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Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation

Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation
Literature review current through: Jan 2024.
This topic last updated: Jan 11, 2023.

INTRODUCTION — Deep vein thrombosis (DVT) and acute pulmonary embolism (PE) are two manifestations of venous thromboembolism (VTE). Extending therapeutic anticoagulation beyond the conventional period of three months may benefit select patients who are at increased risk of recurrent thrombosis when anticoagulation is stopped.

This topic discusses the approach to continuing or discontinuing anticoagulation in patients who have completed a finite course of anticoagulant therapy for lower extremity DVT and acute PE (table 1). The content does not apply to anticoagulant therapy in patients with thrombosis in other sites such as upper extremity DVT, splanchnic thrombosis, cerebral vein thrombosis, or portal vein thrombosis. Initiation of anticoagulant therapy in patients with acute VTE is discussed in detail separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)

Our approach is, for the most part, consistent with guidelines set out by the American College of Chest Physicians, the International Society on Thrombosis and Hemostasis, the International Consensus Statement on the Prevention and Treatment of Venous Thromboembolism, the American College of Physicians, the European Society of Cardiology, the European Respiratory Society, the American Society of Hematology, and others [1-8]. These guidelines should not substitute for clinical judgement and none can account for the critical impact of individual patient values and evolving data.

RATIONALE — The rationale for extending anticoagulant therapy beyond three months in select patients is based upon an estimated high risk of venous thromboembolism (VTE) recurrence if anticoagulation is stopped. In such cases, anticoagulant therapy can potentially reduce recurrence by 80 percent or more [1,9-13]. While data demonstrate a clear benefit from a recurrence standpoint, few studies report a mortality benefit from prolonged anticoagulant therapy.

However, anticoagulant therapy cannot be given without some increase in the risk of major bleeding. Thus, indefinite anticoagulation is most likely to benefit those at the greatest risk of recurrence in whom the risk of bleeding is low. Furthermore, we believe that in the era of direct oral anticoagulants, the safety profile of extending anticoagulant therapy is more acceptable than that of warfarin therapy. The decision also has to take into account that the consequences of a major bleed may be worse than the consequences of a recurrent episode of VTE. For example, approximately 12 percent of major bleeds associated with warfarin are fatal while only 4 percent of recurrent thrombotic episodes are fatal [1,14,15]. Data describing risks of recurrence and bleeding associated with individual agents are discussed below. (See 'Agents' below.)

CLINICAL ASSESSMENT — In patients with venous thromboembolism (VTE) who have completed a finite course of therapeutic anticoagulation, we individualize assessment for the suitability of extending anticoagulant therapy indefinitely. We perform a detailed evaluation of the patient's individual risk of recurrence and bleeding in the context of their personal values and preferences. (See 'Assessing risk of recurrence' below and 'Assessing the risk of bleeding' below and 'Patient values and preferences' below.)

Assessing risk of recurrence — For patients with acute VTE who are nearing completion of a finite course of anticoagulant therapy, we assess the risk of recurrence, should anticoagulation be discontinued. The risk of VTE recurrence off anticoagulation is highest in the ensuing one to two years and is cumulative [16,17]. Thus, when discussing risk with patients, we prefer to estimate cumulative risk over a longer period (eg, five years) (table 1 and table 2). To assess risk, we obtain details regarding the index VTE event and risk factors (if any) associated with the index and any previous VTE event(s). We also ascertain any current risk factors that could impact potential future events. We characterize risk factors as transient or persistent, major or minor, and malignant or nonmalignant. Once assessed, the patient should be categorized according to the estimated risk of recurrence as the following; we assumed that individuals are no longer at risk after the recurrent event and that the risk of recurrence remains constant over time (table 2) [5,16,18-21]:

Low – Less than 3 percent per year (<14 percent over 5 years)

Intermediate – Between 3 and 5 percent per year (between 14 and 30 percent over 5 years)

High – Greater than 5 percent per year (>30 percent over 5 years)

Guidance on how to estimate high, intermediate, and low risk is limited. A number of risk prediction models have been proposed but their clinical value, particularly in the era of direct oral anticoagulants (DOACs), is unclear [22,23]. In most cases, we estimate risk by gestalt based upon a working knowledge of the following:

Baseline risk (see 'Identify baseline risk based upon presence or absence of risk factors and number of events' below)

Additional factors that may increase the baseline risk (see 'Characterize risk factors' below)

Identify baseline risk based upon presence or absence of risk factors and number of events — We estimate the baseline risk of recurrence using the following information:

The presence or absence of risk factors associated with the index (most recent) VTE event (ie, whether the event is provoked by a known risk factor; this is also known as "provoked" or "unprovoked").

and

The presence or absence of other VTE events (ie, whether the index event is a first or recurrent event).

Several studies have assessed this risk in patients with acute VTE in whom anticoagulant therapy has been discontinued:

A 2012 meta-analysis of The American College of Chest physicians has estimated the risk as the following (table 2) [6]:

First episode of VTE without a precipitating risk factor ("unprovoked") – 10 percent for the first year; 5 percent/year thereafter.

Second episode of VTE without a precipitating risk factor ("unprovoked") – 15 percent for the first year; 7.5 percent/year thereafter.

First episode of VTE precipitated by a non-surgical risk factor ("provoked") – 5 percent for the first year; 2.5 percent/year thereafter. However, "non-surgical" risk factors are a heterogenous group of risk factors leading to a wide range of recurrence risk. For example, the risk is likely at the lower end of this range for patients with VTE due to the oral contraceptive pill or pregnancy, and higher among those with VTE associated with prolonged travel or minor trauma to a leg muscle.

First episode of VTE provoked by a surgical factor ("provoked") – 1 percent for the first year; 0.5 percent/year thereafter.

In a 2019 Danish cohort study of nearly 74,000 patients with VTE, six month rates of recurrence were similar in patients with VTE who had or did not have an identifiable risk factor, presumably, because both patient populations were receiving anticoagulation during this period (ie, "provoked" and "unprovoked," respectively; 6.8 versus 6.9 percent per year) [24]. Patients with cancer had the highest rates at six months (9 percent per year). However, at 10 years follow-up, rates were higher in patients without an identifiable risk factor ("unprovoked") compared with those who had an identifiable risk factor ("provoked"; 2.8 and 2.2 percent per year; hazard ratio [HR] 1.17) and approximated that of patients with cancer-related VTE (3.7 percent per year).

The terms "provoked" and "unprovoked" have been criticized as this binary designation suggests the pathogenesis of VTE can be separated into two distinct groups, whereas many patients may exist within a spectrum of risk factor severity [19,25]. Thus, while patients with unprovoked VTE (ie, VTE without any identifiable risk factor) have a high risk of recurrence, it should not be misconstrued that patients with provoked VTE (ie, VTE with an identifiable risk factor) have a low risk of VTE recurrence. In fact, patients with VTE provoked by persistent minor factors, such as heart failure, immobility, and frequent flyers with extended travel, have a cumulative risk of 15 percent over five years compared with 3 percent over five years in patients with a VTE provoked by major risk factor, such as orthopedic surgery [26]. Similarly, patients with reversible risk factors, whether recent surgery or use of estrogen-containing agents (eg, oral contraceptives), appear to be at low risk for recurrence after the risk factor is no longer present [16,27,28].

Characterize risk factors

Characteristics (major, minor, transient, persistent, malignant, nonmalignant) — Risk factor characteristics impact the risk of recurrence and facilitate the decision regarding whether to proceed with indefinite anticoagulation. We classify risk factors as major or minor, transient or persistent, and malignant or nonmalignant (table 1). Typically, the factor associated with the greatest risk of recurrence is the major determinant of risk, although additional factors likely increase the risk further by an unknown amount.

Transient or persistent – Risk factors that are transient (ie, reversible) or persistent (ie, irreversible) are usually self-evident with persistent risk factors increasing the life-time risk more than transient ones.

Nonmalignant major or nonmalignant minor – Distinguishing nonmalignant major from nonmalignant minor risk factors is also important since, although counterintuitive, for patients whose VTE occurs in association with a transient minor risk factor (eg, travel), the risk of recurrence is significantly higher than for patients whose VTE was precipitated by a transient major risk factor such as surgery.

Active malignancy – Patients with active cancer have rates of recurrence estimated to be as high as 15 to 20 percent per year [6,17,24,29,30]. Risk of recurrence and role of extended anticoagulation in this population are discussed separately. (See 'Any VTE associated with active cancer not precipitated by a major provoking event' below and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

While major thrombophilic conditions (eg, antiphospholipid syndrome, antithrombin deficiency) increase the risk of a first VTE event, their impact on the risk of a recurrent event is less clear. In this population, it is likely that the major factors that influence recurrence is less likely the thrombophilic condition itself but rather the provoking risk factors associated with that event (ie, provoked or unprovoked, risk factor characteristics). Thus, factors that determine extending anticoagulation in these patients are likely similar to those who do not have a major thrombophilic condition. (See "Antithrombin deficiency", section on 'Management' and "Management of antiphospholipid syndrome".)

D-dimer level — We do not routinely measure D-dimer levels in all patients. We suggest measuring D-dimer levels in female patients with VTE in whom there is uncertainty regarding the appropriateness of extended anticoagulant therapy [20,31-41]. In female patients with a negative D-dimer, the risk of recurrent VTE is approximately 3 percent per year (approximately 1 percent if VTE occurred in association with estrogen use) and may justify stopping anticoagulant therapy. D-dimer is less useful in male patients, has low specificity, and its predictive value varies depending on the assay and the cutoff used.

In a prospective study of 293 patients with a first unprovoked VTE, anticoagulants were stopped if D-dimer was negative on therapy and one month after stopping therapy [20]. All remaining patients continued anticoagulant therapy. At five years, among those who had stopped anticoagulant therapy, the annualized (and cumulative) rate of recurrent VTE was 5.1 (29.7) percent in men, 3.8 (17) percent in female patients with VTE not associated with estrogens, and 0.4 (2.3) percent in female patients with VTE associated with estrogens.

In another prospective cohort of 732 patients with unprovoked VTE who were treated with 12 months or more of anticoagulant therapy, patients were subjected to serial D-dimer testing (0, 15, 30, 60 days) and followed for 18 months [42]. Patients with a positive D-dimer who were treated with 2.5 mg of the DOAC apixaban (ie, low-dose) had significantly fewer VTE events compared with those with a negative D-dimer level who remained off anticoagulation (0.9 versus 6.2 percent per year). Recurrence was more common in males than females. Among patients with a negative D-dimer, VTE recurrence was lowest in those who were younger (<51 years) and female who presented with isolated PE as an index event associated with hormonal therapy.

ln a prospective study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if D-dimer was negative on therapy and 1 month after stopping therapy while all other patients remained on anticoagulant therapy [20]. Recurrence after stopping therapy in response to negative D-dimer testing was 5.1 percent per patient-year, higher in males compared with females (7.5 versus 3.8 percent per patient-year) and lowest in females who had VTE associated with estrogen therapy (0.4 percent per patient-year).

Meta-analyses of observational studies have consistently reported an elevated rate of VTE recurrence in patients with an elevated D-dimer (>500 ng/mL) at three to four weeks following cessation of anticoagulant therapy compared with patients with a normal D-dimer (9 to 17 percent/year versus 3 to 7 percent/year) [38-40].

An observational study (PROLONGII) reported a high risk of recurrent VTE in patients who had VTE without an identifiable risk factor (ie, "unprovoked" VTE) and a late and persistently elevated D-dimer at 3 to 12 months, compared with those who had a normal D-dimer (27 versus 3 percent per year; HR 7.9, 95% CI 2.1-30) [43]. Patients in whom the D-dimer was normal at the third month but became abnormal thereafter had risk of recurrent VTE that was 11 percent per year.

Patients with VTE without an identifiable risk factor (ie, "unprovoked" VTE) who had persistently negative D-dimer levels by three months together with no or stable residual vein thrombosis had a low recurrence rate of 3 percent per year over a two-year period [44]. Among those who had elevated D-dimer levels at three months, anticoagulant therapy reduced the rate of recurrence from 9 to 0.7 percent per year. In the subgroup of patients with isolated PE who had a positive D-dimer, the recurrence rate was 11 percent per year, and the majority of recurrent events were PE, as opposed to DVT [41].

Less well-validated risk factors — Less well-validated risk factors for recurrent VTE include the following:

Male sex – Male sex is a frequently cited risk factor for recurrence following a first episode of VTE. However, studies are conflicting. Several randomized trials and meta-analyses have reported increased risk of recurrence among male patients after cessation of oral anticoagulant therapy, with relative risks varying from 1.3 to 3.6 [14,32,45-51].

Pulmonary embolism (PE) versus deep venous thrombosis (DVT) – While DVT tends to recur as DVT and PE tends to recur as PE, the case fatality associated with recurrent PE may be higher. This factor carries more weight in patients with poor cardiopulmonary reserve [41,52-54].

Residual vein obstruction (RVO) – While imaging to detect resolution of clot or RVO may be useful as a baseline test to help interpret imaging for suspected future recurrences [55], we do not advocate the use of routine imaging to facilitate the decision of whether to continue or discontinue anticoagulation at the end of a finite period (eg, three months). Data are conflicting regarding the of the presence of RVO as a reliable predictor of recurrence [56-64]. In addition, analyses are limited by significant heterogeneity in the study population, timing, and definition of RVO. However, the studies that have found an association between RVO and recurrence risk were mostly done in European centers where "two-point" ultrasound is performed (ie, femoral and popliteal points). It is not clear that the presence of RVO on "whole leg" ultrasound has any utility in estimating the risk of recurrent VTE. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Duration of treatment'.)

Miscellaneous – Several other factors including sleep apnea, increased thrombin generation, postthrombotic syndrome (PTS), and c-reactive protein have been associated with recurrence but are poorly validated and not well established [65-69]. (See "Post-thrombotic (postphlebitic) syndrome".)

Clinical prediction rules — Several clinical prediction rules have been proposed to estimate the risk of recurrence in VTE not provoked by an identifiable risk factor (ie, "unprovoked" VTE) following discontinuation of anticoagulation, but none have become routinely integrated into clinical practice.

HERDOO2 rule – The HERDOO2 rule (hyperpigmentation, edema, or redness in either leg; D-dimer level ≥250 mcg/L; obesity with body mass index ≥30; or age ≥65 years) was prospectively studied in a population of female patients with a first episode of VTE without an identifiable risk factor (unprovoked) after a period of 5 to 12 months of anticoagulation [22]. At one year, female patients who had none or one of these criteria had a lower rate of VTE when compared with those who had two or more criteria (3 percent versus 8 percent per year) but remained higher than those who were anticoagulated (1.6 percent per year).

DASH score – Data from seven prospective studies were pooled to generate the DASH score (+2 for positive postanticoagulation D-dimer, +1 for age ≤50 years, +1 for male sex, -2 for hormone use at time of initial VTE in female patients only) that predicts recurrence risk in patients with a first episode VTE without an identifiable risk factor (unprovoked) after discontinuing anticoagulation [70]. Abnormal D-dimer level (≥500 mcg/L), age <50 years, male sex, and VTE not associated with hormonal therapy (in females) were the main predictors of recurrence and were used to derive a DASH score. The annualized recurrence risk was reported for a score ≤1 (3.1 percent), a score =2 (6.4 percent), and a score ≥3 (12.3 percent).

Assessing the risk of bleeding — For all patients in whom indefinite anticoagulation is being considered, we assess the risk of major bleeding. Major bleeding is typically considered as overt bleeding associated with a decrease in the hemoglobin level of 2 g/dL or more, bleeding requiring a blood transfusion of two or more units of blood, bleeding into a critical site, or bleeding that contributed to death [71,72].

Baseline risk — Several studies have evaluated the rates of bleeding among patients on indefinite anticoagulant therapy. The majority of these studies calculate bleeding rates in low-risk patients and are therefore useful for calculating a baseline risk.

Rates have varied with one meta-analysis reporting an absolute rate of 2.7 percent per year [6,73] while another meta-analysis reported a major bleeding rate of 0.45 percent per year [74]. The difference between these analyses may reflect higher bleeding rates in older studies where warfarin was the anticoagulant of choice and newer analyses that include patients taking DOACs which, as a class, cause less major bleeding than warfarin. A 2021 meta-analysis of 14 randomized trials further supports the lower annualized rates of major bleeding with DOACs compared with warfarin (1.12 versus 1.74 percent) [75]. The five-year cumulative incidence of major bleeding could not be calculated for DOACs, but for warfarin was 6.3 percent per year. Rates of bleeding were highest among patients >65 years and those with a creatinine clearance <50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level <10 mg/L.

Characterizing the risk of bleeding — We take a detailed history of any previous episodes of bleeding on or off anticoagulant therapy as well as risk factors that could impact future bleeding events (table 3). We also assess for conditions that may affect the half-life of the administered anticoagulant (eg, renal failure, weight loss). In general, indefinite anticoagulation should only be considered in those at low risk of bleeding (eg, ≤3 percent per year) and should, if possible, be avoided in patients with a high risk of bleeding (eg, >3 percent per year). Importantly, clinicians should remember that the bleeding risk is cumulative and discussions with patients should emphasize cumulative rather than annualized rates.

When assessing the risk of bleeding, many clinicians use gestalt estimates. However, several tools are also available to predict a patient's risk of bleeding while on anticoagulation. These models are discussed below. (See 'Bleeding risk models' below.)

It should be noted that bleeding risk is dynamic such that frequent reassessment is important; for example, bleeding risk increases with age or the development of a new condition such as a gastric ulcer, or it may decrease following recovery from trauma or gastric ulcer treatment. (See 'Follow-up' below.)

Bleeding risk models — When assessing the risk of bleeding, many clinicians use gestalt estimates. However, several tools are available to help predict a patient's risk of bleeding while on anticoagulant therapy, none of which has been proven superior. While some use a three-tiered system of low, intermediate, and high risk (eg, American College of Chest Physicians [ACCP] model) (table 4), others predict an absolute rate (eg, HAS-BLED (calculator 1)). However, we prefer a binary system of low risk and high risk (eg, VTE-BLEED (calculator 2)) because the intermediate risk category is not substantially different from the low risk category and usually unhelpful in clinical decision making. Furthermore, the VTE-BLEED scoring system is the one that has been best studied in patients taking anticoagulants for VTE (as opposed to other indications). A systematic review of 17 studies published by the International Society of Thrombosis and Hemostasis has suggested that VTE-BLEED and the ACCP risk table are among the most externally validated for bleeding risk assessment in patients in whom indefinite anticoagulation is being considered [76].

VTE-BLEED – This score used data derived from randomized trials that studied the direct oral thrombin inhibitor, dabigatran, as an anticoagulant for VTE compared with warfarin [77]. VTE-BLEED includes six variables: active cancer (2 points), male patients with uncontrolled arterial hypertension at baseline (1 point), anemia (1.5 points), history of bleeding (1.5 points), age ≥60 years (1.5 points), and renal dysfunction (1.5 points) (calculator 2). Patients are considered the following:

Low risk (<2 points) – Bleeding rate 2.8 percent per year

High risk (≥2 points) – Bleeding rate 12.6 percent per year

The ACCP model – The ACCP have proposed a bleeding risk model containing a comprehensive list of 17 risk factors (table 3) [6]. The risk of bleeding is proportionate to the number of risk factors present (table 4):

Low risk (no risk factors present) – 1.6 percent during the first three months; 0.8 percent/year thereafter

Intermediate risk (one risk factor present) – 3.2 percent during the first three months; 1.6 percent/year thereafter

High risk (two or more risk factors) – 12.8 percent during the first three months; ≥6.5 percent/year thereafter

The RIETE score – The RIETE registry has proposed a score to assess bleeding risk during the first three months of anticoagulation therapy [78]. This score is composed of six variables including recent bleeding (2 points), abnormal creatinine levels (1.5 points), anemia (1.5 points), age >75 years (1 point), PE (1 point), and cancer (1 point):

Low risk (0 points) – Bleeding rate 0.3 percent during first three months

Intermediate risk (1-4 points) – Bleeding rate 2.6 percent during first three months

High risk (>4 points) – Bleeding rate 7.3 percent during first three months

The HAS-BLED bleeding risk score – This score was originally proposed to assess bleeding risk in atrial fibrillation but has also been validated in patients with VTE to estimate the risk of bleeding during the first six months of anticoagulant therapy (calculator 1) [79-81]. However, it has not been validated in the extended duration setting. It is discussed in detail separately. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores'.)

Patient values and preferences — We discuss the risks and benefits of indefinite anticoagulant therapy in the context of the patients' personal values and preferences. Patients' preferences and values are particularly important in patients of intermediate risk of recurrence where the benefit of lifelong anticoagulation is less clear. Individual patients attach a variable degree of value on issues such as clinical and laboratory monitoring of warfarin (eg, medication adjustments, telephone calls, frequency of office visits), inconvenience of or pain associated with injections (for low molecular weight heparin), and possible modification of (or restrictions upon) recreational activities that involve an increased risk of blunt trauma [82-86]. In addition, patients weigh benefits and harms differently depending on their occupation, hobbies, comorbidities, and life expectancy.

As an example, a young patient who is an avid mountain climber and has an indication for indefinite anticoagulation may accept the increased risk of VTE over their lifetime and avoid indefinite anticoagulant therapy rather than increase their risk of bleeding from accidental falls. In contrast, an older patient with active cancer may choose to remain on anticoagulation and accept the higher risk of bleeding.

The impact of patient values was illustrated in an observational study that reported that 10 percent of patients declined indefinite anticoagulation despite being good candidates for it [44].

HIGH RECURRENCE RISK — In most patients who have completed a finite course of anticoagulation for an index venous thromboembolic (VTE) event (eg, three months) who are at high risk of recurrence (table 2 and table 1) and in whom the bleeding risk is not high, we typically administer extended/indefinite anticoagulant therapy rather than discontinuing therapy [1,6-8]. Patients at high risk of bleeding are not typically treated with indefinite anticoagulant therapy, although each patient should be considered on a case-by-case basis.

Patients at high risk of recurrent VTE are considered those with an estimated risk of greater than 5 percent per year or cumulative 5 year risk of greater than 23 percent, although this cutoff has been poorly defined (see 'Assessing risk of recurrence' above). Examples of what we consider high risk are in the sections below.

Recurrent proximal DVT and/or symptomatic PE without identifiable risk factors — For patients who have a bleeding risk that is not high and who have more than one episode of proximal DVT and/or symptomatic PE, and all episodes occurred without an identifiable risk factor (ie, >1 "unprovoked" VTE), we recommend indefinite rather than three months of anticoagulant therapy. For those with a high bleeding risk, the benefits of indefinite anticoagulant therapy are less certain and depend heavily on patient-specific thrombotic and bleeding risk as well as the patient's values and preferences.

The recommendation for indefinite anticoagulation in patients with more than one episode of unprovoked DVT or symptomatic PE is based upon recurrence rates that are approximately 15 percent at one year and 45 percent at five years [6,46,87-89]. One 2012 meta-analysis of five randomized trials of patients with VTE reported that, extending therapy in patients with a second unprovoked VTE event resulted in 132 and 396 fewer events per 1000 patients at one year and five years, respectively, compared with a three or six month period of anticoagulation [6].

Any VTE associated with active cancer not precipitated by a major provoking event — Active malignancy is a risk factor for VTE with rates of recurrence as high as 15 to 20 percent per year in the absence of anticoagulant therapy [6,17,24,29,30]. Patients with VTE who have active cancer are typically appropriate candidates for consideration of indefinite anticoagulation. However, the decision is challenging since this population are also at higher risk of bleeding on anticoagulant therapy and patients may have personal factors that weigh into the decision (eg, life expectancy). Recommendations for this population are provided separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

First episode proximal DVT and/or symptomatic PE without identifiable risk factor — For most patients with proximal DVT and/or symptomatic PE who have no identifiable risk factors (ie, "unprovoked" VTE) and in whom the bleeding risk is not high, we suggest indefinite treatment with anticoagulant therapy rather than treatment for three to six months. For patients with a high bleeding risk, the benefits of indefinite anticoagulant therapy are likely outweighed by the high risk of bleeding such that indefinite anticoagulation is not generally performed.

However, within this population, there is debate as to whether a subgroup may avoid indefinite anticoagulation. In such cases, some clinicians use the D-dimer level or calculate the DASH score (D-dimer, Age, Sex, Hormonal therapy; 1 point each) to facilitate this decision. For example, in female patients (but not in male patients) with unprovoked VTE and a low posttreatment D-dimer level (eg, four weeks after discontinuing anticoagulant therapy), the estimated eight-year recurrence risk is approximately 17 percent [20]. Similarly, data suggest that those with a DASH score ≤1 have an annualized risk of 3.1 percent (see 'Clinical prediction rules' above). In situations of uncertainty such as these, some experts including us, may decide not to administer anticoagulant therapy. We do, however, as a general rule in patients with unprovoked VTE maintain a low threshold to continue anticoagulation, for example, when the D-dimer becomes consistently elevated, there is a preference for avoidance of VTE (eg, avoidance of a life-threatening event in a patient with poor cardiopulmonary reserve), or the development of new VTE event. (See 'D-dimer level' above and 'Less well-validated risk factors' above and 'Clinical prediction rules' above.)

The rationale for indefinite anticoagulation in this population is based upon the high estimated lifetime risk of recurrent VTE, which can be which can be reduced by 80 percent or more when anticoagulant therapy is continued beyond the conventional three months [6,7,9,10,14,16,24,77,90-96]. However, this benefit occurs at the expense of an increased rate of bleeding and without a mortality benefit. Prior duration of anticoagulant therapy does not affect the risk of future recurrence once it is discontinued [45,91].

In a meta-analysis of five trials of patients with a first episode of unprovoked VTE, recurrence rates were reported as 10 percent for the first year and 5 percent/year thereafter [6].

In another meta-analysis of 18 studies involving 7515 patients with a first event of unprovoked VTE in whom anticoagulation was discontinued, the cumulative incidence for recurrent VTE was 10 percent in the first year, 16 percent at two years, 25 percent at 5 years, and 36 percent at 10 years [14].

In a Danish cohort study of nearly 74,000 patients with VTE, among those with unprovoked VTE, rates of recurrence were 6.9 percent in the first 6 months followed by 2.8 percent per year for the next 10 years [24].

In patients with unprovoked proximal DVT and/or symptomatic PE, therapeutic anticoagulation is associated with an over 80 percent reduction in the rate of recurrence compared with placebo [6]. Low-intensity warfarin regimens and aspirin are less effective (approximately 60 and 30 percent rate reduction in recurrence respectively compared with placebo). Data for individual agents are discussed below. (See 'Agents' below.)

In a 2021 meta-analysis of 15 trials, anticoagulation with both warfarin and direct oral anticoagulants (DOACs) in patients with unprovoked VTE was associated with a lower rate of VTE recurrence (warfarin: risk ratio [RR] 0.51, 95% CI 0.26-1.01; DOACs: RR 0.17, 95% CI 0.11-0.26), which occurred at the expense of an increased rate of major bleeding (warfarin: RR 2.91, 95% CI 1.12-7.56; DOACs: RR 1.97, 95% CI 0.29-13.64) [1]. However, results favored DOACs over warfarin for both outcomes.

INTERMEDIATE RECURRENCE RISK — We individually assess patients who have completed a finite course of anticoagulation (eg, three months) for an index venous thromboembolic (VTE) event who are considered to have an intermediate risk of recurrence (table 2 and table 1) and who are not at high risk of bleeding. This approach is based upon a risk of recurrence that is wide-ranging and an efficacy and safety profile for indefinite anticoagulation that is ill-defined and poorly studied. Patients in this category who are at high risk of bleeding are not typically treated with anticoagulant therapy.

Patients at intermediate risk of recurrent VTE are considered those with an estimated risk of 3 to 5 percent per year or 14 to 23 percent over 5 years, although this cutoff has been poorly defined (see 'Assessing risk of recurrence' above). Examples of what we consider intermediate risk are in the sections below.

First VTE with persistent nonmalignant risk factor — In patients with any acute thromboembolic event (eg, distal or proximal DVT, symptomatic PE) and persistent nonmalignant risk factors (eg, obesity, active inflammatory bowel disease, active autoimmune disease, nephrotic syndrome, recurrent long-haul flights expected, continued hormonal therapy (table 1)), we typically have a low threshold to offer indefinite anticoagulation, provided the bleeding risk is not high.

The range of recurrence risk is likely wide in this population due to the heterogeneous nature of this group. While a meta-analysis and other studies report an estimated risk of VTE recurrence of 5 percent at one year and 15 percent at five years in this population, these figures likely under- or over-estimate the actual risk in individual patients [6-9,97]. Thus, in this group, we pay attention to individual risk factors when assessing recurrence. For example, we believe that risk of recurrence associated with obesity is possibly lower than that associated with active inflammatory bowel disease and nephrotic syndrome, although the actual risk is undetermined.

First episode VTE due to transient minor risk factor — This group includes patients who develop VTE in association with transient minor risk factors including a long-haul flight, minor surgery <30 minutes, hospitalization <3 days, reduced mobility at home ≥3 days, lower extremity injury without fracture with reduced mobility ≥3 days (table 1).

Some experts favor indefinite anticoagulation in this population based upon the premise that VTE in the presence of a minor risk factor may represent a propensity for thrombosis. However, others prefer not to indefinitely anticoagulate this population [1]. In such situations, use of additional factors and the patient's preferences is particularly important in helping the patient and clinician come to a decision. For example, a male patient with VTE associated with a long-haul flight who has an elevated D-dimer level off anticoagulation or a family history of DVT in the absence of proven inherited thrombophilias may warrant indefinite anticoagulant therapy, whereas a female patient with VTE following a long-haul flight who has no other risk factors and a normal D-dimer may not necessarily warrant indefinite anticoagulation.

Recurrent VTE provoked by transient or persistent nonmalignant risk factor — While in the past most clinicians treated patients with a second episode of VTE with life-long anticoagulation, we now recognize that there is a wide range of risk in this group. For example, patients with more than one episode of VTE associated with a transient major risk factor such as surgery do not necessarily need indefinite anticoagulation, while those with recurrent VTE associated with a persistent risk factor or minor transient risk factor (table 1) may be reasonably considered for indefinite anticoagulation, provided the bleeding risk is not high.

Data describing the risk of recurrence in this heterogeneous group are derived from observational cohorts as well as studies that examined recurrence risk in mixed populations of patients with VTE (ie, patients on or off anticoagulant therapy, patients with and without provoking risk factors) [88,89,98]. As examples:

One study that prospectively followed 738 patients with DVT for four to nine years, reported that the five-year cumulative incidence of recurrent VTE increased from 22 percent after a first DVT to 28 percent after a second DVT [88]. In addition, a prior history of VTE was an independent predictor of recurrence (relative risk [RR] 1.71, 95% CI 1.16-2.52).

Another prospective study of 131 patients with a late second episode of VTE (ie, more than one year after the first event) reported a recurrence rate of 6 percent per year [89].

Another multicenter trial evaluated the outcome of 227 patients with a second episode of VTE who were randomly assigned to receive either six months of oral warfarin or extended therapy for four years [98]. Extended therapy (target international normalized ratio [INR] 2 to 2.85) was associated with a lower rate of recurrence (3 versus 21 percent, RR 0.13, 95% CI 0.04-0.40) but at the expense of a higher risk for major hemorrhage (9 versus 3 percent; RR 3.3, 95% CI 0.9-10). Whether expected bleeding rates would be lower with direct oral anticoagulants is unstudied.

LOW RECURRENCE RISK — In most patients who are considered at low risk of recurrence (table 1), we do not routinely administer indefinite anticoagulant therapy [6-8]. Although the risk of an index venous thromboembolic (VTE) event in this setting is high (thereby justifying the term "major" risk factor), the risk of recurrent future events is low. In this population, the estimated risk of VTE is less than 3 percent per year or <14 percent at 5 years, although this cutoff has been poorly defined (see 'Assessing risk of recurrence' above). For patients in this category, extended anticoagulant therapy likely confers more risk than benefit. Patients considered at low risk are those who have a VTE event following a major transient risk factor.

First episode VTE with transient major risk factor — For most patients who have a first episode of VTE (proximal or distal DVT, symptomatic or asymptomatic PE) provoked by a major transient risk factor (typically surgical), we recommend anticoagulation for three months rather than for periods of longer or shorter duration.

Patients in this group include those who, less than approximately six weeks prior to the index VTE event, had one of the following: surgery with general anesthesia for >30 minutes, were confined to bed with "bathroom privileges" ≥3 days due to acute illness, underwent cesarian delivery, or were hospitalized for major trauma. Patients who develop VTE during pregnancy or the puerperium and patients who develop estrogen-associated VTE are also in this category provided the estrogen has been discontinued.

In surgical patients, the risk of VTE recurrence is estimated to be 1 percent at one year and 3 percent at five years (approximately 0.5 percent per year after the first year) [6-9,16,20,32].

SPECIAL POPULATIONS

VTE with prothrombotic conditions — Management of anticoagulant therapy in patients with prothrombotic disorders is complex and likely depends upon the underlying thrombotic disorder and the provoking event. In our experience, in patients with prothrombotic disorders, the main factors driving recurrence are similar to those in patients who do not have a prothrombotic disorder (eg, provoked or unprovoked, major or minor provoking risk factors, presence of cancer active cancer).

Major ("high-risk) prothrombotic conditions – Most patients with underlying major prothrombotic conditions (eg, antiphospholipid syndrome and anti-thrombin deficiency) and a first episode of acute VTE are treated indefinitely with anticoagulant therapy, provided the bleeding risk is not high (algorithm 1). For those with a high bleeding risk, the benefits of indefinite anticoagulant therapy are less certain, and depend heavily on patient-specific thrombotic and bleeding risk as well as the patient's values and preferences.

However, a possible exception would be a patient with VTE associated with a major transient risk factor such as surgery or pregnancy (ie, a strong provoking event) (table 1); whether or not such patients derive net benefit from indefinite anticoagulant therapy is unknown. For example, in a patient with persistent laboratory evidence of antiphospholipid antibodies whose only thrombotic event is a proximal DVT two weeks after total knee arthroplasty, many experts would not have a clear preference for lifelong anticoagulant therapy. Further details on the management of major prothrombotic conditions are provided separately. (See "Management of antiphospholipid syndrome" and "Antithrombin deficiency", section on 'Management'.)

"Lower risk" thrombophilias – In patients who have a first episode of VTE and "lower risk" thrombophilias (such as heterozygous for the factor V Leiden or prothrombin gene mutation), most clinicians, including us, do not indefinitely anticoagulate. However, indefinite anticoagulation in those with protein S or C deficiency is more controversial. This approach is based upon the rationale that similar to patients with major prothrombotic disorders, the main factors driving recurrence are similar to those in patients who do not have a prothrombotic disorder. Management of patients with "lower risk" inherited thrombophilias and VTE are discussed separately. (See "Factor V Leiden and activated protein C resistance", section on 'Patients with VTE' and "Prothrombin G20210A", section on 'Patients with VTE' and "Antithrombin deficiency", section on 'Management' and "Protein C deficiency", section on 'Management' and "Protein S deficiency", section on 'Patients with VTE'.)

Recurrent provoked and unprovoked proximal deep venous thrombosis and/or symptomatic PE — The recurrence rate associated with an unprovoked first event followed by a provoked second event, or vice versa, is unknown but probably carries a risk of recurrence no lower than that of a single unprovoked event, thereby warranting indefinite anticoagulation in many patients, providing the bleeding risk is low. (See 'First episode proximal DVT and/or symptomatic PE without identifiable risk factor' above.)

Isolated distal deep vein thrombosis — The approach in this population is unclear. We suggest the following general principles:

Unprovoked distal deep venous thrombosis (DVT) – In patients with isolated unprovoked distal DVT (ie, calf vein DVT), the optimal strategy is unknown. While many patients in this category are not typically anticoagulated indefinitely, a small proportion of patients may benefit [6]. As an example, provided the bleeding risk is not high, we sometimes offer anticoagulant therapy to patients with an unprovoked isolated distal DVT with additional risk factors such as active cancer, a strong family history of VTE, male sex, persistently elevated D-dimer, or other persistent risk factors.

Data to support this approach in patients with isolated unprovoked distal DVT are limited. In one pooled analysis of 18 trials of patients with a first episode of unprovoked VTE and in whom anticoagulant therapy was discontinued, a subgroup analysis of patients with distal DVT reported a recurrence rate of 1.9 percent (95% CI 0.5 to 4.3) in the first year, compared with 10.6 percent for patients with proximal DVT [14]. Data from randomized trials of patients with unselected VTE (ie, provoked and unprovoked) also report a 20 to 50 percent lower recurrence risk following a conventional course of anticoagulant therapy in patients with distal DVT when compared with patients who have proximal DVT [9,90,92,93].

Recurrent unprovoked distal DVT – Recurrent isolated unprovoked distal DVT is an unusual scenario. In addition, it can be difficult to distinguish a second recurrence from residual clot in the same calf. However, we typically anticoagulate indefinitely when it is clear that the patient had two different unprovoked isolated distal DVT events (eg, one event in each calf), provided the bleeding risk is not high.

Provoked distal DVT – Patients with isolated provoked distal DVT are not typically anticoagulated indefinitely.

Incidental subsegmental PE without identifiable risk factors — The efficacy and safety of indefinite anticoagulation in patients with an asymptomatic PE (ie, incidental PE, typically small subsegmental PE [SSPE]) in the absence of a provoking risk factor is unknown.

While some experts feel it is appropriate to wait until a second event occurs before prescribing indefinite anticoagulation (eg, patients without active malignancy), others evaluate based upon the presence of additional risk factors as well as size and location of PE. For example, the threshold to indefinitely anticoagulate may be higher in an asymptomatic patient with SSPE compared with an asymptomatic patient with an isolated lobar PE.

Importantly, a discussion with the patient should clarify that the risk of recurrence is unknown and that the threshold should be low to investigate for recurrence, if indefinite anticoagulation is deferred.

Limited data regarding recurrence rates in patients with SSPE who have cancer and indications for anticoagulant therapy in patients with a first episode of SSPE are provided separately. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Patients with subsegmental PE' and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Incidental and small subsegmental pulmonary embolism'.)

Others — Other patients that warrant indefinite anticoagulation are discussed in the followed linked topics:

Coronary artery disease (see "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy")

Chronic thromboembolic pulmonary hypertension (see "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Anticoagulant therapy (indefinite)')

AGENT SELECTION

Agents — Since the first-line agent for most patients with acute venous thromboembolism (VTE) is a direct oral anticoagulant (DOAC), most patients continue on their DOAC [1,6,99]. In addition, DOACS are generally preferred for their convenience, reduced need for laboratory monitoring, and lower risk of bleeding compared with warfarin. Lower-intensity regimens may be an option in select patients. (See 'Low-intensity regimens following a finite course' below.)

Occasionally, agents need to be switched or are started de novo following a period off anticoagulation (eg, high risk of bleeding that has since resolved). Reasons for switching agents and suggested transition strategies among parenteral and oral agents (table 5) are discussed separately. (See 'Patient values and preferences' above and "Venous thromboembolism: Anticoagulation after initial management", section on 'Switching anticoagulants during therapy' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

Direct oral anticoagulants (factor Xa and direct thrombin inhibitors) — Several randomized trials of DOACs (ie, oral factor Xa and direct thrombin inhibitors) have proven efficacy in the prevention of recurrence in patients with VTE without an apparent risk factor (ie, "unprovoked" VTE) [46,94,100-105]. (See 'First episode proximal DVT and/or symptomatic PE without identifiable risk factor' above and "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

RivaroxabanRivaroxaban, an oral factor Xa inhibitor, was studied in 1556 patients (EINSTEIN) with acute VTE (mostly patients without an identifiable risk factor [ie, "unprovoked" VTE]), who had completed 6 to 12 months of either rivaroxaban (20 mg once daily) or warfarin [100]. Compared with placebo, an additional 6 to 12 months of rivaroxaban was superior for the prevention of recurrent DVT (1.3 versus 7 percent). The incidence of nonfatal major bleeding was no different between the groups (0.7 versus 0 percent). Although non-major bleeding events were higher in those taking rivaroxaban (5.4 versus 1.2 percent), the low rate of major bleeding among the rivaroxaban-treated patients underscores the safety of extended rivaroxaban in patients who have completed 6 to 12 months of anticoagulant therapy.

Comparisons of low-intensity rivaroxaban with both a full-intensity regimen and with low-dose aspirin is discussed below [104]. (See 'Low-intensity regimens following a finite course' below.)

ApixabanApixaban, an oral factor Xa inhibitor, was studied in 2482 patients with VTE, most of whom had unprovoked VTE and who had already completed 6 to 12 months of apixaban or warfarin (AMPLIFY-EXT) [94]. Twelve months of apixaban administered at a therapeutic dose (5 mg) resulted in lower rates of symptomatic VTE or VTE-related death compared with placebo (1.7 percent versus 8.8 percent), as well as lower rates of the composite endpoint of recurrent VTE or all-cause death (4.2 versus 11.6 percent) and the composite endpoint of non VTE-associated death/myocardial infarction/stroke (0.6 versus 1.3 percent). The benefits of apixaban occurred without an increased risk in major bleeding events (0.1 versus 0.5 percent).

Dabigatran – Extended courses (6 to 36 months) of the oral direct thrombin inhibitor dabigatran were compared with warfarin (RE-MEDY; 2856 patients) or placebo (RE-SONATE; 1343 patients), in patients at risk of recurrence who had completed at least three months of either dabigatran or warfarin (most patients had unprovoked VTE) [103]. Dabigatran, when compared with warfarin, resulted in a similar rate of recurrent VTE (1.8 versus 1.3 percent) and a significantly lower rate of major or clinically relevant bleeding (5.6 versus 10.2 percent), but a significantly higher rate of acute coronary syndrome (0.9 versus 0.2 percent). Dabigatran resulted in a lower rate of recurrent VTE (0.4 versus 5.6 percent) and a higher rate of major or clinically relevant bleeding (5.3 versus 1.8 percent) when compared with placebo.

Warfarin — Warfarin is an alternative in those patients for whom factor Xa or direct thrombin inhibitors are not available (eg, due to cost). Several trials have reported reduced VTE recurrence rates from extended anticoagulation with warfarin therapy for the treatment of unprovoked VTE [6,10,21,31,87,98,106,107]. These trials compared patients receiving warfarin at varied International Normalized Ratio (INR) targets with patients who stopped therapy at three or six months and were followed for one to three years.

In a 2012 meta-analysis of five trials of patients with unprovoked VTE, extending anticoagulation beyond three or six months with full intensity warfarin (target INR 2.5) reduced the five-year recurrence rate by 90 percent (risk ratio [RR] 0.12, 95% CI 0.05-0.25) [6]. This benefit was at the expense of a 2.6-fold increase in major bleeding at five years (RR 2.63, 95% CI 1.02-6.67). The estimated absolute reduction in VTE events was reported as 88 and 264 fewer events per 1000 patients treated at one year and five years, respectively.

Another randomized trial of 371 patients with a first episode of unprovoked PE (PADIS-PE) reported that following an initial six months of treatment with warfarin, an additional 18 months of treatment reduced the rate of VTE recurrence (3 versus 14 percent) when compared with those treated for six months [10]. However, benefit was not maintained after discontinuation of anticoagulation therapy. The rate of bleeding was higher in those receiving warfarin (2 versus 0.5 percent).

Aspirin — In patients with a first episode of unprovoked VTE who have completed a conventional course of anticoagulation, rates of VTE recurrence on the antiplatelet, low-dose ASA (ASA; 100 mg/day) are reduced by at least one-third when compared with placebo or observation [11,108-112]. Consequently, most experts do not consider aspirin unless patients decline therapeutic anticoagulation (eg, due to cost or convenience).

One multicenter trial (WARFASA) randomly assigned 402 patients with a first episode of unprovoked VTE who were treated with 6 to 18 months of warfarin therapy to receive aspirin or placebo for an additional two years [108]. Aspirin was associated with a 40 percent reduction in the rate of recurrent VTE (7 versus 11 percent per year; hazard ratio [HR] 0.58, 95% CI 0.36-0.93). Bleeding rates were similar between the groups (0.3 percent per year), although the event rate was too low in both groups to make a firm conclusion regarding safety.

In contrast, in another trial of 822 patients (ASPIRE), most of whom had received anticoagulation for 6 to 12 months for a first episode of unprovoked VTE aspirin did not reduce VTE recurrence over a four year period compared with placebo  (5 versus 7 percent per year) [109]. The rates of bleeding and serious adverse events were similar (approximately ≤1 percent), but events were again too low to assess safety.

A prospectively planned combined analysis of the WARFASA and ASPIRE trials reported that aspirin, as compared with placebo, significantly reduced the rate of VTE recurrence by 32 percent (HR 0.68, 95% CI 0.51-0.90) with no excess risk of bleeding [110,111].

In a meta-analysis of 12 trials (12,000 patients), aspirin was associated with a 30 percent risk reduction in VTE recurrence when compared with placebo or observation [11].

Several other studies have reported that from a recurrence risk perspective, aspirin is inferior to therapeutic anticoagulant therapy with warfarin or DOACs [12,104].

Others — Low molecular weight (LMW) heparin and fondaparinux are potential agents of value for indefinite anticoagulation. However, only indirect evidence from trials using shorter durations of therapy (eg, six months) are available and the potential for drug-induced osteoporosis may be increased when LMW heparin is administered for prolonged periods (eg, years) [113]. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Low molecular weight heparin'.)

Sulodexide, a glycosaminoglycan that has antithrombotic and profibrinolytic activity, has been shown to reduce the risk of recurrence in patients with unprovoked VTE [114], but this agent remains investigational and while it is available in Europe, is not available in the United States.

LOW-INTENSITY REGIMENS FOLLOWING A FINITE COURSE — We do not administer low-intensity warfarin regimens. However, in patients who have completed 6 to 12 months of standard-intensity treatment with a factor Xa inhibitor (eg, rivaroxaban, apixaban, edoxaban), we may administer reduced-intensity regimens with a direct oral anticoagulant (DOAC) that has been evaluated for long-term secondary prevention (eg, apixaban, rivaroxaban), typically with a lower-intensity regimen. This choice is based upon randomized trial data and limited meta-analyses reporting that low-dose and therapeutic-dose factor Xa inhibitor regimens have similar efficacy and safety when used for the long-term secondary prevention of VTE [1,42,94,104,105]. The direct thrombin inhibitor, dabigatran has not been assessed in this setting, and as such we do not use it. However, in some patients, low-dose DOAC regimens may not be appropriate, even after 6 to 12 months of standard-dose treatment (eg, patients with high body weight [eg, >120 kg] or patients with highly prothrombotic conditions [eg, cancer]). Low-dose warfarin regimens are less effective (and not clearly safer) than standard-intensity warfarin; thus, for patients on warfarin, we administer full-intensity regimens. We do not advocate the use of aspirin in this setting unless all other options are exhausted. (See 'High recurrence risk' above.)

Limited data in select populations of VTE without an identifiable risk factors that support a lower-intensity regimen include the following:

Low intensity rivaroxaban versus aspirin – In a randomized trial of patients with unprovoked VTE, who had completed 6 to 12 months of anticoagulation, rivaroxaban at either a treatment dose (20 mg daily) or prophylactic dose (10 mg daily) resulted in similar rates of VTE recurrence (1.5 and 1.2 percent, respectively) compared with 4.4 percent in patients taking 100 mg of aspirin daily [104]. Similar rates of major bleeding (0.5 versus 0.4 versus 0.3 percent, respectively) and clinically relevant nonmajor bleeding (<3 percent) were also reported among all three groups. A meta-analysis of two studies that included this study which analyzed outcomes with reduced-intensity DOACs in the extended setting showed similar results [105].

Apixaban – In 2482 patients with unprovoked VTE and who had already completed 6 to 12 months of apixaban or warfarin, 12 months of low-intensity (2.5 mg twice daily) or therapeutic-intensity (5 mg twice daily) anticoagulation with apixaban resulted in similar rates of the composite end point of symptomatic VTE or VTE-related death (1.7 percent each) without an increased risk in major bleeding events (<0.2 percent) [94]. A prospective cohort study of 732 patients with unprovoked VTE reported a low rate of VTE compared with patients in whom anticoagulation was held after 12 months or more of therapy (0.9 versus 6.2 percent per year) [42].

Warfarin – In a 2012 meta-analysis of five trials of patients with unprovoked VTE, extending anticoagulation beyond three or six months with full-intensity warfarin (target INR 2.5) or low-intensity warfarin (target INR 1.75) reduced the five-year recurrence rate by 90 and 64 percent, respectively, compared with patients not treated with warfarin (risk ratio 0.12, 95% CI 0.05-0.25) [6].

FOLLOW-UP — Although the optimal period of follow-up for patients on indefinite anticoagulation is unknown, most clinicians and societal guidelines suggest regular review of the risks and benefits for patients who remain on therapy (eg, annually) [6,7]. During follow-up patients should be assessed for recurrence, the development of contraindications to anticoagulation, altered bleeding risk, and chronic hemorrhage, as well as for changes in agent preference.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism" and "Society guideline links: Anticoagulation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Deep vein thrombosis (blood clot in the leg) (The Basics)")

Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Rationale – Most patients with a first episode of venous thromboembolism (VTE; proximal lower extremity deep venous thrombosis [DVT] and/or pulmonary embolus [PE]) are anticoagulated for a finite period of three to six months. Select patients benefit from indefinite anticoagulation, which is administered with the primary goal of reducing the lifetime risk of recurrent thrombosis. (See 'Introduction' above and 'Rationale' above.)

Clinical assessment – In patients with VTE who have completed a finite course of therapeutic anticoagulation, we perform an individualized assessment of the patient's risk of recurrence and bleeding and personal values and preferences (see 'Clinical assessment' above):

To estimate VTE risk, we obtain details regarding the index event and risk factors (if any) associated with that event and with any previous event(s). We characterize risk factors as transient or persistent, major or minor, and malignant or nonmalignant (table 1). We estimate cumulative risk over a one-year or five-year period and categorize it as the following (table 2):

-High (>5 percent per year; >25 percent over five years)

-Intermediate (3 to 5 percent per year; 14 to 23 percent over five years)

-Low (<3 percent per year; <14 percent over five years)

Several clinical prediction rules have been proposed to estimate the risk of recurrence in VTE not provoked by an identifiable risk factor (ie, "unprovoked" VTE) following discontinuation of anticoagulation; none have become routinely integrated into clinical practice but may be used when uncertainty exists. (See 'Assessing risk of recurrence' above.)

Similarly, we take a detailed history of any previous episodes of bleeding on or off anticoagulant therapy, risk factors that could impact future bleeding events (table 3), and conditions that may affect the half-life of the administered anticoagulant (eg, renal failure, weight loss). Although prediction tools are available (calculator 2), many clinicians use gestalt estimates for the risk of bleeding and categorize it as high or low. In patients with a low bleeding risk in whom a factor Xa or direct thrombin inhibitor is being administered (ie, a direct oral anticoagulant [DOAC]), the annual risk of bleeding is likely lower (eg, <1.5 percent per year) than that seen in older studies, which largely included patients on warfarin (eg, <3 percent per year). (See 'Assessing the risk of bleeding' above.)

High-risk VTE recurrence – In general, patients at high risk of VTE recurrence (table 2) in whom the bleeding risk is not high are considered good candidates for indefinite anticoagulant therapy. In these patients, indefinite anticoagulation reduces recurrence by about 80 percent; however, the absolute risk reduction varies depending upon the baseline risk. (See 'High recurrence risk' above.)

For patients who have more than one episode of unprovoked proximal DVT and/or symptomatic PE and more than one episode was unprovoked, we recommend indefinite rather than three months of anticoagulant therapy (Grade 1B). The baseline risk of recurrence in this group is unacceptably high (eg, 15 percent at one year and 45 percent at five years). For those with a high bleeding risk, the benefits of indefinite anticoagulant therapy are less certain and depend heavily on patient-specific thrombotic and bleeding risk as well as the patient's values and preferences. (See 'Recurrent proximal DVT and/or symptomatic PE without identifiable risk factors' above.)

Patients with VTE who have active cancer are typically appropriate candidates for consideration of indefinite anticoagulation. However, the decision is challenging since this population is also at higher risk of bleeding on anticoagulant therapy, and patients may have personal factors that weigh into the decision (eg, life expectancy). Recommendations for this population are provided separately. (See 'Any VTE associated with active cancer not precipitated by a major provoking event' above and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Duration of anticoagulation'.)

For most patients with a first episode of unprovoked proximal DVT and/or symptomatic PE, we suggest indefinite anticoagulant therapy rather than treatment for three to six months (Grade 2B). In this population, the estimated baseline risk of recurrent VTE without treatment is approximately 10 to 16 percent for the first year and 5 percent per year thereafter. For patients with a high bleeding risk, the benefits of indefinite anticoagulant therapy are likely outweighed by the high risk of bleeding, such that indefinite anticoagulation is not generally performed. (See 'First episode proximal DVT and/or symptomatic PE without identifiable risk factor' above.)

However, we believe that a subgroup may avoid indefinite anticoagulation. For select patients who are at lower risk (eg, females with unprovoked VTE and a low posttreatment D-dimer level or DASH score ≤1), we suggest not administering anticoagulant therapy indefinitely (Grade 2C). Close observation and a low threshold to anticoagulate is prudent. This suggestion does not apply to males.

Intermediate-risk VTE recurrence – In general, for patients at intermediate risk of VTE recurrence (table 2), we typically assess the benefits and harms of extending anticoagulant therapy indefinitely on a case-by-case basis. These decisions are influenced by the number and type of risk factors as well as the values and preferences of the patient. This approach is based upon a risk of recurrence that is wide-ranging (3 to 5 percent per year; 14 to 23 percent over five years) and an efficacy and safety profile for indefinite anticoagulation that is ill-defined and poorly studied, such that patients may reasonably opt for not anticoagulating indefinitely. Patients in this category who are at high risk of bleeding are not typically treated with anticoagulant therapy. The following general principles apply (see 'Intermediate recurrence risk' above):

Patients in whom we are more likely to opt for indefinite anticoagulation include those on the higher end of this risk range:

In patients with a first episode of VTE (eg, distal or proximal DVT, symptomatic PE) and persistent nonmalignant risk factors (eg, obesity, active inflammatory bowel disease, active autoimmune disease, nephrotic syndrome, recurrent long-haul flights expected, continued hormonal therapy), we typically have a low threshold to offer indefinite anticoagulation, provided the bleeding risk is not high. (See 'First VTE with persistent nonmalignant risk factor' above.)

In patients who develop VTE in association with transient minor risk factors including a long-haul flight, minor surgery <30 minutes, hospitalization <3 days, reduced mobility at home ≥3 days, and lower extremity injury without fracture with reduced mobility ≥3 days, we favor extending anticoagulant therapy based upon the observation that the development of VTE in this population may represent a high propensity for thrombosis. (See 'First episode VTE due to transient minor risk factor' above.)

In patients with a second episode of VTE provoked by a transient or persistent nonmalignant major or minor risk factor, the range of risk is wide. For example, patients with more than one episode of VTE associated with a major transient risk factor such as surgery do not necessarily need indefinite anticoagulation, while those with recurrent VTE associated with a persistent risk factor or minor transient risk factor may be reasonably considered for indefinite anticoagulation, provided the bleeding risk is not high. (See 'Recurrent VTE provoked by transient or persistent nonmalignant risk factor' above and 'First VTE with persistent nonmalignant risk factor' above.)

Low recurrence risk – For patients with a first episode of VTE provoked by a major transient risk factor (table 2 and table 1), we recommend a three- to six-month finite course of anticoagulant therapy rather than administering indefinite anticoagulant therapy (Grade 1B). This approach is based upon a low risk of recurrence in this population (<3 percent per year or <15 percent at five years). Patients with major reversible risk factors include those who had surgery with general anesthesia for >30 minutes, were confined to bed with "bathroom privileges" ≥3 days due to acute illness, underwent cesarian delivery, or were hospitalized for major trauma. Pregnancy, the puerperium, and estrogen supplementation are also generally considered major transient risk factors. (See 'Low recurrence risk' above.)

Special populations – Populations that require special consideration include those with "prothrombotic" conditions, patients with mixed recurrent provoked and unprovoked events, patients with distal deep vein thrombosis, and patients with incidental small subsegmental PE. (See 'Special populations' above.)

Agent choice and regimens – For most patients in whom indefinite anticoagulant therapy is chosen, we suggest a factor Xa inhibitor (eg, rivaroxaban, apixaban) rather than warfarin (Grade 2B) or aspirin (Grade 2C). However, alternate agents may need to be initiated for a variety of reasons during therapy. For many patients on a factor Xa inhibitor, we suggest full intensity or reduced anticoagulant therapy (eg, patients with unprovoked VTE) (Grade 2C). However, low-dose factor Xa regimens may not be appropriate in some patients (eg, patients with high body weight [eg, >120 kg] or patients with highly prothrombotic conditions [eg, cancer]). For patients on warfarin, we suggest full-intensity dose warfarin rather than reduced intensity warfarin (Grade 2C). We do not advocate the use of aspirin in this setting unless all other options are exhausted. (See 'Agent selection' above.)

Follow-up – During follow-up we assess patients at least annually for recurrence, adequacy of therapeutic control, the development of contraindications to anticoagulation, altered bleeding risk, and chronic hemorrhage, as well as for changes in agent preference. (See 'Follow-up' above.)

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Topic 94740 Version 59.0

References

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