Advantages of Anticoagulant Therapy
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) showed that they were similar, with risk of recurrent DVT of 4%, a risk of pulmonary embolism (PE) of 2%, and a risk of major bleeding of 3%. [1, 2]
Initial Anticoagulation Therapy
Initial anticoagulation therapy traditionally involves continuous 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%. [3, 4]
Continuous IV heparin for therapy initiation has been increasingly replaced by single or twice-daily subcutaneous injections of low-molecular-weight heparin (LMWH). LMWH antithrombotic effects correlate with body weight and permit fixed dosing without laboratory monitoring; it also allows for outpatient treatment of uncomplicated deep venous thrombosis (DVT). [5, 6, 7] However, IV heparin remains the treatment of choice for those with end-stage renal failure.
The current guidelines recommend short-term anticoagulation with LMWH subcutaneously (SC) (Grade 1A), unfractionated heparin (UFH) IV (Grade 1A), fixed-dose UFH SC (Grade 1A), or fondaparinux SC (Grade 1A). 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 24 hours (Grade 1C). A vitamin K antagonist such as warfarin should be initiated together with LMWH, UFH, or fondaparinux on the first treatment day (Grade 1A). 
Factor Xa and direct thrombin inhibitors
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. [9, 10] 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 vitamin K antagonist (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  and EINSTEIN-PE  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).
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. Apixaban was originally approved by the FDA in December 2012 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
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. [11, 12]
Dabigatran (Pradaxa) inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It was approved in 2010 to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. In April 2014, it was approved 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.
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. [13, 14]
The RE-SONATE trial and RE-MEDY trials included patients (n=2856) 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. 
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 to 10 days. Approval was based on the Hokusai-VTE study that included 4,921 patients with DVT and 3,319 patients with PE. Among patients with PE, 938 had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide 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. 
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 resulted in a 25% incidence of recurrent thrombosis.  Oral vitamin K antagonists (warfarin) remain the preferred approach for long-term treatment, which allows for single-dosing oral therapy that can be continued on an outpatient basis.
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. [17, 7]
The duration of therapy with warfarin has been evaluated by multiple prospective, randomized clinical trials. [5, 18, 19] 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 deep venous thrombosis (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.  However, the benefit of anticoagulation is lost after stopping treatment at 1 year, prompting many physicians to continue treatment indefinitely.  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 2 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. 
Limitations of Anticoagulation
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.  The estimated fatality rate for each episode of major bleeding is 13%.  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.
Anticoagulation for Calf Vein DVT
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.