patients differs, however, according to individual characteristics, such as age, comorbid conditions (eg, previous gastrointestinal bleeding, stroke, chronic renal disease, metastatic malignancy, alcohol-related disease, or diabetes), and use of concomitant antiplatelet therapy.^{26,63,66,67,69–73} The risk of bleeding is highest soon after starting anticoagulant therapy^66,67,69 and is higher still if anticoagulation is difficult to control.⁶⁷ After the first 6 months of therapy, long-term anticoagulation of patients with unprovoked VTE is associated with an annual risk of major bleeding of 1% in patients younger than 65 years old without risk factors for bleeding.⁶³ Randomized trials have demonstrated that computer-assisted warfarin dosing results in better control of anticoagulant therapy than traditional dosing even by experienced medical staff.⁷⁴ Likewise, a multicomponent intervention that promotes patient education and participation in anticoagulant management provides better anticoagulation control than usual care.⁷⁵ Importantly, the multicomponent intervention halved the frequency of major bleeding during the first 6 months of anticoagulant therapy.⁷⁵

Two prospectively validated prediction rules have been published for assessing individual risk of major bleeding during the first 3 months^70,71 and subsequent anticoagulant therapy.⁷⁰ Hereditary factors, such as polymorphisms of the cytochrome P450 system, may predispose patients to bleeding by increasing sensitivity to VK antagonists.^76,77

	Relative Importance of Recurrent VTE or Major Bleeding

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
In addition to considering the absolute difference in risk of thrombosis and major bleeding with and without anticoagulant therapy, the consequences of each of these outcomes must be considered. Because most patients with recurrent VTE or major bleeding that is not fatal recover without residua, this discussion focuses on the case fatality rates of each condition.

As noted previously, the likelihood of dying from recurrent VTE depends on whether the recurrence is DVT or PE case fatality rates of these conditions are 2% and 15%, respectively. Initial presentation as PE, rather than DVT, is the only factor, other than an indwelling vena caval filter (a risk factor only for DVT) that influences whether the recurrent event is a PE rather than a DVT.³² After 3 months of initial anticoagulant therapy, case fatality rates for recurrent VTE is 10% after PE and 5% after DVT (see above).

The case fatality rate with major bleeding during long-term anticoagulant therapy for VTE is 10%.⁶⁸ It is likely higher with major bleeding in patients with previous noncardioembolic stroke because a greater proportion of these bleeds are intracranial (50% case fatality rate).^78,79

Balancing Reduction in VTE Against Bleeding During Long-Term Anticoagulation
Comparison of associated case fatality rates suggests that the consequence of a major bleed during long-term anticoagulation is similar to that of recurrent VTE after PE, and approximately twice as severe as the consequences of recurrent VTE after DVT. Therefore, given a risk reduction for recurrent VTE of >90% during long-term anticoagulation and a 2% annual rate of major bleeding on anticoagulant therapy,^8,22 the annual risk of VTE must exceed 1.5% after PE and 3% after DVT to offset fatal bleeding.

	Comparisons of Different Durations of Anticoagulant Therapy

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Short-Term (4 to 6 Weeks) Versus Conventional (3 to 6 Months) Therapy
Three large trials have assessed the safety of shortening the duration of oral anticoagulant therapy from 3 to 6 months to 4 to 6 weeks in heterogeneous groups of patients (ie, those with transient or permanent risk factors or unprovoked VTE) generally with first episodes of VTE (Table 2).^1,3,37 The 3 studies that enrolled patients with proximal DVT or PE found that briefer anticoagulation nearly doubled the frequency of recurrent VTE (Table 2).^1–3 Major bleeding was uncommon during the extended period of anticoagulation in these studies (7 episodes among 1009 patients during 259 patient-years of additional treatment [2.7% per year]).^1–3 The main conclusion was that anticoagulant therapy should not be shortened to 4 to 6 weeks in patients with VTE.

View this table: [in this window] [in a new window]   TABLE 2. Recurrent Venous Thromboembolism in Randomized Trials Comparing Durations and Intensities of Anticoagulant Therapy

Subgroup analysis in 1 study suggested that isolated calf vein thrombosis provoked by a transient risk factor can be safely treated with only 6 weeks of therapy.³ A fourth study, which compared 6 versus 12 weeks of therapy in patients with isolated calf DVT (unprovoked or secondary, diagnosed mainly by ultrasound imaging), found no evidence that abbreviated therapy increased recurrence (relative risk 0.6; 95% CI, 0.01 to 3.4); in general, the frequency of recurrent VTE with isolated calf DVT was low (2% in the first year).³⁷ Based on these findings, shortening the duration of anticoagulation for proximal DVT or PE from 3 to 6 months to 4 to 6 weeks is associated with a substantial increase in the frequency of recurrent VTE without a clinically important reduction in bleeding.

Anticoagulant Therapy: 6 to 12 Months Versus 3 Months
Pinede et al compared 3 and 6 months of anticoagulant therapy in patients with a first episode of proximal DVT or PE (unprovoked or secondary) (Table 2).³⁷ After 15 months of follow-up, the frequency of recurrent VTE did not differ between the 2 groups (relative risk 0.9 in favor of 3-month group; 95% CI, 0.5 to 1.6).

Agnelli et al compared stopping anticoagulant therapy at 3 months versus an additional 9 months of treatment after a first episode of unprovoked proximal DVT (Table 2).⁵² By the end of the first year, recurrent VTE was less frequent in the group given extended anticoagulant therapy (3.0% versus 8.3%), but this benefit was lost 2 years after stopping anticoagulation (relative risk 1.0; 95% CI, 0.6 to 1.7).

Agnelli et al also compared extending oral anticoagulation for a first PE from 3 to 6 months in patients with a transient risk factor, and from 3 to 12 months in patients with unprovoked PE (Table 2).³⁰ Although recurrent VTE was uncommon with extended anticoagulation, there was no difference in the rate of recurrent VTE after 3 years of follow-up (rate ratio 0.8 in favor of longer therapy; 95% CI, 0.4 to 1.6). Based on these results, reduction in recurrent VTE achieved by extending anticoagulation for 3 or 9 months after an initial 3 months of treatment is lost if therapy is then stopped.

Long-Term Versus Conventional Durations of Anticoagulant Therapy
Three trials compared long-term anticoagulation (target INR ranges of 2.0 to 2.85,³⁵ 2.0 to 3.0,⁸ and 1.5 to 2.0³⁸) with stopping therapy in patients with VTE at high risk for recurrence (Table 2). Schulman et al compared 6 months with 4 years of warfarin therapy in patients with a second episode of VTE (Table 2). ³⁵ Recurrent VTE was markedly reduced by long-term anticoagulation (0.65% versus 5.2% per patient-year by intention-to-treat [ITT] analysis) but was associated with a higher rate of major bleeding (2.2% versus 0.45% per year). Overall, there was no convincing benefit of long-term anticoagulation in this population.

We compared an additional 2 years of anticoagulant therapy versus placebo in patients with a first episode of unprovoked VTE who had completed 3 months of warfarin therapy (Table 2).⁸ The trial was stopped after an average of 10 months when interim analysis revealed unexpectedly high recurrence rates (27% per patient-year) in patients who discontinued treatment after 3 months. Long-term warfarin therapy resulted in a 95% reduction in risk of recurrent VTE but was associated with more major bleeding (3 episodes [3.8% per patient-year] versus none).⁸

Ridker et al, in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, compared long-term anticoagulation at a lower intensity (INR 1.5 to 2.0) with placebo in patients with unprovoked VTE (distal or proximal DVT or PE) who had completed at least 3 months (median 6.5 months) of initial anticoagulant therapy (INR 2.0 to 3.0) (Table 2).³⁸ The trial was stopped after an average of 2.1 years of follow-up because of a 64% risk reduction for recurrent VTE with extended low-intensity anticoagulation (2.6% versus 7.2% per patient-year according to ITT analysis) and a small increase in the absolute frequency of major bleeding (5 [0.9% per patient-year] versus 2 [0.4% per patient-year] episodes).³⁸ Using a target INR of 1.5 to 2.0, the risk reduction for VTE was 80% among those who remained on treatment.³⁸

Findings in studies of long-term anticoagulation (INR 2.0 to 3.0) are consistent with a 95% risk reduction for recurrent VTE among patients without cancer who remain using treatment (see next section).^8,35,38,63 The benefits of long-term anticoagulation appear to exceed the risks in patients with unprovoked proximal DVT or PE, even after a first episode.

	Optimal Intensity of Anticoagulation With VK Antagonists

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Hull et al established that acute treatment of VTE (ie, first 3 months) with a target INR of 2.0 to 3.0 was as effective as, but caused less bleeding than, treatment to a target INR of 3.0 to 4.0.⁸⁰ In patients with VTE and an antiphospholipid antibody, Crowther et al showed that targeting VK antagonist therapy to an INR of 2.5 is as effective as an INR target of 3.5.⁸¹

Two trials^8,35 that reported no episodes of recurrent VTE among patients using extended-duration anticoagulant therapy (INR 2.0 to 3.0) suggest that lowering the intensity of anticoagulation to a target INR of 1.5 to 2.0 after the first 3 months of treatment might reduce bleeding without loss of efficacy. This hypothesis was tested in the Extended Low-intensity Anticoagulation for Unprovoked Thromboembolism (ELATE) study, a double-blind comparison of a target INR of 1.5 to 1.9 with a 2.0 to 3.0 INR for long-term treatment of unprovoked VTE (Table 2).⁶³ Contrary to expectations, the lower-intensity anticoagulation was less effective at preventing recurrent VTE (1.9% versus 0.7% per patient-year by ITT analysis; hazard radio 2.8 [95% CI, 1.1 to 7.0]) and associated with the same frequency of major bleeding as conventional intensity therapy (1.1% versus 0.9% per patient-year; hazard ratio 1.2 [95% CI, 0.4 to 3.0]).⁶³ Based on these findings, a target INR of 2.0 to 3.0 appears optimal for both acute and long-term treatment of VTE.

	Alternatives to VK Antagonists

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Unfractionated and LMWH
Various subcutaneous heparin regimens have been used instead of VK antagonists to treat VTE for 3 or 6 months.^5,82–96 Of these studies, the 13 most recent compared widely differing LMWH regimens with VK antagonists (INR 2.0 to 3.0)^5,82–96 or, in 1 small study, unfractionated heparin.⁸⁵ Three months of low-dose unfractionated heparin (5000 U twice daily) was inadequate treatment for proximal DVT.^82,83 Three or 6 months of unfractionated heparin^84,85 or LMWH,^5,85–96 in doses that varied from one-third^5,86,89,90 to full^91–94,96 therapeutic doses were effective. A meta-analysis of 7 of these studies (total of 1379 patients)^{5,86,88–91,93} found 3 months of LMWH therapy associated with less recurrent VTE (odds ratio 0.7; 95% CI, 0.4 to 1.1) and less major bleeding (odds ratio 0.4; 95% CI, 0.2 to 1.1) than treatment with a VK antagonist for 3 months. Compared with VK antagonists, between-study differences in mean daily dose of LMWH had little effect on efficacy but did influence bleeding (odds ratio of 0.2 with 4000 IU/d to 0.7 with 12 000 IU/d for major bleeding relative to the VK antagonist groups).⁹⁷

Two studies not included in this analysis suggest that prolonged treatment with LMWH is preferable to VK antagonists in patients with active cancer.^92,96 In the larger of these 2 studies (700 patients), daily injections of LMWH (dalteparin 200 IU/kg for the first month and then 150 IU/kg for 5 months) was associated with half the frequency of recurrent VTE during 6 months of treatment (9% versus 17% with VK antagonists) with no significant increase in major bleeding (6% versus 4%).⁹⁶

Oral Direct Thrombin Inhibitors
After 6 months of initial treatment with VK antagonists, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) prevented recurrent VTE by 84% without an apparent increase in bleeding (see Weitz article in this issue).³⁶

	Nonanticoagulant Treatment

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Wearing below-knee graduated compression stockings for 2 years after acute DVT halves the frequency of the post-thrombotic syndrome⁹⁸ but does not influence the risk of recurrent thrombosis.⁹⁸

	Recommended Durations of Anticoagulation in Individual Patients

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 
Based largely on the preceding analysis of risk factors for recurrent thrombosis and bleeding, and on studies comparing different durations and intensities of anticoagulation, Table 3 outlines an approach to anticoagulation of individual patients with VTE. Because the presence of a reversible risk factor for VTE, lack of a provoking factor, or cancer at the time of thrombosis has the greatest prognostic influence on recurrence, this assessment carries the most weight.

View this table: [in this window] [in a new window]   TABLE 3. Guidelines for Duration of Anticoagulant Therapy for VTE

For patients with VTE associated with a major transient risk factor such as recent surgery, stopping anticoagulant therapy after 3 months of treatment is associated with a subsequent risk of recurrent VTE of 3% in the first year and 10% over 5 years.^{1,2,5,6,10,30,36–38} This rate is not high enough to justify treatment for longer than 3 months.

For patients with unprovoked VTE, stopping anticoagulant therapy after 6 or more months of treatment is associated with a subsequent risk of recurrent VTE of 10% in the first year and 30% over 5 years,^3,6,37,52 justifying long-term anticoagulation for the majority of such patients. The argument favoring long-term therapy is stronger if the unprovoked episode was PE; if a second or subsequent episode of unprovoked VTE occurs; or if an antiphospholipid antibody, homozygous factor V Leiden mutation, deficiency of antithrombin, protein C or S, or combined heterozygous state for factor V Leiden and the prothrombin gene mutation is present. Because there was a very high rate of recurrence when treatment was interrupted after 3 months in patients with a first unprovoked VTE in our own study,⁸ we avoid stopping treatment before 6 months in this situation. Patients with active cancer should generally maintain long-term anticoagulant therapy (LMWH or VK antagonists) because the risk of recurrent VTE is >10% within 1 year of stopping treatment.

Patients who do not clearly fall into one or another of these 3 categories have a risk of recurrence higher than that of patients with a major reversible risk factor but lower than those in patients with unprovoked VTE after anticoagulant therapy. I favor treating such patients for 6 months, although 3 months may be adequate.

When oral anticoagulant therapy is relatively contraindicated by a high risk of bleeding because of risk factors or lack of access to appropriate anticoagulant monitoring, the duration of anticoagulation for unprovoked VTE may be shortened to 3 to 6 months. This does not apply to extended treatment with LMWH in patients with malignancy. Annual review is recommended for patients using long-term therapy to ensure that the benefits continue to outweigh the risks.

	Footnotes

 
Dr Kearon is an Investigator of the Canadian Institutes of Health Research.

	References

Top Abstract Introduction Risk of Recurrent VTE... Risk of Bleeding During... Relative Importance of Recurrent... Comparisons of Different... Optimal Intensity of... Alternatives to VK Antagonists Nonanticoagulant Treatment Recommended Durations of... References

 

1. Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet. 1992; 340: 873–876.[Medline] [Order article via Infotrieve]
   
2. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost. 1995; 74: 606–611.[Medline] [Order article via Infotrieve]
   
3. Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995; 332: 1661–1665.[Abstract/Free Full Text]
   
4. Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med. 1992; 327: 1128–1133.[Abstract]
   
5. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin the prevention of recurrence after deep vein thrombosis. Thromb Haemost. 1994; 72: 191–197.[Medline] [Order article via Infotrieve]
   
6. Palareti G, Legnani C, Cosmi B, et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost. 2002; 87: 7–12.[Medline] [Order article via Infotrieve]
   
7. Baglin T, Luddington R, Brown K, et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003; 362: 523–526.[CrossRef][Medline] [Order article via Infotrieve]
   
8. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999; 340: 901–907.[Abstract/Free Full Text]
   
9. Palareti G, Legnani C, Cosmi B, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation. 2003; 108: 313–318.[CrossRef][Medline] [Order article via Infotrieve]
   
10. Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125: 1–7.[Abstract/Free Full Text]
    
11. Ridker PM, Miletich JP, Stampfer MJ, et al. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation. 1995; 92: 2800–2802.[Medline] [Order article via Infotrieve]
    
12. Simioni P, Prandoni P, Lensing AW, et al. The risk of recurrent venous thromboembolism in patients with an Arg⁵⁰⁶–>Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med. 1997; 336: 399–403.[Abstract/Free Full Text]
    
13. Eichinger S, Pabinger I, Stumpflen A, et al. The risk of recurrent venous thromboembolism in patients with and without Factor V Leiden. Thromb Haemost. 1997; 77: 624–628.[Medline] [Order article via Infotrieve]
    
14. Lindmarker P, Schulman S, Sten-Linder M, et al. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A Allele in the coagulation factor V gene and the G20210A Allele in the prothrombin gene. Thromb Haemost. 1999; 81: 684–689.[Medline] [Order article via Infotrieve]
    
15. Miles JS, Miletich JP, Goldhaber SZ, et al. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol. 2001; 37: 215–218.[Abstract/Free Full Text]
    
16. Simioni P, Prandoni P, Lensing AW, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood. 2000; 96: 3329–3333.[Abstract/Free Full Text]
    
17. Eichinger S, Minar E, Hirschl M, et al. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost. 1999; 81: 14–17.[Medline] [Order article via Infotrieve]
    
18. Margaglione M, Brancaccio, V, Giuliani, N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G-->A²⁰²¹⁰ gene variant. Ann Intern Med. 1998; 129: 89–93.[Abstract/Free Full Text]
    
19. DeStefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med. 1999; 341: 801–806.[Abstract/Free Full Text]
    
20. Kryle P, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Eng J Med. 2000; 343: 457–462.[Abstract/Free Full Text]
    
21. Kraaijenhagen RA, in’t Anker PS, Koopman MM, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost. 2000; 83: 5–9.[Medline] [Order article via Infotrieve]
    
22. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998; 104: 332–338.[CrossRef][Medline] [Order article via Infotrieve]
    
23. Eichinger S, Stumpflen A, Hirschl M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost. 1998; 80: 566–569.[Medline] [Order article via Infotrieve]
    
24. Eichinger S, Minar E, Bialonczyk C, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA. 2003; 290: 1071–1074.[Abstract/Free Full Text]
    
25. Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000; 160: 761–768.[Abstract/Free Full Text]
    
26. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002; 100: 3484–3488.[Abstract/Free Full Text]
    
27. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000; 132: 689–696.[Abstract/Free Full Text]
    
28. Hoibraaten E, Qvigstad E, Arnesen H, et al. Increased risk of recurrent venous thromboembolism during hormone replacement therapy—results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost. 2000; 84: 961–967.[Medline] [Order article via Infotrieve]
    
29. Piovella F, Crippa L, Barone M, et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica. 2002; 87: 515–522.[Abstract/Free Full Text]
    
30. Agnelli G, Prandoni P, Becattini C, et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003; 139: 19–25.[Abstract/Free Full Text]
    
31. Lindmarker P, Schulman S. The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg. The DURAC Trial Study Group. J Intern Med. 2000; 247: 601–606.[Medline] [Order article via Infotrieve]
    
32. Murin S, Romano PS, White RH, et al. Comparison of outcomes after hospitalization for deep vein thrombosis or pulmonary embolism. Thromb Haemost. 2002; 88: 407–414.[Medline] [Order article via Infotrieve]
    
33. White RH, Zhou H, Kim J, et al. A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism. Arch Intern Med. 2000; 160: 2033–2041.[Abstract/Free Full Text]
    
34. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998; 338: 409–415.[Abstract/Free Full Text]
    
35. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997; 336: 393–398.[Abstract/Free Full Text]
    
36. Schulman S, Wahlander K, Lundström T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Eng J Med. 2003; 349: 1713–1721.[Abstract/Free Full Text]
    
37. Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation. 2001; 103: 2453–2460.[Medline] [Order article via Infotrieve]
    
38. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism. N Eng J Med. 2003; 348: 1425–1434.[Abstract/Free Full Text]
    
39. Spiezia L, Bernardi E, Tormene D, et al. Recurrent thromboembolism in fertile women with venous thrombosis: incidence and risk factors. Thromb Haemost. 2003; 90: 964–966.[Medline] [Order article via Infotrieve]
    
40. Kearon C, Crowther M, Hirsh J. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med. 2000; 51: 169–185.[CrossRef][Medline] [Order article via Infotrieve]
    
41. Lane DA, Mannucci PM, Bauer KA, et al. Inherited Thrombophilia: Part 1. Thromb Haemost. 1996; 76: 651–662.[Medline] [Order article via Infotrieve]
    
42. Lane DA, Mannucci PM, Bauer KA, et al. Inherited Thrombophilia: Part 2. Thromb Haemost. 1996; 76: 824–834.[Medline] [Order article via Infotrieve]
    
43. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999; 353: 1167–1173.[CrossRef][Medline] [Order article via Infotrieve]
    
44. Van den Belt AG, Sanson BJ, Simioni P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med. 1997; 157: 2227–2232.[Abstract]
    
45. Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost. 1999; 81: 165–176.[Medline] [Order article via Infotrieve]
    
46. Den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the prevention of secondary deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. J Thromb Haemost. 2003; 1 (Suppl 1): OC161.
    
47. Hutten BA, Prins M, Gent M, et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol. 2000; 18: 3078–3083.[Abstract/Free Full Text]
    
48. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001; 134: 191–202.[Abstract/Free Full Text]
    
49. Palareti G, Legnani C, Lee A, et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost. 2000; 84: 805–810.[Medline] [Order article via Infotrieve]
    
50. Douketis JD, Kearon C, Bates S, et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998; 279: 458–462.[Abstract/Free Full Text]
    
51. Kniffin WD Jr., Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994; 154: 861–866.[Abstract]
    
52. Agnelli G, Prandoni P, Santamaria MG, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep vein thrombosis. N Engl J Med. 2001; 345: 165–169.[Abstract/Free Full Text]
    
53. Bell WR, Simon TL. Current status of pulmonary embolic disease: pathophysiology, diagnosis, prevention, and treatment. Am Heart J. 1982; 103: 239–262.[CrossRef][Medline] [Order article via Infotrieve]
    
54. Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest. 1995; 108: 978–981.[Abstract/Free Full Text]
    
55. Kearon C. Natural history of venous thromboembolism. Circulation. 2003; 107: 122–130.
    
56. Goldhaber SZ, Visni L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999; 353: 1386–1389.[CrossRef][Medline] [Order article via Infotrieve]
    
57. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med. 1999; 159: 445–453.[Abstract/Free Full Text]
    
58. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, et al. Echocardiography doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J. 1997; 134: 479–487.[CrossRef][Medline] [Order article via Infotrieve]
    
59. Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared with weekdays. N Engl J Med. 2001; 345: 663–668.[Abstract/Free Full Text]
    
60. Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med. 1995; 155: 1031–1037.[Abstract]
    
61. Fedullo PF, Auger WR, Kerr KM, et al. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2001; 345: 1465–1472.[Free Full Text]
    
62. Prandoni P, Lensing AW, Prins MH, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002; 137: 955–960.[Abstract/Free Full Text]
    
63. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003; 349: 631–639.[Abstract/Free Full Text]
    
64. Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA. 1999; 282: 2058–2067.[Abstract/Free Full Text]
    
65. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999; 131: 492–501.[Abstract/Free Full Text]
    
66. White RH, Beyth RJ, Zhou H, et al. Major bleeding after hospitalization for deep-venous thrombosis. Am J Med. 1999; 107: 414–424.[CrossRef][Medline] [Order article via Infotrieve]
    
67. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet. 1996; 348: 423–428.[CrossRef][Medline] [Order article via Infotrieve]
    
68. Linkins L, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med. 2003; 139: 893–900.[Abstract/Free Full Text]
    
69. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med. 1993; 95: 315–328.[CrossRef][Medline] [Order article via Infotrieve]
    
70. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998; 105: 91–99.[CrossRef][Medline] [Order article via Infotrieve]
    
71. Kuijer PMM, Hutten BA, Prins MH, et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999; 159: 457–460.[Abstract/Free Full Text]
    
72. Pengo V, Legnani C, Noventa F, et al. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding. A Multicenter Inception Cohort Study. Thromb Haemost. 2001; 85: 418–422.[Medline] [Order article via Infotrieve]