Anticoagulation in Deep Venous Thrombosis

Anticoagulant therapy remains the mainstay of medical therapy for deep venous thrombosis (DVT) because it is noninvasive, it treats most patients (approximately 90%) with no immediate demonstrable physical sequelae of DVT, it has a low risk of complications, and its outcome data demonstrate an improvement in morbidity and mortality. Meta-analyses of randomized trials of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have shown that they are similar, with a 4% risk of recurrent DVT, a 2% risk of pulmonary embolism (PE), and a 3% risk of major bleeding. ^{[1, 2]}

First-line therapy for non-high risk venous thromboembolism (VTE) or pulmonary embolism (PE) consists of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, or edoxaban) over VKAs. ^{[3, 4, 5]}  Vitamin K antagonists (VKAs) are also recommended over low-molecular-weight heparin (LMWH), unless VTE is associated with malignancy, in which case LMWH is preferred over VKAs or any direct oral anticoagulants. ^[3]

Note that it is not recommended that inferior vena cava filters be placed in patients with acute VTE who are on anticoagulant therapy. ^[3]

Heparin

Initial anticoagulation therapy to treat DVT traditionally involves continuous intravenous (IV) heparin until adequate systemic anticoagulation is achieved. Rapid anticoagulation is essential within the first 24 hours of diagnosis, reducing the incidence of recurrent venous thrombosis during the first 3 months from 25% to 5%. ^{[6, 7]}

Continuous IV heparin for therapy initiation has been increasingly replaced by single or twice-daily subcutaneous (SC) injections of LMWH. LMWH antithrombotic effects correlate with body weight and permit fixed dosing without laboratory monitoring; LMWH also allows for outpatient treatment of uncomplicated DVT. ^{[8, 9, 10]} However, IV heparin remains the treatment of choice for those with end-stage renal failure.

Guidelines recommend short-term anticoagulation with LMWH SC, unfractionated heparin (UFH) IV, fixed-dose UFH SC, or fondaparinux SC. ^[11] Initial treatment with LMWH, UFH, or fondaparinux should continue for at least 5 days and until the international normalized ratio (INR) is 2 or higher for at least 24 hours. A vitamin K antagonist (VKA) such as warfarin should be initiated together with LMWH, UFH, or fondaparinux on the first treatment day. ^[11]

Patients with recurrent VTE while on treatment with a non-LMWH anticoagulant should be switched to LMWH therapy. ^[3] Those who suffer recurrent VTE while on LMWH therapy should receive an increased dose of LMWH. ^[3]

Factor Xa and direct thrombin inhibitors

Rivaroxaban

Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in November 2012 for treatment of DVT or PE and for reduction of the risk of recurrent DVT and PE after initial treatment. ^{[12, 13]} Approval for this indication was based on studies totaling 9478 patients with DVT or PE. Participants were randomly assigned to receive rivaroxaban, a combination of enoxaparin and a VKA (eg, warfarin), or a placebo. Study endpoints were designed to measure the number of patients who experienced recurrent symptoms of DVT, PE, or death after receiving treatment.

Data from a pooled analysis of the EINSTEIN-DV ^[12] and EINSTEIN-PE ^[13] trials suggested that use of rivaroxaban is as effective in preventing venous thromboembolism (VTE) recurrence as administering enoxaparin followed by a VKA, and it may be associated with less bleeding; in addition, the data suggested that there are no grounds for avoiding rivaroxaban use in high-risk groups (eg, fragile patients, cancer patients, and patients with a large clot).

Approximately 2.1% of patients treated with rivaroxaban experienced recurrent DVT or PE, compared with 1.8-3% treated with the enoxaparin and VKA combination. ^{[12, 13]}  In addition, results from extended treatment demonstrated a reduced risk of recurrent DVT and PE. Approximately 1.3% in the rivaroxaban group experienced recurrent DVT or PE, compared with 7.1% in the placebo group. ^{[14, 15]}

Apixaban

In March 2014, the FDA approved apixaban (Eliquis) for the additional indication of prophylaxis of DVT and PE in adults who have undergone hip- or knee-replacement surgery. Support for this new indication was a result of the ADVANCE 1, 2, and 3 clinical trials that enrolled nearly 12,000 patients. ^{[16, 17, 18]} Apixaban was originally approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).

In August 2014, apixaban was approved for treatment of DVT and PE. The approval for treatment of PE and prevention of recurrence was based on the outcome of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) and AMPLIFY-EXT studies, in which apixaban therapy was compared with enoxaparin and warfarin treatment. The AMPLIFY study showed that, in comparison with the standard anticoagulant regimen, apixaban therapy resulted in a 16% reduction in the risk of a composite endpoint that included recurrent symptomatic VTE or VTE-associated death. ^{[19, 20]}

Data from the AMPLIFY-EXT trial showed that extended anticoagulation (12 months) with apixaban shortened hospital stays, reduced symptomatic recurrent venous thromboembolism or all-cause death without an associated increase in major episodes of hemorrhage when compared with placebo. ^[21]

Dabigatran

Dabigatran (Pradaxa) inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It was FDA approved in 2010 to reduce the risk of stroke in patients with NVAF. In April 2014, the FDA approved it for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days. In addition, it was approved to reduce the risk of DVT and PE recurrence in patients who have been previously treated. Approval was based on results from four global phase III trials that showed dabigatran was noninferior to warfarin and had a lower risk of major or clinically relevant bleeding compared with warfarin. ^{[22, 23, 24]} There have been reports of severe and fatal bleeding in users of the drug.

The RE-COVER and RE-COVER II trials included patients with DVT and PE who were treated with parenteral anticoagulant therapy for 5-10 days. Results showed dabigatran was noninferior to warfarin in reducing DVT and PE after a median of 174 days of treatment with a lower risk of bleeding compared with warfarin. ^{[22, 23]}

The RE-SONATE trial and RE-MEDY trials included 2856 patients with acute DVT and PE who had completed at least 3 months of anticoagulant therapy. Results from this trial showed dabigatran was noninferior to warfarin in the extended treatment of VTE and carried a lower risk of major or clinically relevant bleeding than warfarin. ^[24]

Edoxaban

Edoxaban (Savaysa) was approved by the FDA in January 2015 for treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days. Approval was based on the Hokusai-VTE study that included 4,921 patients with DVT and 3,319 patients with PE. ^[25] Among patients with PE, 938 had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. The rate of recurrent VTE in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group. Edoxaban was noninferior to high-quality standard warfarin therapy and caused significantly less bleeding in a broad spectrum of patients with VTE, including those with severe PE. ^[25]

Betrixaban

Betrixaban (Bevyxxa), a FXa inhibitor, was approved by the FDA in June 2017. ^[26] It is indicated for the prophylaxis of VTE in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE. ^[26]

Approval of betrixaban was based on data from the phase 3 APEX studies. ^{[27, 28]} These randomized, double-blind, multinational clinical trials compared extended-duration betrixaban (35-42 days) to short-duration enoxaparin (6-14 days) for VTE in 7,513 acutely medically ill hospitalized patients with VTE risk factors. ^{[26, 27, 28]} Patients in the betrixaban group received an initial dose of 160 mg orally on day 1, followed by 80 mg once daily for 35-42 days, and received a placebo injection once daily for 6-14 days. Patients in the enoxaparin group received 40 mg subcutaneously once daily for 6-14 days and took an oral placebo once daily for 35-42 days. ^{[26, 27, 28]}

Efficacy was measured in 7,441 patients using a composite outcome score composed of the occurrence of asymptomatic or symptomatic proximal DVT, nonfatal PE, stroke, or VTE-related death. ^{[26, 27, 28]}  Those who received betrixaban showed significant decreases in VTE events (4.4%) compared with patients in the enoxaparin group (6%).

Long-term anticoagulation is necessary to prevent the high frequency of recurrent venous thrombosis or thromboembolic events. Interruption of anticoagulation within the first 12 weeks of therapy appears to result in a 25% incidence of recurrent thrombosis. ^[8] Oral vitamin K antagonists (VKAs) (warfarin) remain the preferred approach for long-term treatment, which allows for single-dosing oral therapy that can be continued on an outpatient basis.

The American College of Chest Physicians (ACCP) recommends cessation of anticoagulant therapy after 3 months of treatment in those with (1) surgery-associated acute proximal deep venous thrombosis (DVT), (2) an acute proximal DVT or pulmonary embolism (PE) provoked by a nonsurgical transient risk factor, and (3) a first unprovoked VTE and a high risk of bleeding. ^[3] (In those with a low or moderate bleeding risk, extend anticoagulation without a scheduled stop date.) ^[3]

When the risk of venous thromboembolism (VTE) recurrence is high in patients with subsegmental PE without DVT, the ACCP recommends anticoagulation over surveillance; when the VTE recurrence risk is low in these patients, surveillance over anticoagulation is suggested. ^[3]

Barring contraindications to aspirin therapy, aspirin is recommended to prevent recurrent VTE in patients with an unprovoked proximal DVT or PE following anticoagulation cessation. ^[3]

Warfarin interrupts the production of vitamin K–dependent coagulation factor production by the liver. The effect is delayed by 72 hours until the existing circulating coagulation factors are cleared or used. The initial effect creates a hypercoagulable state because vitamin K–dependent anticoagulants (protein C and S) are cleared first from the body while vitamin K–dependent procoagulants continue to circulate. During this period, heparin anticoagulation is important to prevent worsening thrombosis. An international normalized ratio (INR) maintenance at 2-3 is recommended; higher ratios do not improve effectiveness, and lower ratios do not reduce bleeding complications. ^{[10, 29]}

The duration of therapy with warfarin has been evaluated by multiple prospective, randomized clinical trials. ^{[8, 30, 31]} Duration of therapy varies depending on patient risk factors and presumed etiology. A first-episode venous thrombosis or thrombotic event due to a transient reversible risk factor should be treated for at least 3 months. Interruption of therapy prior to 12 weeks results in an 8% absolute increase in recurrent thrombosis within the following 12 months. Treatment for the entire 3 months results in an annual recurrent DVT incidence of 3%.

Approval of factor Xa inhibitors (eg, rivaroxaban, apixaban) and direct thrombin inhibitors (eg, dabigatran) for prevention of recurrent DVT following initial therapy allows for more therapeutic options for long-term anticoagulation.

For patients with first-episode idiopathic venous thrombosis, treatment length should be 6-12 months. ^[8] However, the benefit of anticoagulation is lost after stopping treatment at 1 year, prompting many physicians to continue treatment indefinitely. ^[32] The decision to continue anticoagulation should be tailored to each patient, taking into consideration bleeding risk and patient preference, with treatment reassessment at periodic intervals.

For patients with a first-episode venous thrombosis and documented antiphospholipid antibodies or two or more thrombophilic conditions (combined factor V Leiden and prothrombin 20210A gene mutations), at least 12 months of treatment is indicated. Six to 12 months of initial therapy is indicated in those patients with any one of the following: deficiencies of antithrombin, protein C, or protein S; factor V Leiden; prothrombin 20210A; hyperhomocysteinemia; or high factor VIII levels (>90th percentile). Indefinite therapy is also considered in both of these patient populations. ^[8]

Anticoagulation does have its limitations. Although it inhibits propagation, it does not remove the thrombus, and a variable risk of clinically significant bleeding is observed. In 2-4% of patients, deep venous thrombosis (DVT) progresses to symptomatic pulmonary embolism (PE) despite anticoagulation. In the setting of a PE, 8% of patients have recurrences despite anticoagulation, 30-45% of which are fatal. Although anticoagulation markedly reduces the risk of PE and extension of the DVT, it does not reduce the incidence of postthrombotic syndrome (PTS), which requires expedited removal of the existing thrombus without damaging the underlying venous valves.

The main adverse effects of heparin therapy include bleeding and thrombocytopenia. Approximately 2% of patients experience major bleeding within the first 3 months of therapy and 1-3% thereafter per year. ^[33] The estimated fatality rate for each episode of major bleeding is 13%. ^[33] The development of thrombocytopenia must alert clinicians to the diagnosis of heparin-induced thrombocytopenia (HIT), which can occur in up to 3% of patients treated with heparin for more than 4 days. Two types exist: the most common form is a self-limiting nonimmune mediated thrombocytopenia that resolves with cessation of therapy; the less common immune-mediated thrombocytopenia has potentially catastrophic thromboembolic complications.

Treatment of isolated calf vein deep venous thrombosis (DVT) is best individualized, taking into account local preferences, patient reliability, the availability of follow-up care, and an assessment of ongoing risk factors. Despite the lower (but not 0) risk of pulmonary embolism (PE) and mortality associated with calf vein DVT, current guidelines recommend short-term anticoagulation for 3 months in symptomatic patients, albeit with a relatively low Grade 2B recommendation. Asymptomatic patients with isolated calf vein DVT do not require anticoagulation, and surveillance ultrasound studies over 10-14 days to detect proximal extension is recommended instead. At certain centers, patients with isolated calf vein DVT are treated with full anticoagulant therapy.

With the introduction of low-molecular-weight heparin (LMWH) or fondaparinux, selected patients qualify for outpatient treatment only if adequate home care and close medical follow-up can be arranged. As discussed, subcutaneous unfractionated heparin (UFH) may be substituted for LMWH or fondaparinux if insurance issues are a limiting factor. Outpatient therapy with UFH carries a higher risk of heparin-induced thrombocytopenia and remains a second-line drug.

While the patient is initiating therapy with warfarin, the prothrombin time (PT) or international normalized ratio (INR) must be monitored closely (daily or alternate days) until the target is achieved, then weekly for several weeks. When the patient is stable, monitor monthly. Inability to monitor INR precludes outpatient treatment of DVT.

Patients with suspected or diagnosed isolated calf vein DVT may be discharged safely on a nonsteroidal anti-inflammatory drug (NSAID) or aspirin, with close follow-up care and repeat diagnostic studies (ie, ultrasonography) in 7 days to evaluate for proximal extension. Patients with suspected DVT but with negative initial noninvasive study results need to be reassessed by their primary care provider within 7 days. Patients with ongoing risk factors need to be reevaluated at 1 week to detect proximal extension because of the limited accuracy of noninvasive tests for calf vein DVT.

The American Society of Hematology (ASH) released their updated recommendations on the management of venous thromboembolism (VTE) (deep vein thrombosis [DVT] and pulmonary embolism [PE]) in October 2020. ^[34] Select recommendations are outlined below.

Strong Recommendations

For patients with PE and hemodynamic compromise, it is recommended that thrombolytic therapy followed by anticoagulation be used over anticoagulation alone.

For patients with DVT and/or PE who have completed primary treatment and will continue vitamin K antagonist (VKA) therapy as secondary prevention, it is recommended that an international normalized ratio (INR) range of 2.0 to 3.0 be used over a lower INR range (eg, 1.5-1.9).

For patients with a recurrent unprovoked DVT and/or PE, indefinite antithrombotic therapy is recommended over stopping anticoagulation after completion of primary treatment.

Conditional Recommendations

Initial management

For patients with DVT and/or PE, the ASH guideline panel suggests using direct oral anticoagulants (DOACs) over VKAs. No single DOAC is suggested over another.

In most patients with proximal DVT, anticoagulation therapy alone is suggested over thrombolytic therapy in addition to anticoagulation.

For patients with PE with echocardiography and/or biomarkers that are compatible with right ventricular dysfunction but without hemodynamic compromise (submassive PE), anticoagulation alone is suggested over the routine use of thrombolysis in addition to anticoagulation.

For patients with extensive DVT in whom thrombolysis is considered appropriate, the ASH guideline panel suggests using catheter-directed thrombolysis over systemic thrombolysis.

For patients with PE in whom thrombolysis is considered appropriate, systemic thrombolysis is suggested over catheter-directed thrombolysis.

For patients with proximal DVT and significant preexisting cardiopulmonary disease, as well as for patients with PE and hemodynamic compromise, use of anticoagulation alone is suggested rather than anticoagulation plus insertion of an inferior vena cava (IVC) filter.

Primary treatment

For primary treatment of patients with DVT and/or PE, whether provoked by a transient risk factor or by a chronic risk factor or unprovoked, using a shorter course of anticoagulation for primary treatment (3-6 months) is suggested over a longer course of anticoagulation for primary treatment (6-12 months).

Secondary prevention

To guide the duration of anticoagulation for patients with unprovoked DVT and/or PE, the ASH guideline panel suggests against routine use of prognostic scores, D-dimer testing, or ultrasonography to detect residual vein thrombosis.

Indefinite antithrombotic therapy is suggested over anticoagulation cessation after completion of primary treatment for the following:

• Patients with DVT and/or PE provoked by a chronic risk factor
• Patients with unprovoked DVT and/or PE

For patients with DVT and/or PE who have completed primary treatment and will continue to receive secondary prevention, use of anticoagulation is suggested over aspirin.

For patients with DVT and/or PE who have completed primary treatment and will continue with a DOAC for secondary prevention, the ASH guideline panel suggests using a standard-dose DOAC or a lower-dose DOAC.

Recurrent events

For patients with breakthrough DVT and/or PE during therapeutic VKA treatment, the ASH guideline panel suggests using low-molecular-weight heparin (LMWH) over DOAC therapy.

For patients who develop DVT and/or PE provoked by a transient risk factor and have a history of previous unprovoked VTE or VTE provoked by a chronic risk factor, indefinite antithrombotic therapy is suggested over stopping anticoagulation after completing primary treatment.

For patients who develop DVT and/or PE provoked by a transient risk factor and have a history of a previous VTE also provoked by a transient risk factor, anticoagulation cessation after completion of primary treatment is suggested over indefinite antithrombotic therapy.

Other

For patients with DVT and/or PE with stable cardiovascular disease (CVD) who initiate anticoagulation and were previously taking aspirin for cardiovascular risk modification, it is suggested that aspirin be suspended over continuing it for the duration of anticoagulation therapy.

For patients with DVT, with or without an increased risk for postthrombotic syndrome (PTS), the ASH guideline panel suggests against the routine use of compression stockings.

Additional Resources

For more information, please go to Venous Thromboembolism (VTE), Deep Venous Thrombosis (DVT), and Pulmonary Embolism (PE).

For more Clinical Practice Guidelines, please go to Guidelines.