Deep vein thrombosis medical therapy

Editors-in-Chief: C. Michael Gibson, M.S., M.D. Associate Editor-In-Chief: Ujjwal Rastogi, MBBS [mailto:urastogi@perfuse.org]

Overview
The primary purpose of treatment is to prevent the following:
 * Further clot extension,
 * Acute Pulmonary embolism,
 * Recurrence of thrombosis,
 * Prevention of late complications such as:
 * the post-thrombotic syndrome
 * chronic thromboembolic pulmonary hypertension.

Medical Therapy
Anticoagulant therapy is indicated for patients with symptomatic proximal lower extremity DVT, since PE is a fatal complication occurring in half of the untreated patients within few days to weeks.

Five options are available for the initial treatment of DVT: After diagnosis, the current approach is to start both heparin and warfarin (VKA), and to discontinue heparin after 5 days provided the international normalized ratio (INR) is ≥ 2.0 for at least 24 h.
 * 1) Low-molecular-weight heparin (LMWH) administered subcutaneous (SC), without monitoring.
 * 2) IV unfractionated heparin (UFH), with monitoring.
 * 3) SC UFH, with monitoring
 * 4) Weight-based SC UFH, without monitoring.
 * 5) SC fondaparinux, without monitoring

Anticoagulation
Anticoagulation is the usual treatment for DVT. In general, patients are initiated on a brief course (less than a week) of low molecular weight heparin, before they are started on a chronic (3 to 6 month) course of warfarin (or related vitamin K inhibitors).

An abnormal D-dimer level at the end of treatment, signals the need for continued treatment, in patients with first unprovoked proximal deep-vein thrombosis.

Thrombolysis
Thrombolysis is generally reserved for extensive clot, e.g. an iliofemoral thrombosis. Although a meta-analysis of randomized controlled trials by the Cochrane Collaboration shows improved outcomes with thrombolysis, there may be an increase in serious bleeding complications.

Direct factor Xa inhibitor
Rivaroxaban (orally active direct factor Xa inhibitor) has been studied in phase III clinical trials for prevention of VTE in hospitalized medically ill patients (MAGELLAN), treatment and secondary prevention of VTE (EINSTEIN). More than 8,000 patients were enrolled in the rivaroxaban clinical development program overall. The study showed that taking rivaroxaban once daily for 35 days was associated with a reduction in the risk of venous thrombosis, compared with standard 10-day treatment with enoxaparin by subcutaneous injection, in acutely ill medical patients. However, bleeding rates were significantly increased with rivaroxaban.

Compression stockings
Elastic compression stockings should be routinely applied "beginning within 1 month of diagnosis of proximal DVT and continuing for a minimum of 1 year after diagnosis". The stockings in almost all trials were stronger than routine anti-embolism stockings and created either 20-30 mm Hg or 30-40 mm Hg. Most trials used knee-high stockings. A meta-analysis of randomized controlled trials by the Cochrane Collaboration showed reduced incidence of post-phlebitic syndrome. The number needed to treat is quite potent at 4 to 5 patients need to prevent one case of post-phlebitic syndrome.

Recommendation for initial anticoagulation of acute DVT of the leg
1. For patients with objectively confirmed DVT, we recommend short-term treatment with SC LMWH (Grade 1A), IV UFH (Grade 1A), monitored SC UFH (Grade 1A), fixed-dose SC UFH (Grade 1A), or SC fondaparinux (Grade 1A) rather than no such short-term treatment.

2. For patients with a high clinical suspicion of DVT, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C)

3. In patients with acute DVT, we recommend initial treatment with LMWH, UFH, or fondaparinux for at least 5 days and until the INR is > 2.0 for 24 h (Grade 1C).

4. In patients with acute DVT, we recommend initiation of VKA together with LMWH, UFH, or fondaparinux on the first treatment day rather than delayed initiation of VKA (Grade 1A)''.

Recommendation for use of unfractionated Heparin
1. In patients with acute DVT, if IV UFH is chosen, we recommend that after an initial IV bolus (80 U/kg or 5,000 U), it be administered by continuous infusion (initially at a dose of 18 U/kg/h or 1,300 U/h) with dose adjustment to achieve and maintain an activated partial thromboplastin time (APTT) prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 IU/mL anti-Xa activity by the amidolytic assay rather than administration as IV boluses throughout treatment, or administration without coagulation monitoring (Grade 1C)''.

Comparison of subcutaneous unfractionated Heparin with intravenous Heparin
1. In patients with acute DVT, if monitored SC UFH is chosen, we recommend an initial dose of 17,500 U, or a weight-adjusted dose of about 250 U/kg bid, with dose adjustment to achieve and maintain an APTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 IU/mL anti-Xa activity when measured 6 h after injection rather than starting with a smaller initial dose (Grade 1C).

2. In patients with acute DVT, if fixed-dose, unmonitored SC UFH is chosen, we recommend an initial dose of 333 U/Kg followed by 250 U/kg bid rather than non–weight-based dosing (Grade 1C)''.

Recommendation for use of low molecular weight Heparin
1. In patients with acute DVT, we recommend initial treatment with LMWH SC once or twice daily, as an outpatient if possible (Grade 1C), or as an inpatient if necessary (Grade 1A), rather than treatment with IV UFH.

2. In patients with acute DVT treated with LMWH, we recommend against routine monitoring with anti-factor Xa level measurements (Grade 1A).

3. In patients with acute DVT and severe renal failure, we suggest UFH over LMWH (Grade 2C)''.

Guidelines for duration of anticoagulant therapy
1. For patients with DVT secondary to a transient (reversible) risk factor, we recommend treatment with a VKA for 3 months over treatment for shorter periods (Grade 1A).

2. For patients with unprovoked DVT, we recommend treatment with a VKA for at least 3 months (Grade 1A). We recommend that after 3 months of anticoagulant therapy, all patients with unprovoked DVT should be evaluated for the risk-benefit ratio of long-term therapy (Grade 1C). For patients with a first unprovoked VTE that is a proximal DVT, and in whom risk factors for bleeding are absent and for whom good anticoagulant monitoring is achievable, we recommend long-term treatment (Grade 1A). For patients with a second episode of unprovoked VTE, we recommend long-term treatment (Grade 1A). For patients with a first isolated distal DVT that is unprovoked, we suggest that 3 months of anticoagulant therapy is sufficient rather than indefinite therapy (Grade 2B)

3. For patients with DVT and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A). For these patients, we recommend subsequent anticoagulant therapy with VKA or LMWH indefinitely or until the cancer is resolved (Grade 1C).

4. In patients who receive long-term anticoagulant treatment, the risk-benefit ratio of continuing such treatment should be reassessed in the individual patient at periodic intervals (Grade 1C).''

Recommendation for intensity of anticoagulant effect
1. In patients with DVT, we recommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (range, 2.0 to 3.0) for all treatment durations (Grade 1A). For patients with unprovoked DVT who have a strong preference for less frequent INR testing to monitor their therapy, after the first 3 months of conventional-intensity anticoagulation (INR range, 2.0 to 3.0), we recommend low-intensity therapy (range, 1.5 to 1.9) with less frequent INR monitoring over stopping treatment (Grade 1A). We recommend against high-intensity VKA therapy (INR range, 3.1 to 4.0) compared to an INR range of 2.0 to 3.0 (Grade 1A).''

Recommendation for treatment of asymptomatic DVT of the leg
1. In patients who are unexpectedly found to have asymptomatic DVT, we recommend the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 1C).''

AHA Guidelines for duration of anticoagulant therapy
1. Adult patients with IFDVT who receive oral warfarin as first-line long-term anticoagulation therapy should have warfarin overlapped with initial anticoagulation therapy for a minimum of 5 days and until the INR is ≥2.0 for at least 24 hours, and then targeted to an INR of 2.0 to 3.0 (Class I; Level of Evidence A).

2. Patients with first-episode IFDVT related to a major reversible risk factor should have anticoagulation stopped after 3 months (Class I; Level of Evidence A).

3. Patients with recurrent or unprovoked IFDVT should have at least 6 months of anticoagulation and be considered for indefinite anticoagulation with periodic reassessment of the risks and benefits of continued anticoagulation (Class I; Level of Evidence A).

4. Cancer patients with IFDVT should receive LMWH monotherapy for at least 3 to 6 months, or as long as the cancer or its treatment (eg, chemotherapy) is ongoing  (Class I; Level of Evidence A).

5. In children with DVT, the use of LMWH monotherapy may be reasonable (Class IIb; Level of Evidence C).''

Guidelines Resources

 * Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)


 * Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension (A Scientific Statement From the American Heart Association).