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Venous thromboembolism: Anticoagulation after initial management
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Venous thromboembolism: Anticoagulation after initial management
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Dec 02, 2016.

INTRODUCTION — Deep vein thrombosis (DVT) and pulmonary embolism (PE) are forms of venous thromboembolism (VTE). VTE has significant morbidity and mortality for patients in the community and in hospital. Anticoagulation is the mainstay of therapy for VTE. The purpose of anticoagulation is the prevention of recurrent thrombosis, embolization, and death, the risk of which is greatest in the first three to six months following the diagnosis.

Following initial anticoagulation for the first 5 to 10 days, patients with VTE require therapy for a more prolonged period of at least three months. This topic review will discuss the selection of an anticoagulant, the transition from initial therapy, and the duration and monitoring of long-term anticoagulation. The indications for anticoagulation, an overview of DVT treatment, and details regarding initial and indefinite anticoagulation for patients with VTE are discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Venous thromboembolism: Initiation of anticoagulation (first 10 days)" and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)

NOMENCLATURE — For the purposes of discussion in this topic, the following terms apply:

The term unprovoked deep vein thrombosis (DVT) implies that no identifiable provoking environmental event for DVT is evident [1]. In contrast, a provoked DVT is one that is usually caused by a known event (eg, surgery, hospital admission). VTE events can be provoked by transient major risk factors (ie, major surgery >30 minutes, hospitalization or immobility ≥3 days, cesarian section), transient minor risk factors (minor surgery <30 minutes, hospitalization <3 days, pregnancy, estrogen therapy, reduced mobility ≥3 days) or persistent risk factors. Persistent risk factors include reversible conditions (eg, curable malignancy, inflammatory bowel disease that resolves) and irreversible conditions such as inheritable thrombophilias, chronic heart failure, and metastatic end-stage malignancy. (See "Overview of the causes of venous thrombosis".)

Initial anticoagulation refers to systemic anticoagulation administered for the first few days (typically up to 10 days) following a diagnosis of acute VTE. Long-term anticoagulant therapy is administered for a finite time beyond the initial period, usually three to six months, and occasionally up to 12 months (ie, there is a scheduled stop date). Extended anticoagulation refers to therapy that is administered indefinitely (ie, no scheduled stop date). (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)" and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)

Oral factor Xa and direct thrombin inhibitors have been referred to using a variety of names including newer/novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants (NOAs, NOACs), direct oral anticoagulants (DOACs), and target-specific oral anticoagulants (TOACs, TSOACs) [2]. Throughout this topic, we refer to these agents by their pharmacologic class, factor Xa and direct thrombin inhibitors. (See "Direct oral anticoagulants: Dosing and adverse effects".)

INDICATIONS — Details of the indications for anticoagulation for deep vein thrombosis and pulmonary embolism are discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Indications' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

SELECTION OF AGENT — Long-term anticoagulant therapy is administered beyond the initial few days of anticoagulation for a finite period of typically three to six months, and up to 12 months in some cases (ie, scheduled stop date). Options for long-term anticoagulation include oral anticoagulants (ie, factor Xa inhibitors, direct thrombin inhibitors, and warfarin) and parenteral subcutaneous anticoagulants (low molecular weight [LMW] heparin and fondaparinux). While the factor Xa and thrombin inhibitors are typically preferred, choosing among these options frequently depends upon clinician experience and availability, the risks of bleeding, patient comorbidities and preferences, cost, and convenience (table 1) [3].

Patient values and preferences are critical in selecting a long-term agent for anticoagulation in acute venous thromboembolism (VTE). Variations exist in the perceptions of burden by patients. For example, while some patients want to avoid daily injections, others may consider them preferable to weekly international normalized ratio (INR) monitoring [4]. As another example, patients who place a high value on antidote availability and cost may choose warfarin, while others who place a high value on a lower risk of bleeding may prefer the direct oral anticoagulants. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Patient values and preferences'.)

General population — As a general principle, oral agents are typically preferable to parenteral agents. For most non-pregnant patients who do not have severe renal insufficiency (eg, creatinine clearance [CrCl <30 mL/minute) or active cancer, we suggest the direct oral anticoagulants, rivaroxaban, apixaban, edoxaban, or dabigatran, rather than warfarin (table 2) and suggest warfarin rather than LMW heparin. Factors that influence agent selection including feasibility of oral administration are discussed below (table 1).

Factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) and oral direct thrombin inhibitors (dabigatran) – These oral agents are our preferred anticoagulant for most hemodynamically-stable, non-pregnant patients who do not have severe renal insufficiency (eg, CrCl <30 mL/minute) or active cancer (table 2). While rivaroxaban and apixaban can be administered as monotherapy, edoxaban and dabigatran are preferably administered following a five day course of heparin (ie, as dual therapy; LMW or unfractionated heparin [UFH]).

Our preference for these agents is based upon their similar efficacy, reduced need for monitoring, and lower bleeding risk profile, when compared with warfarin. In addition, theoretically patients may spend more time in the therapeutic range with these agents when compared with warfarin. Clinicians should be aware that although the risk of bleeding is lower with these agents, experience with antidotes is limited. No agent is superior to the other and dosing for each agent is per product information. When prescribing these agents, we prefer that they be administered by clinicians knowledgeable in their use in accordance with study criteria that proved their efficacy. (See 'Direct thrombin and factor Xa inhibitors' below and "Direct oral anticoagulants: Dosing and adverse effects" and "Management of bleeding in patients receiving direct oral anticoagulants" and 'Risk of bleeding' below.)

Importantly, these agents are NOT suitable for the treatment of hemodynamically unstable pulmonary embolism (PE), massive iliofemoral deep vein thrombosis (DVT; eg, phlegmasia cerulea dolens), or for those who are pregnant. While these agents are contraindicated in those with severe renal insufficiency (CrCl <30 mL/minute), our preference is to avoid them in all patients with renal insufficiency, although renally-adjusted dosing can be made in those with mild impairment (eg, 30 to 50 mL/minute). Similarly, many experts avoid them in those with chronic liver disease in whom the INR may be elevated. For those in whom monitoring compliance and agent reversal is important, avoidance may also be appropriate.

Issues concerning long-term safety, drug-drug interactions, and use of these agents in those with hepatic disease still need to be clarified in future trials.

Warfarin – Warfarin is our preferred anticoagulant for patients in whom factor Xa or direct thrombin inhibitors are not available and for patients with severe renal insufficiency (CrCl <30 mL/minute) (table 2).

Warfarin requires multiple office visits for INR monitoring and has a higher bleeding risk when compared with direct oral anticoagulants; however, antidotes for warfarin-related bleeding are more readily available. Thus, it may also be preferred in those with a preference or requirement for a readily reversible antidote (eg, need for frequent interventions) and those in whom therapeutic anticoagulation needs to be monitored (eg, poor compliance). Dosing for warfarin is discussed below. (See 'Warfarin' below.)

Although warfarin is not absolutely contraindicated in patients with known protein C or S deficiency who are at increased risk of warfarin-induced skin necrosis, patients can be treated with warfarin overlapped with heparin, if direct oral anticoagulants cannot be administered. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

Low molecular weight (LMW) heparin – Subcutaneous LMW heparin is an acceptable alternative for non-pregnant patients in whom oral medications are not feasible (eg, malabsorption). It is the preferred therapy for DVT during pregnancy and for patients with active malignancy. Some experts also prefer this agent in those with liver disease since the elevated INR in this population may not reflect the effect of warfarin. Laboratory monitoring is not required. No agent is superior to the other and dosing for each agent is per product information. They are contraindicated in patients with severe renal dysfunction (CrCl <30 mL/minute); dosing adjustment for mild renal insufficiency are listed in the table (table 3). (See 'Low molecular weight heparin' below.)

Fondaparinux – Fondaparinux is a subcutaneous factor Xa inhibitor. Like LMW heparin, monitoring is not necessary in routine practice and it is contraindicated in patients with severe real dysfunction. It is an alternative to LMW heparin when LMW heparin cannot be administered because of a history or diagnosis of heparin-induced thrombocytopenia [HIT]. (See 'Fondaparinux' below and "Fondaparinux: Dosing and adverse effects".)

Special populations — Special populations of patients with acute VTE require specific consideration, including those listed below (table 1).

Malignancy — For patients with malignancy and VTE, LMW heparin is the preferred anticoagulant for long-term use. The treatment of VTE and duration of anticoagulation in patients with malignancy is discussed in detail separately. (See "Treatment of venous thromboembolism in patients with malignancy".)

Pregnancy — LMW heparin is the preferred agent for long-term anticoagulation in pregnant women with acute VTE (table 4). The treatment of VTE, duration of therapy, and use of anticoagulants in pregnancy are discussed in detail separately. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)

Heparin-induced thrombocytopenia — For patients with VTE and a diagnosis of heparin-induced thrombocytopenia (HIT), anticoagulation with heparin, including UFH and LMW heparin, is contraindicated. Anticoagulation with a non-heparin anticoagulant (eg, warfarin or fondaparinux) should be administered. The management of patients with HIT is discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

AGENTS FOR LONG-TERM ANTICOAGULATION — Full anticoagulation should be ensured during the transition from initial to long-term (maintenance) therapy. Interruptions should be minimized during the first three months of anticoagulation because this is the period that has the highest risk of recurrent thrombosis. The optimal transition strategy varies with the long-term anticoagulant chosen. In some patients, the agent chosen for long-term use is the same agent that was selected for initial anticoagulation (eg, low molecular weight [LMW] heparin, rivaroxaban, and apixaban), but in others, the initial agent and the selected long-term agent belong to different classes, such that transitioning from one agent to another is necessary (eg, heparin to warfarin, heparin to edoxaban or dabigatran). Transition strategy, dosing, and efficacy of specific anticoagulants are discussed in the sections below.

Direct thrombin and factor Xa inhibitors — For patients with acute venous thromboembolism (VTE), factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) and direct thrombin inhibitors (dabigatran) are first-choice oral anticoagulants for long-term anticoagulation in most non-pregnant patients who do not have severe renal insufficiency (creatinine clearance [CrCl] <30 mL/minute) or active cancer (table 2). (See 'Selection of agent' above.)

They are fixed-dose oral agents that, unlike warfarin, do not require routine laboratory monitoring and dose adjustments. These agents reach their peak efficacy within one to four hours after ingestion so that a prolonged period of bridging therapy is not required when switching from initial treatment (eg, with unfractionated heparin [UFH] or LMW heparin) to these agents. However, their anticoagulant effect cannot be reversed by fresh frozen plasma and antidotes are not readily available; details regarding treatment of bleeding on these agents and reversibility agents are discussed separately. (See "Direct oral anticoagulants: Dosing and adverse effects" and "Management of bleeding in patients receiving direct oral anticoagulants".)

Dosing — When an oral factor Xa or direct thrombin inhibitor is chosen for long-term anticoagulation, we prefer that they be initiated in accordance with study criteria that demonstrated their efficacy [5-10].

Rivaroxaban and apixaban can be administered as monotherapy (ie, no overlap or prior treatment with heparin is necessary) but short courses of heparin should be administered when there is a delay in obtaining these agents (eg, not available in local pharmacy).

Edoxaban and dabigatran are preferably administered following a five day course of heparin.

None of the factor Xa or direct thrombin inhibitors require bridging or need to be overlapped, unlike warfarin, since the anticoagulant effect is assured within one to four hours after ingestion. Thus, when switching patients from LMW heparin, factor Xa or direct thrombin inhibitors are generally given within 6 to 12 hours following the last dose of a twice daily regimen of subcutaneous LMW heparin or within 12 to 24 hours for once daily regimens. Factor Xa and direct thrombin inhibitors can be ingested immediately upon the discontinuation of intravenous (IV) UFH infusion. Transition regimens are discussed in detail below. (See 'Switching anticoagulants during therapy' below.)

Typical initial doses in those with normal renal function are:

Rivaroxaban 15 mg by mouth twice daily for three weeks followed by 20 mg once daily

Apixaban 10 mg twice daily for seven days followed by 5 mg twice daily

Edoxaban 60 mg once daily

Dabigatran 150 mg twice daily

Since many of these agents are renally excreted, most experts generally avoid these agents in patients with renal insufficiency. However, randomized trials in patients with VTE report similar safety and efficacy when the dose is renally-adjusted for those with mild renal dysfunction (eg, CrCl of ≥30 mL/minute). Patients with a CrCl of <30 mL/minute were excluded from many of the trials such that patients with this degree of renal insufficiency should not be considered for rivaroxaban, apixaban, and dabigatran. Edoxaban should be avoided in those with a CrCl of <15 mL/minute, and the dose reduced to 30 mg per day in patients with a CrCl of 15 to 50 mL/minute or low body weight ≤60 kg [11]. (See 'Direct thrombin and factor Xa inhibitors' above and "Direct oral anticoagulants: Dosing and adverse effects" and "Management of bleeding in patients receiving direct oral anticoagulants".)

There is a boxed warning in the US label not to use edoxaban for patients with atrial fibrillation who have a CrCl >95 mL/minute as estimated by the Cockcroft-Gault equation due to a higher rate of ischemic stroke when compared to warfarin. Whether a similar increased risk of VTE occurs in this population is unknown. However, until these data are available in patients with VTE, we prefer to avoid the use of edoxaban in patients with a CrCl >95 mL/minute. When calculating CrCl, we suggest a more precise assessment if edoxaban is to be used (calculator 1). (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Dosing of non-vitamin K antagonist oral anticoagulants'.)

Other concerns regarding these agents include their distribution and efficacy in the obese population, which is unknown [12], as well as drug interactions with other agents, which are discussed in the table (table 5). While randomized trials report efficacy for standard dosing in those with a body weight (BW) ≤100 kg or body mass index (BMI) ≤30 kg per m2, preliminary subgroup and pharmacokinetic analyses suggest reduced efficacy in those with a BW ≥120 kg or BMI ≥40 kg per m2 [12]. The efficacy is less clear in those with a BW between 101 to 119 kg or BMI 31 to 39 kg per m2.

Manufacturer recommendations on compatibility of direct oral anticoagulants with feeding tube administration vary for each agent. For example, apixaban may be crushed and suspended in water whereas dabigatran capsules should not be opened due to substantial increase in drug exposure. These and other pharmacokinetic details are provided in the Lexicomp drug monographs included within UpToDate, "administration" field.

Efficacy — Large randomized trials and one meta-analysis have reported the safety and efficacy of these agents for the treatment and prevention of recurrent VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) [5-10,13]. Most of these trials were performed in stable patients and were designed as noninferiority trials that compare the newer agent with standard anticoagulation (ie, heparin followed by warfarin) and showed comparable safety and efficacy.

Rivaroxaban – Rivaroxaban is an oral factor Xa inhibitor that demonstrated similar efficacy to conventional therapy (heparin followed by warfarin) for the treatment of acute VTE in a large, prospective, randomized controlled trial. For most patients receiving rivaroxaban, no parenteral anticoagulation was administered, and rivaroxaban was the initial anticoagulant used. EINSTEIN-DVT and EINSTEIN-PE were open-label randomized trials that enrolled a total of 8281 patients with acute DVT or PE and demonstrated the noninferiority of rivaroxaban (15 mg twice daily for three weeks followed by 20 mg once daily) to conventional therapy (enoxaparin followed by warfarin) for a treatment period of 3, 6, or 12 months [5,6]. Compared with conventional therapy, rivaroxaban resulted in similar rates of recurrent DVT (2.1 versus 3 percent), PE (2.1 versus 1.8 percent), and total bleeding events (8.1 versus 8.1 [EINSTEIN-DVT]; 10.3 versus 11.4 percent [EINSTEIN-PE]). In a post-hoc analysis of EINSTEIN-DVT, rivaroxaban was associated with a nonsignificant reduction in the rate of post-thrombotic syndrome [14]. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Compression stockings for the prevention of PTS' and "Post-thrombotic (postphlebitic) syndrome".)

Apixaban – Apixaban is an oral factor Xa inhibitor. AMPLIFY was a prospective, randomized, double-blind trial that compared apixaban (10 mg twice daily for seven days for initial anticoagulation followed by 5 mg twice daily for six months) with conventional anticoagulation (subcutaneous enoxaparin for five days followed by warfarin for six months) in 5395 patients for the treatment of acute VTE (DVT and/or PE) [7]. There was no difference in the rates of recurrent symptomatic VTE or VTE-related death (2.3 versus 2.7 percent) between the groups, and fewer bleeding events were reported in the apixaban group (4.3 versus 9.7 percent). Subgroup analysis suggested that the efficacy of apixaban for the prevention of VTE or VTE-related deaths occurred in all patient groups (eg, DVT, PE, unprovoked VTE, extensive PE).

Edoxaban – Edoxaban is an oral factor Xa inhibitor that has been shown to have a similar efficacy and superior safety profile when compared with warfarin for the treatment of acute VTE. In one trial, 4921 patients with acute VTE (DVT and/or PE) were randomized to receive 3 to 12 months of edoxaban or warfarin following initial therapy for five days with unfractionated or LMW heparin [8]. Edoxaban was administered orally at 60 mg once daily. A lower dose (30 mg once daily) was used for patients with a CrCl of 30 to 50 mL per minute or low body weight ≤60 kg. Compared with warfarin, edoxaban had a similar rate of recurrent symptomatic VTE or VTE-related death (3.2 versus 3.5 percent) and fewer bleeding events (8.5 versus 10.3 percent). A post-hoc analysis of the patients on low dose edoxaban showed similar results [11].

Of potential clinical interest was the superior efficacy in the prespecified subgroup of patients with PE that had right ventricular (RV) dysfunction as assessed by elevated brain natriuretic peptide (BNP) or increased RV dimensions on computed tomography (CT). However BNP is a nonspecific biomarker of RV dysfunction, and echocardiography is a more accurate test than CT for the assessment of RV dysfunction. Further study of this agent in this population of patients with severe PE and RV dysfunction by echocardiogram is warranted to validate these findings.

Dabigatran – Dabigatran is an oral direct thrombin inhibitor. A large, randomized controlled trial suggested that dabigatran has similar efficacy to warfarin for the prevention of recurrent VTE. However, concerns have been raised about its efficacy and risk of thrombosis given the broad inferiority margin set in one of the trials (RE-COVER), and its safety and risk of bleeding events given the irreversibility of this drug. In a randomized, double-blind trial (RE-COVER I), 2539 patients with acute VTE were treated for six months with either dabigatran (150 mg by mouth twice per day) or warfarin, each after seven days of initial parenteral anticoagulation [9]. Compared with warfarin, dabigatran had a similar incidence of recurrent VTE (2.4 versus 2.1 percent), VTE-related deaths (0.1 versus 0.2 percent), major bleeding events (1.6 versus 1.9 percent), and any bleeding event (16.1 versus 21.9 percent). These results suggest that the efficacy and safety profile of dabigatran is similar to that of warfarin for the treatment of acute VTE. Similar results were reported in an identically designed trial of 2589 patients with acute DVT (RECOVER II) [10] and in a pooled analysis of RE-COVER I and II [15]. In a post hoc analysis of these trials, the efficacy appears to be maintained in patients with thrombophilia and anti-phospholipid syndrome [16].

The bleeding risk of these agents is discussed in greater detail below. (See 'Factor Xa and direct thrombin inhibitors' below.)

Warfarin

Dosing — Warfarin is the preferred agent for non-pregnant patients in whom factor Xa or direct thrombin inhibitors are not available and for patients with severe renal dysfunction (eg, CrCl <30 mL/minute). It may also be preferred in those with a preference or requirement for a readily reversible antidote and those in whom therapeutic anticoagulation needs to be closely monitored (table 2). (See 'Selection of agent' above.)

When warfarin is chosen as the agent for long-term anticoagulation, it is generally started on the same day with LMW heparin or UFH (day 1) at a typical initiating dose of 5 mg/day for the first two days (range 2 to 10 mg/day) (table 6) [17,18]. Dosing is then adjusted until the INR is within the therapeutic range (2 to 3; target 2.5) for two consecutive days. Initial doses at the lower range (2 to 5 mg/day) may be considered in those assessed at high bleeding risk (eg, older adults), and doses in the higher range (5 to 10 mg/day) may be selected in healthy individuals who are at low risk for bleeding. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Initial dosing' and "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Anticoagulant agents'.)

The premature cessation of heparin before warfarin has taken its full effect (ie, therapeutic INR for two days) may result in inadequate protection against recurrent thrombosis. This overlap is required because it takes a number of days for all of the vitamin K-dependent factors to become depleted (factors II, VII, IX, and X). During the first few days of warfarin therapy, prolongation of the prothrombin time (PT; as reflected by the INR) mainly reflects the depression of factor VII, which has a short half-life (hours) (figure 1). Importantly, this does not represent adequate anticoagulation because additional vitamin K-dependent factors are insufficiently reduced (takes approximately five days with adequate dosing). In addition, reduction of protein C and S occurs shortly after warfarin therapy and potentially renders a procoagulant state. Together, these factors increase the likelihood of recurrent thrombosis should patients not be fully anticoagulated with parenteral heparin. (See "Overview of hemostasis" and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.)

Efficacy — Data that support the efficacy of warfarin as an anticoagulant in patients with VTE are derived from older studies that compared warfarin with no anticoagulation or low-dose subcutaneous heparin and from randomized trials and meta-analyses of variable durations of therapeutic anticoagulation [19-29]. In the seminal trial, performed in 1960, that compared warfarin with observation in patients with acute DVT, warfarin resulted in a dramatic reduction in recurrence (0 versus 26 percent), which translated into a mortality benefit (26 versus 0 percent) [29]. Since then, most other trials have compared various durations of warfarin therapy to provide an estimate of the risk of recurrence [20,28]. Cumulatively, these data all support low rates of recurrent VTE and death in patients treated with warfarin therapy for proximal DVT, with the greatest benefit occurring within the first few days or weeks of the initial event. As an example, one 2010 meta-analysis of 13 prospective cohort studies and 56 randomized clinical trials reported rates of recurrent VTE and fatal VTE during the first three months of warfarin therapy as 3.4 and 0.4 percent, respectively [28].

Low molecular weight heparin

Dosing — Low molecular weight (LMW) heparin is the preferred agent for those in whom treatment with one of the oral agents is not feasible (eg, patients with poor or no oral intake). (See 'Selection of agent' above.)

When subcutaneous LMW heparin is chosen for long-term anticoagulation and UFH is the initial anticoagulant being used, LMW heparin can be administered and the UFH infusion immediately discontinued.

The initiating dose of LMW heparin is individualized according to each product. Dosing is typically weight-based and continued at the same dose used for initial anticoagulation. Dosing for patients with renal insufficiency is listed in the table (table 3). LMW heparin is contraindicated in patients with severe renal insufficiency (CrCl <30 mL/minute). (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Low molecular weight heparin' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW heparin'.)

Efficacy — Several randomized trials and meta-analyses have shown that LMW heparin is at least as effective as warfarin in the prevention of recurrent VTE (DVT and/or PE) with a similar rate of major bleeding and mortality [30-32]. However, many of the trials have potential bias for the assessment of recurrent VTE and imprecision in the assessment of major bleeding and mortality, which limits the analysis.

As examples:

A 2012 meta-analysis of 15 trials of patients with VTE (total 3197 patients) compared LMW heparin with warfarin [31]. LMW heparin was as effective as warfarin in preventing symptomatic VTE (odds ratio [OR] 0.82; 95% CI 0.59-1.13) and was associated with a nonsignificant trend in lower bleeding rates (OR 0.62, 95% CI 0.36-1.07). No difference in mortality was observed.

Another 2012 meta-analysis of eight trials that restricted analysis to only those trials that used ≥50 percent of the full therapeutic dose of LMW heparin, reported a reduction in recurrent VTE compared to warfarin (risk reduction [RR] 0.62, 95% CI 0.46-0.84) with a similar rate of major bleeding and mortality [30].

Randomized trials have also suggested that, compared with warfarin, long-term anticoagulation with LMW heparin lowers the frequency of post-thrombotic syndrome (PTS), a treatable, late complication of acute DVT [33-35]. One 2011 systematic review of nine trials of patients with DVT reported that, compared with other agents (mostly warfarin), LMW heparin was associated with a reduction in the rate of PTS signs and symptoms (OR 0.77), recanalization of thrombosed veins (RR 0.66), and venous ulceration (RR 0.13) [35]. However, the major indication for anticoagulation is the prevention of recurrence rather than the prevention of PTS such that the latter does not practically influence agent selection. (See "Post-thrombotic (postphlebitic) syndrome" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Compression stockings for the prevention of PTS'.)

Long-term anticoagulation with LMW heparin has never been directly compared with factor Xa or direct thrombin inhibitors. (See 'Direct thrombin and factor Xa inhibitors' above.)

Fondaparinux — Fondaparinux is an alternative to LMW heparin when the latter is contraindicated in patients with heparin-induced thrombocytopenia (HIT). (See 'Selection of agent' above.)

When transitioning from initial anticoagulation with UFH, subcutaneous fondaparinux can be administered and the UFH infusion immediately discontinued. Fondaparinux is typically dosed according to the usual initiating dose. Subcutaneous fondaparinux is contraindicated in patients with severe renal insufficiency (CrCl <30 mL/minute). Accumulation also occurs in patients with moderate renal insufficiency (CrCl 30 to 50 mL/minute) such that the dose should be reduced by 50 percent. Although fondaparinux is less well studied than LMW heparin as a long-term anticoagulant, fondaparinux appears to have a similar efficacy and safety profile to the LMW heparin, enoxaparin when used as an initial anticoagulant. Detailed discussion of fondaparinux as an initial anticoagulant as well as dosing are provided separately. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Fondaparinux' and "Fondaparinux: Dosing and adverse effects".)

Unfractionated heparin (subcutaneous) — Anecdotally, subcutaneous UFH may be a useful alternative in patients who are unable or unwilling to take warfarin or LMW heparin (eg, patients with renal insufficiency unable to take an oral medication). In one randomized open-label study of 697 patients with acute DVT, there were no differences in efficacy or bleeding rates between fixed-dose subcutaneous UFH (333 units/kg initially, followed by 250 units/kg twice daily) and low molecular weight heparin (enoxaparin/dalteparin) when used as initial anticoagulants and overlapped with warfarin [36]. However, long-term anticoagulation with subcutaneous UFH has been inadequately studied and has never been compared with factor Xa or direct thrombin inhibitors.

DURATION OF TREATMENT

Duration — It is critical that the duration of anticoagulation therapy be individualized according to the presence or absence of provoking events and risk factors, risk for recurrence and bleeding (table 7 and table 8), as well as to the individual patient preferences and values (algorithm 1). Our approach is consistent with guidelines set out by the American College of Chest Physicians, the International Society of Thrombosis and Hemostasis, and the International Consensus Statement on the Prevention and Treatment of Venous Thromboembolism [3,19,30,37]. Importantly, the data in this section do NOT apply to patients with cancer, pregnant women, or patients in whom indefinite anticoagulation should be considered; anticoagulation in these populations is discussed separately. (See "Treatment of venous thromboembolism in patients with malignancy" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)

In general, the following applies:

Most patients with a first episode of venous thromboembolism (VTE; provoked or unprovoked) should receive anticoagulation for a minimum of three months.

Extending anticoagulation beyond three months is NOT routinely considered in patients who have a provoked episode of VTE with the following: transient risk factors, assuming the risk factor is no longer present (eg, surgery, cessation of hormonal therapy), isolated distal DVT, subsegmental or incidental pulmonary embolism (PE), or those in whom the risk of bleeding is considered to be high. (See 'Risk of bleeding' below.)

In select populations, anticoagulation is extended to 6 or 12 months (eg, phlegmasia cerulea dolens, a persisting but reversible risk factor), although the benefits of this are unproven.

Patients who should be considered as candidates for indefinite anticoagulation are discussed separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism" and "Treatment of venous thromboembolism in patients with malignancy", section on 'Extended therapy'.)

Supporting evidence — Evidence supporting anticoagulation for a minimum of three months is derived from randomized trials and meta-analyses in patients with acute VTE that comprised a significant proportion of patients with an unprovoked event (also known as idiopathic or spontaneous VTE). The evidence is weaker for patients with distal deep vein thrombosis (DVT), particularly episodes that are provoked by a reversible or transient factor (eg, orthopedic surgery) and for patients with asymptomatic, incidental, or small subsegmental PE.

Cumulatively, evidence from randomized trials and meta-analyses suggests that:

Without adequate anticoagulation (eg, no anticoagulation, prophylactic doses of anticoagulants) the risk of recurrent venous VTE (DVT and PE) is highest during the first three months following the initial event [19-27,30]. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Recurrence with and without anticoagulation'.)  

Shortening the course of anticoagulation from three or six months to four or six weeks is associated with an increased risk for recurrent thrombosis [21,25,26].

As examples:

A 2012 meta-analysis of five randomized trials reported that, compared with three months of warfarin therapy, four to six weeks resulted in an increase in the absolute risk of recurrent VTE (53 more episodes of VTE per 1000), compared with only a small decrease in the risk of major bleeding (5 fewer major bleeding episodes per 1000) [30].

In another 2011 meta-analysis of seven randomized trials of patients without cancer who had a first episode of VTE, recurrence was higher if anticoagulation (usually warfarin) was stopped at four or six weeks, compared with three months or later (hazard ratio [HR] 1.52, 95% CI 1.14-2.02) [26].

However, the majority of patients in these trials had proximal DVT and/or PE (provoked and unprovoked). Although patients with distal DVT have a low risk of recurrence (approximately 1 percent per year), it is unknown whether shorter courses (four to six weeks) are adequate in this population [30]. Nonetheless, based upon data extrapolated from the population of patients with proximal DVT, we prefer that patients with distal DVT be anticoagulated for three months [19,30].

Many experts extend anticoagulation for finite periods (eg, 6 to 12 months) in some patients, including those with extensive or life-threatening episodes of provoked VTE or patients with provoked VTE and persistent reversible risk factors (eg, prolonged immobility, continued estrogen use), provided the risk of bleeding is low [19,26,30]. This practice is in contrast to data from randomized trials and meta-analyses that, in general, report no benefit to cessation of long-term therapy after a more prolonged, finite period beyond three months (eg, 6 or 12 months) in patients at average risk:

One 2012 meta-analysis of five trials of patients with acute VTE reported that, compared with three months of warfarin therapy, 6 or 12 months of therapy did not convincingly lower the risk of recurrence (RR 0.89, 95% CI 0.69-1.14), but did increase the risk of bleeding by approximately 2.5-fold [30].

In a 2011 meta-analysis of seven randomized trials VTE recurrence was similar if treatment was stopped at three months, compared with six months or later (RR 1.19, 0.86-1.65) [26].

The rationale for altering practice in these "higher risk" patients is that many trials excluded such patients. This disparity between clinical practice and published trials may be due to the exclusion from trials of patients that may theoretically benefit from longer courses of anticoagulation (eg, extensive or life-threatening VTE). In addition, the data suggest that the risk of recurrence does continue to decline between three and six months on anticoagulant therapy. For these reasons, guidelines and many experts use a three- to six-month range for an optimal duration of therapy for patients with provoked VTE who are at low risk of bleeding and in whom the risk of recurrence is still assessed by the clinician as high [19]. By the same token, completing therapy at three months is also appropriate for patients with a moderate to high bleeding risk.  

Some clinicians advocate flexible durations of therapy based upon the identification of residual clot. For example, one study (AESOPUS) used ultrasound for the detection of residual thrombosis after three months of anticoagulation to determine whether therapy should be extended in some patients to six months [38]. Compared with a fixed duration of three months, flexible duration of therapy that was ultrasound directed resulted in a reduction in recurrent VTE (12 versus 17 percent) [38]. Although this practice is not validated in a large randomized trial setting, it may be considered on a case-by-case basis. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Provoked VTE with persistent risk factors' and "Diagnosis of suspected deep vein thrombosis of the lower extremity".)

SWITCHING ANTICOAGULANTS DURING THERAPY — Interruptions should be limited especially during the first three months of anticoagulation. However, anticoagulants may need to be changed for medical reasons as well as for altered patient preferences. Reasons for switching agents include:

The development of renal insufficiency (prolongs the half-life of low molecular weight [LMW] heparin, fondaparinux, and factor Xa and direct thrombin inhibitors)

Perceived burdens of laboratory testing for warfarin

Poor compliance or difficulty with international normalized ratio (INR) testing

Resolution of active cancer

Pain or inflammation at injection sites

Cost

Need for repeated invasive procedures

Recurrence despite therapeutic anticoagulation

Clinicians should alert their patients that switching anticoagulants is associated with an unquantifiable increased risk of both bleeding and recurrence. these risks are less well studied in patients transitioning to and from factor Xa and direct thrombin inhibitors [39]. When switching to or from these agents, we prefer to use protocols that are similar to that performed in trials that studied these agents in patients with atrial fibrillation and venous thromboembolism (VTE).

In general, the following applies:

Transitioning from LMW heparin:

To warfarin should be the same as for initial anticoagulation. Warfarin and heparin are simultaneously administered for four to five days until the INR is therapeutic for a minimum of 24 hours or two consecutive days. (See 'Agents for long-term anticoagulation' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Duration of therapy for heparin'.)

To factor Xa or direct thrombin inhibitors is generally done by administering the oral agent within 6 to 12 hours after to the last scheduled dose of a twice daily LMW heparin regimen, and within 12 to 24 hours of a once daily regimen. This approach is in accordance with study protocols that proved efficacy for these agents as therapies for the treatment of VTE. (See 'Direct thrombin and factor Xa inhibitors' above.)

Transitioning from warfarin:

To LMW heparin is usually done by administering LMW heparin two hours prior to the last scheduled dose of warfarin, which is then omitted. The optimal target INR within the therapeutic range (2 to 3) for starting LMW heparin is unknown. However, it is reasonable to start LMW heparin when the INR is therapeutic, preferably as close to 2 as is feasible, especially if the risk of bleeding is thought to be increased. Our preference for this transition is based upon an assumption that the risk of thromboembolism is high and that maintaining therapeutic anticoagulation is desired.

The perioperative management of warfarin and bridging for a procedure is different. (See "Perioperative management of patients receiving anticoagulants".)

To factor Xa and direct thrombin inhibitors has not been well established. For patients with VTE, we prefer starting these agents when the INR is within the therapeutic range 2 to 3. This preference is based upon the assumption that, during the first three months following a diagnosis of DVT, the risk of recurrence is outweighed by the risk of bleeding. The optimal target INR for starting a newer agent within this range is unknown; however, we believe it is reasonable to start a newer agent when the INR is therapeutic and as close to 2 as is feasible, especially if the risk of bleeding is thought to be increased. For rivaroxaban a maintenance dose of 20 mg daily, apixaban 5 mg twice daily, edoxaban 60 mg once daily, and dabigatran 150 mg twice daily should be sufficient to maintain effective anticoagulant (ie, initial higher "loading" doses are not necessary). Warfarin can be stopped after the first dose. A transitioning strategy for patients with atrial fibrillation is discussed separately. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Transition to NOAC from warfarin'.)

Transitioning from factor Xa or direct thrombin inhibitors:

To LMW heparin can be performed by administering LMW heparin 24 hours after the last dose of an agent that is administered once daily (eg, rivaroxaban and edoxaban) and within 12 hours after the last dose of agent administered twice daily (eg, apixaban and dabigatran). However, for patients who are on dabigatran with a creatinine clearance (CrCl) <30 mL/minute, we suggest waiting 24 hours after the last dose before initiating treatment with a parenteral anticoagulant. These suggested transitions have not been studied and are based upon the known pharmacokinetics of each class of agent.

To warfarin may be performed by coadministering warfarin with the newer anticoagulant for at least two (rivaroxaban and apixaban) to three (dabigatran) days prior to stopping these agents when renal function is normal; one to two days overlap may be reasonable for patients on dabigatran with a CrCl <30 mL/minute. Practitioners should also be aware that these agents can alter the INR, causing uncertainty as to when the patient is properly anticoagulated with warfarin. In some cases, consideration can also be given to transitioning onto LMW heparin, as described above, then following a typical heparin/warfarin overlap scenario similar to the initial anticoagulation strategy. Additional details regarding transitioning patients to warfarin in patients with atrial fibrillation are discussed separately. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Transition from NOAC to warfarin'.)

To another factor Xa or direct thrombin inhibitor may be performed by administering the new agent at the time that the next dose of the older agent would have been taken. An example of how this might be done is listed in the package insert for apixaban [40].

Perioperative management of anticoagulation is discussed separately. (See "Perioperative management of patients receiving anticoagulants".)

MONITORING — All patients on anticoagulation should be monitored clinically for therapeutic efficacy (recurrence), bleeding, as well as the development of conditions that affect the half-life of the medications used (eg, renal failure, pregnancy, weight gain/loss) and adverse effects of the medications (eg, skin necrosis, thrombocytopenia, osteoporosis). Laboratory monitoring varies with the long-term anticoagulant used:

Factor Xa and direct thrombin inhibitors – These agents do not require routine laboratory monitoring because laboratory parameters have not been correlated with clinical endpoints. They should be administered by physicians knowledgeable in their use and in accordance with study criteria that proved their efficacy. Patients should be carefully monitored clinically for bleeding and for renal failure. Monitoring therapeutic efficacy is difficult but is performed on rare occasions. In addition, a practice tool aimed at monitoring patients for the complications of these agents is published but not routinely used [41]. Further details regarding monitoring patients on these agents are discussed separately. (See 'Direct thrombin and factor Xa inhibitors' above and "Direct oral anticoagulants: Dosing and adverse effects".)

Warfarin – The most common laboratory test used to monitor warfarin is the prothrombin time (PT) ratio, usually expressed as the international normalized ratio (INR). The goal INR is 2 to 3 (target 2.5) [18,42]. Once the anticoagulant effect and the patient's warfarin dose requirements are stable, the INR should be monitored usually every three to four weeks throughout the course of warfarin therapy for venous thromboembolism (VTE). More frequent monitoring is indicated if factors are present that may produce an unpredictable response to warfarin (eg, concomitant therapy with drugs that interact with warfarin); longer intervals (eg, up to 12 weeks) are feasible if the INR response is predictable [18]. Warfarin dosing must be individualized because factors including drug interactions, increased age, and specific genotypes alter the response to warfarin [43]. Genotype-guided dosing has no proven value over conventional monitoring in achieving this goal. Self-monitoring practices have proven efficacy in patients who demonstrate competency in self-management strategies. Further details regarding monitoring patients on warfarin are discussed separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Self-monitoring and self-management' and "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR'.)

Low molecular weight heparin and fondaparinux – These agents do not require routine laboratory monitoring because laboratory parameters have not been correlated with clinical endpoints (recurrence and bleeding). However, patients should be monitored for the development of renal insufficiency, which can prolong their half-life. If there is any question as to the correct dose of low molecular weight (LMW) heparin (eg, for those with obesity or renal insufficiency), measuring antifactor Xa activity testing is sometimes used. Fondaparinux was not monitored in clinical studies and is therefore not monitored routinely in clinical practice. Measurement of fondaparinux drug levels may be appropriate in patients with major bleeding. Details regarding the therapeutic use of LMW heparin and fondaparinux and issues that may affect interinstitutional variability among tests used to monitor these agents are discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW heparin' and "Clinical use of coagulation tests", section on 'Anti-factor Xa activity' and "Fondaparinux: Dosing and adverse effects", section on 'Pharmacology'.)

RISK OF BLEEDING — All patients should be regularly assessed during anticoagulant therapy for bleeding risk (table 9 and table 8).  

Warfarin and low molecular weight heparin — Evidence from randomized trials and meta-analyses suggest that the rate of bleeding on warfarin and low molecular weight (LMW) heparin are generally low. As an example, one meta-analysis of 13 prospective cohort studies and 56 randomized clinical trials of patients treated for deep vein thrombosis (DVT) reported that during the first three months of anticoagulant therapy, rates of major bleeding and major fatal bleeding were 1.6 percent and 0.2 percent, respectively [28]. Rates of any bleeding events are usually higher, ranging from 5 to 15 percent, and the risk of bleeding is almost twice as high with the concomitant use of additional agents including nonsteroidal anti-inflammatories or aspirin (hazard ratio [HR] 2.37 and 1.50, respectively) [44]. However, reported rates may not accurately reflect those expected to occur in clinical practice, where the risk of bleeding varies significantly among individuals.

Factor Xa and direct thrombin inhibitors — For patients on factor Xa and direct thrombin inhibitors, data from randomized trials and meta-analyses have reported that rates of major bleeding events range from 0.6 to 1.6 percent and any bleeding events range from 4 to 16 percent (odds ratio 0.57 to 0.68) [45].

Randomized trials and meta-analyses report similar efficacy and reduced rates of bleeding when these agents are compared with warfarin [45-52]. As examples:

A 2015 meta-analysis of 11 randomized trials, that included all of the major studies discussed above, reported that compared with conventional anticoagulation (heparin plus warfarin), use of direct thrombin or factor Xa inhibitors was associated with similar rates of venous thromboembolism (VTE) and mortality, and reduced rates of bleeding (odds ratio 0.57 to 0.68) [45].

Another meta-analysis of five randomized trials of patients with VTE reported that, compared with warfarin, these agents (rivaroxaban, dabigatran, apixaban, and edoxaban) were associated with a reduction in the risk for major bleeding (risk reduction [RR] 0.6, 95% CI 0.41-0.88), with no difference in the risk for recurrent VTE or mortality [47].

Similar results were reported in another meta-analysis that included additional trials of patients on these agents for atrial fibrillation [50].

Although bleeding rates may be lower with factor Xa and direct thrombin inhibitors, it is important to note that reported rates reflect that in study patients with a baseline low bleeding risk and may not represent that of the general population. As an example, in the months following the approval of dabigatran in other settings, the US Food and Drug Administration (FDA) received many reports of serious and fatal bleeding events associated with its use and reports of bleeding rates in older populations have been conflicting [10,53-57].

An independent analysis of bleeding events and bleeding-related fatalities from reports submitted to the FDA (from 2011 through 2012) showed that, compared with warfarin, higher rates of bleeding events (4270 versus 827 events) and bleeding fatalities (638 versus 44 fatalities) were reported for dabigatran [55].

While a 2013 mini-Sentinel analysis by the FDA suggested that dabigatran was being used in accordance with its labeled indications and bleeding rates did not appear to be higher than those associated with warfarin, a subsequent 2014 FDA analysis reported an increased rate of gastrointestinal bleeding among patients older than 65 years [53,54].

A pooled analysis of bleeding events with dabigatran in RECOVER I/II reported that a lower bleeding risk with dabigatran was only evident in younger patients and that, in those over the age of 85 years, the bleeding risk was lower with warfarin [10].

The Institute for Safe Medication Practices analyzed 1734 reports to the FDA from patients on warfarin, dabigatran, and rivaroxaban [56]. Dabigatran bleeds were five times more likely than warfarin to result in death (19 versus 4 percent; odds ratio [OR] 5.2, 95% CI 3.4-8.0). The estimate of higher odds for a fatal outcome with dabigatran persisted after adjusting for age, gender, and report source.

Postmarketing reports of bleeding, particularly for dabigatran, dampened initial enthusiasm for its use as anticoagulant therapy for VTE [53,54,58]. Increased risk of bleeding has also been reported in older patients (>75 years) on dabigatran [10,59,60]. Dabigatran is renally excreted, and, although unproven, this risk may be due to the higher prevalence of renal insufficiency and longer half-life of dabigatran in older patients [61].

Preliminary reports on the safety of direct thrombin or factor Xa inhibitors, reflective of their use in general practice are limited. One 2016 retrospective analysis reported that 80 percent of patients with VTE were treated with warfarin and that warfarin and direct thrombin or factor Xa inhibitors were associated with similar rates of recurrent VTE (1.2 versus 2.1 percent) and bleeding (0.5 percent) [62]. Another retrospective review reported that over half of patients prescribed direct thrombin or factor Xa inhibitors (for atrial fibrillation and VTE) were underdosed, when compared with the manufacturer recommendations [63]. The rate of thromboembolic events was 11 percent (apixaban), 4 percent (rivaroxaban), and 5 percent (dabigatran); bleeding event rates were 18 percent (apixaban), 18 percent (rivaroxaban), and 24 percent (dabigatran). Some of the factors that may have influenced reduced-dose prescribing were previous history of bleeding and potential drug interactions. Further reports regarding use of these agents in practice are pending.

There are concerns regarding reversibility for the treatment of bleeding in patients on direct thrombin and factor Xa inhibitors. Unlike warfarin, where fresh frozen plasma and vitamin K are universally available for use, factor Xa and direct thrombin inhibitors require more complex therapies for reversal in the event of life-threatening bleeding (eg, three-factor or four-factor prothrombin complex concentrates [PCCs], hemodialysis, monoclonal antibody therapy). The treatment of bleeding associated with these agents is discussed separately. (See "Management of bleeding in patients receiving direct oral anticoagulants".)

Risk factors and predictive tools — Risk factors for bleeding on anticoagulation therapy in patients with VTE are presented in the Table (table 9).

Tools are available for estimating the risk of bleeding on anticoagulation including the HAS-BLED score (calculator 2), or the same TT2R2 score [64]. However, the HAS-BLED score has not been validated in patients anticoagulated for VTE, and none of the scores can reliably predict bleeding risk in a particular patient. Absolute and relative contraindications to anticoagulation as well as scoring systems that estimate the risk of bleeding are discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Bleeding risk' and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Patients with contraindications to anticoagulation' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Assessing the risk of bleeding' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Bleeding risk' and "Anticoagulation in older adults", section on 'Bleeding risk models' and "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Estimating bleeding risk'.)

RECURRENT VENOUS THROMBOEMBOLISM ON ANTICOAGULATION — Some patients may have a thromboembolic event while receiving anticoagulation. In these patients, the diagnosis of recurrence should be confirmed with radiologic testing (eg, repeat compression ultrasonography or computed tomographic pulmonary angiography). Subtherapeutic anticoagulation is the most common reason, but several other etiologies including ongoing thrombotic stimulus (eg, cancer) may be present. Occasionally no obvious cause is evident (idiopathic). The causes and management of suspected recurrence are discussed separately. (See "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Management of recurrence on therapy' and "Treatment of venous thromboembolism in patients with malignancy", section on 'Management of recurrence'.)

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 clots in the legs) (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

Long-term (maintenance) anticoagulant therapy for venous thromboembolism (VTE) is administered beyond the initial period of anticoagulation for a finite period of 3 to 12 months. (See 'Nomenclature' above.)

Options for long-term anticoagulation include oral anticoagulants (ie, factor Xa inhibitors, direct thrombin inhibitors, and warfarin) and parenteral subcutaneous anticoagulants (low molecular weight [LMW] heparin and fondaparinux). While the oral factor Xa and direct thrombin inhibitors are typically preferred, choosing among these options frequently depends upon clinician experience and availability, the risks of bleeding, patient comorbidities and preferences, cost, and convenience (table 2 and table 1). In general, the following applies (see 'Selection of agent' above):

For most non-pregnant patients who do not have severe renal insufficiency (eg, creatinine clearance <30 mL/minute) or active cancer, we suggest a direct oral anticoagulant (ie, apixaban, edoxaban, rivaroxaban, or dabigatran) rather than other agents (Grade 2B). In general, these agents have similar efficacy to warfarin and a lower risk of bleeding; however, access to a reversal agent may be limited. Direct oral anticoagulants are NOT suitable for the treatment of hemodynamically unstable pulmonary embolism (PE), massive iliofemoral deep vein thrombosis (DVT), those who are pregnant, or those with severe renal insufficiency. Dosing of these agents is individualized. (See 'Selection of agent' above and 'Direct thrombin and factor Xa inhibitors' above.)

Warfarin is an alternative for patients in whom there is concern about the poor availability of reversal agents and in those severe renal insufficiency (CrCl <30mL/minute). Warfarin should be overlapped with heparin until the international normalized ratio (INR) is therapeutic for 24 hours. (See 'Selection of agent' above and 'Warfarin' above and 'Monitoring' above.)

LMW heparin and fondaparinux are also effective treatments and may be preferred in some special populations without severe renal failure. Dosing requirements are product specific, and no laboratory monitoring is required. (See 'Selection of agent' above and 'Low molecular weight heparin' above and 'Fondaparinux' above and 'Monitoring' above.)

Anticoagulant therapy in patients who are pregnant or have active malignancy, in whom LMW heparin is the long-term agent of choice, and patients with heparin-induced thrombocytopenia, in whom heparin should be avoided, are discussed separately. (See 'Special populations' above and "Use of anticoagulants during pregnancy and postpartum" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Treatment of venous thromboembolism in patients with malignancy" and "Management of heparin-induced thrombocytopenia".)

For patients with a first episode of acute VTE, the duration of anticoagulant therapy should be individualized according to the presence or absence of provoking events and risk factors, while taking into account the estimated risk for recurrence and bleeding and the individual patient's preferences and values (table 8 and table 7). In general the following applies (see 'Duration of treatment' above):

For most patients with proximal DVT and/or symptomatic PE, we recommend anticoagulation for a minimum of three months rather than for shorter periods (eg, four or six weeks), regardless of whether or not the event was provoked (Grade 1B). The optimal duration of therapy for patients with distal DVT and small subsegmental PE is less certain; in general we treat these patients for three months as well.

For patients with a provoked episode of VTE who have persistent but reversible risk factors (eg, continued estrogen use, prolonged immobility following trauma), we suggest extending anticoagulation for a finite period until the risk factor is resolved, rather than stopping anticoagulation at three months (Grade 2C).

Select patients benefit from indefinite anticoagulation and are discussed separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)

Therapeutic anticoagulation should be ensured during transition periods. The strategy used depends upon the anticoagulants used for such periods. Interruptions during the first three months should be minimized due to the high risk of recurrent thrombosis during this period. (See 'Agents for long-term anticoagulation' above and 'Switching anticoagulants during therapy' above.)

All patients with acute DVT who are anticoagulated, especially those on factor Xa and direct thrombin inhibitors and those >75 years, should be monitored clinically for recurrence and bleeding, as well as for the signs and symptoms of conditions that may affect the half-life of the anticoagulant used (eg, renal failure, weight gain or loss) and adverse effects of the medications (eg, skin necrosis, thrombocytopenia, osteoporosis). (See 'Monitoring' above.)

Major bleeding rates on warfarin and LMW heparin during the first three months of anticoagulant therapy are low (less than 2 percent). Factor Xa and direct thrombin inhibitors have lower bleeding rates compared to warfarin; however, these rates may not reflect those in clinical practice and reversal of the anticoagulant effect is considerably more complex than that for warfarin. (See 'Risk of bleeding' above.)

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