Лікарські препарати для лікування тромбозу глибоких вен

There are several strategies for anticoagulation of patients with DVT:

• Initial treatment with an injectable heparin (unfractionated or low molecular weight) followed after several days by long-term treatment with an oral drug (warfarin, a factor Xa inhibitor, or a direct thrombin inhibitor)

• Initial and long-term treatment with a LMWH

• Initial and long-term treatment with certain oral factor Xa inhibitors (rivaroxaban or apixaban)

Dosing regimens for treatment of DVT differ from those used for prevention of thromboembolism in patients with atrial fibrillation.

Some, but not all, of the direct oral anticoagulants are alternatives to warfarin as 1st-line treatment for DVT and PE and may also be used as monotherapy (see table Oral Anticoagulants). Compared to warfarin, these medications have been shown to give similar protection against recurrent DVT and have similar (or with apixaban, perhaps lower) risk of serious bleeding (1).

Their advantages are that they are effective within several hours and thus do not require a period of overlapping treatment with heparin (bridging treatment), although edoxaban and dabigatran require at least 5 days of pretreatment with an injectable anticoagulant. Also, they are given as a fixed dose and thus, unlike warfarin, do not require ongoing laboratory testing.

The main disadvantage is the higher cost compared to warfarin and the high cost of DOAC reversal agents in the case of bleeding or need for an urgent surgery or procedure.

Duration of treatment varies. Patients with transient risk factors for DVT (eg, immobilization, surgery) can usually stop taking anticoagulants after 3 to 6 months. Patients with idiopathic (or unprovoked) DVT with no known risk factors, or recurrent DVT should take anticoagulants for at least 6 months and, in selected patients, probably for life unless they are at high risk for bleeding complications. Patients with cancer-associated thrombosis should receive at least 3 months of anticoagulation. Treatment is usually longer in patients receiving ongoing cancer therapy and in patients with advanced, metastatic disease. Patients with selected hypercoagulable states (eg, antiphospholipid syndrome or protein C, protein S, or antithrombin deficiency) should also be considered for extended-duration anticoagulation.

A low molecular weight heparin (eg, enoxaparin, dalteparin, tinzaparin) is one of the initial treatments of choice because LMWHs can be given on an outpatient basis. LMWHs are as effective as unfractionated heparin (UFH) for reducing DVT recurrence, thrombus extension, and risk of death due to PE (2). Like UFH, LMWHs catalyze the action of antithrombin (which inhibits coagulation factor proteases), leading to inactivation of coagulation factor Xa and, to a lesser degree, factor IIa. LMWHs also have some antithrombin–mediated anti-inflammatory properties, which facilitate clot organization and resolution of symptoms and inflammation.

LMWHs are typically given subcutaneously in a standard weight-based dose (eg, enoxaparin 1.5 mg/kg subcutaneously once a day or 1 mg/kg subcutaneously every 12 hours or dalteparin 200 units/kg subcutaneously once a day). Patients with renal insufficiency may be treated with UFH or with reduced doses of LMWH. Monitoring is not reliable because LMWHs do not significantly prolong the results of global tests of coagulation. Furthermore, they have a predictable dose response, and there is no clear relationship between the anticoagulant effect of LMWH and bleeding. If warfarin is used after initial anticoagulation, treatment with LMWH is continued until full anticoagulation is achieved with warfarin (typically about 5 days). Transition to the oral agents rivaroxaban or apixaban can be done at any time with no overlap. Transition to edoxaban or dabigatran requires at least 5 days of LMWH treatment, but no overlap is needed.

LMWHs and direct oral anticoagulants are first-line treatment options for patients with cancer-associated DVT (3), including in patients who have a central venous catheter and develop DVT. Warfarin is a 2nd-line alternative due to its low cost, but use requires careful monitoring.

Complications of LMWHs include bleeding, thrombocytopenia, urticaria, and, rarely, thrombosis and anaphylaxis. Inpatients and possibly outpatients should be screened for bleeding with serial complete blood counts and, where appropriate, testing for occult blood in stool.

Unfractionated heparin may be used instead of LMWH for patients who are hospitalized and for patients who have renal insufficiency or failure (creatinine clearance 10 to 30 mL/minute, (0.17 to 0.5mL/s/m²) because UFH is not cleared by the kidneys. UFH is given as a bolus and infusion to achieve full anticoagulation (eg, activated partial thromboplastin time [aPTT] 1.5 to 2.5 times that of the reference range). For outpatients, UFH 333 units/kg initial bolus, then 250 units/kg subcutaneously every 12 hours can be substituted for IV UFH to facilitate mobility; the dose does not need adjustment based on aPTT. If warfarin is used after initial anticoagulation, UFH is continued until full anticoagulation has been achieved with warfarin (about 5 days).

Complications of UFH are similar to those of LMWHs, except that heparin-induced thrombocytopenia, which is rare and may be life-threatening, is more common with UFHs. Long-term use of UFH causes hyperkalemia, liver enzyme elevations, and osteopenia. Rarely, UFH given subcutaneously causes skin necrosis. Inpatients and possibly outpatients being given UFH should be screened for bleeding.

Rivaroxaban and apixaban can be started as monotherapy immediately upon diagnosis or used in transition from an injectable heparin at any time without overlap. Dosing of rivaroxaban is 15 mg orally twice a day for 3 weeks followed by 20 mg orally once a day for a total of 3 to 6 months. Apixaban dosing is 10 mg orally twice a day for 7 days followed by 5 mg orally twice a day for 3 to 6 months.

Before edoxaban is started, an initial 5 to 7 days of treatment with LMWH or UFH is required. Then edoxaban is given 60 mg orally once a day. To transition from an injectable anticoagulant, the factor Xa inhibitor is typically started within 6 to 12 hours after the last dose of a twice-daily LMWH regimen and within 12 to 24 hours after a once-daily LMWH regimen.

There is evidence that apixaban, edoxaban, and rivaroxaban can be used in select patients with cancer-associated venous thromboembolism (VTE) as an alternative to monotherapy with LMWH (4, 5, 6).

Fondaparinux, a parenteral selective factor Xa inhibitor, may be used as an alternative to UFH or LMWH for the initial treatment of DVT or PE. It is given in a fixed dose of 7.5 mg subcutaneously once a day (10 mg for patients > 100 kg, 5 mg for patients < 50 kg). It has the advantage of fixed dosing and is less likely to cause thrombocytopenia.

Dabigatran 150 mg orally twice a day is given only after an initial 5 days of treatment with LMWH. It is typically started within 6 to 12 hours after the last dose of a twice-daily LMWH regimen and within 12 to 24 hours after a once-daily regimen.

Parenteral direct thrombin inhibitors (argatroban, bivalirudin, desirudin) are available but do not have a role in treatment or prevention of DVT or PE. Argatroban may be useful to treat DVT in patients with heparin-induced thrombocytopenia.

Warfarin is a treatment option for patients with DVT who are not pregnant. It is also an option for patients with severe renal dysfunction. Warfarin is also a second-line option for patients with cancer-associated VTE.

Warfarin 5 to 10 mg can be started immediately along with heparin because it takes about 5 days to achieve desired therapeutic effect. Older patients and patients with a liver disorder typically require lower warfarin doses. Therapeutic goal is an international normalized ratio (INR) of 2.0 to 3.0. INR is monitored weekly for the first 1 to 2 months of warfarin treatment and monthly thereafter; the dose is increased or decreased by 0.5 to 3 mg to maintain the INR within this range. Patients taking warfarin should be informed of possible drug interactions, including interactions with foods and nonprescription medicinal herbs.

Rarely, warfarin causes skin necrosis in patients with inherited protein C deficiency or protein S deficiency.

1. 1. Kearon C, Aki EA, Ornelas J, et al: CHEST Guideline and Expert Panel Report: Antithrombotic therapy for VTE disease. Chest 149:315–352, 2016. doi: https://doi.org/10.1016/j.chest.2015.11.026

2. 2. Segal JB, Streiff MB, Hofmann LV, Thornton K, Bass EB: Management of venous thromboembolism: a systematic review for a practice guideline [published correction appears in Ann Intern Med 2007 Mar 6;146(5):396. Hoffman, Lawrence V [corrected to Hofmann, Lawrence V]]. Ann Intern Med 146(3):211–222, 2007. doi:10.7326/0003-4819-146-3-200702060-00150

3. 3. Schrag D, Uno H, Rosovsky R, et al: Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial. JAMA 329(22):1924–1933, 2023. doi:10.1001/jama.2023.7843

4. 4. Agnelli G, Becattini C, Meyer G, et al: Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 382:1599–1607, 2020. doi: 10.1056/NEJMoa1915103

5. 5. Raskob GE, van Es N, Verhamme P, et al: Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med Dec 12, 2017. doi: 10.1056/NEJMoa1711948

6. 6. Young AM, Marshall A, Thirlwall J, et al: Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 36: 2017–2023, 2018. doi: 10.1200/JCO.2018.78.8034

Many of the anticoagulants have specific reversal agents. If these are unavailable or ineffective, clotting factors, typically in the form of 4-factor prothrombin complex concentrate or sometimes fresh frozen plasma, can be given. Some anticoagulants can be removed by hemodialysis or have absorption blocked by activated charcoal.

With the heparins, bleeding can be stopped or slowed with protamine. It is more effective on UFH than on LMWH because protamine only partially neutralizes LMWH inactivation of factor Xa. The dose is 1 mg protamine for each 100 units of UFH given or for each milligram of LMWH; protamine is infused slowly over 10 to 20 minutes (maximum dose 50 mg in 10 minutes). The dose is lowered depending on the time since UFH was given. If a 2nd dose is required, it should be one half the first dose. During all infusions, patients should be observed for hypotension and a reaction similar to an anaphylactic reaction. Because UFH given IV has a half-life of 30 to 60 minutes, protamine is typically not given to patients who have received UFH > 60 to 120 minutes beforehand) or is given at a reduced dose based on the amount of heparin estimated to be remaining in plasma, based on the half-life of UFH.

Warfarin anticoagulation can be reversed with vitamin K; the dose is 1 to 2.5 mg orally if INR is 5 to 9, 2.5 to 5 mg orally if INR is > 9, and 5 to 10 mg IV (given slowly to avoid anaphylaxis) if there is active hemorrhage. If hemorrhage is severe, prothrombin complex concentrate should be given; fresh frozen plasma may be used if prothrombin complex concentrate is unavailable. Selected patients with overanticoagulation (INR 5 to 9) who are neither actively bleeding nor at increased risk of bleeding can be managed by omitting 1 or 2 warfarin doses and monitoring INR more frequently, then giving warfarin at a lower dose.

With dabigatran, a humanized monoclonal antibody idarucizumab 5 g IV is an effective antidote to bleeding. If the agent is not available, 4-factor prothrombin complex concentrate 50 units/kg IV can be given. Hemodialysis also may help because dabigatran is not highly protein bound. Oral activated charcoal is an option if the last dose of dabigatran was within 2 hours.

With factor Xa inhibitors, andexanet alfa is an antidote available in the United States; however, its use is restricted in part due to its high cost (1). If the patient is on a high dose of a factor Xa inhibitor (eg, rivaroxaban > 10 mg or apixaban > 5 mg), or if the patient took the medication < 8 hours before presentation, a high dose of andexanet alfa (800 mg IV at 30 mg/minute followed by 960 mg IV at 8 mg/minute) is given. If the patient is on a low dose of a factor Xa inhibitor or took the medication > 8 hours before presentation, a lower dose of andexanet alfa (400 mg IV at 30 mg/minute followed by 480 mg IV at 8 mg/minute) is given. Fondaparinux anticoagulation can theoretically be reversed with andexanet alfa although this has not been studied in research trials. If andexanet alfa is unavailable, 4-factor prothrombin complex concentrate may be considered. Oral activated charcoal is an option in patients who took an oral factor Xa inhibitor within a few hours of presentation (8 hours for rivaroxaban, 6 hours for apixaban, and 2 hours for edoxaban). Hemodialysis is not effective for removal of the oral factor Xa inhibitors.

Other reversal agents for direct oral anticoagulants are currently being developed (eg, ciraparantag).

Clotting factors are available in the form of

• Prothrombin complex concentrate

• Fresh frozen plasma

• Individual clotting factors

Prothrombin complex concentrate (PCC) is available in several forms. Three-factor PCC contains high levels of factors II, IX, and X, and 4-factor PCC adds factor VII; both also have proteins C and S. PCCs can be unactivated, or activated, in which some of the factors have been cleaved to the active form. The 4-factor PCC is preferred as it tends to be more effective at reversing bleeding than 3-factor PCC. If 3-factor PCC is used, fresh frozen plasma (FFP) can also be given because FFP contains factor VII, which is not contained in 3-factor PCC. Typical dose is 50 units/kg IV. Because evidence of benefit is uncertain and risk of clotting is significant, PCCs should be reserved for life-threatening bleeding.

Fresh frozen plasma contains all the clotting factors but only at normal plasma levels. It is now typically used only if PCC is unavailable; there is no evidence it is effective in bleeding due to factor Xa inhibitors

Individual clotting factors such as activated recombinant factor VII are available but are not thought to be helpful for anticoagulant-related bleeding.

Antifibrinolytic agents can also be tried; however, their use has not been studied for reversal of bleeding in patients taking anticoagulants. Tranexamic acid 10 to 20 mg/kg IV bolus followed by 10 mg/kg IV every 6 to 8 hours may be used. Aminocaproic acid may be started at 2 gm IV every 6 hours.

Clinical judgment is necessary when deciding whether to permanently stop or lower the dose of anticoagulant.

If a patient has almost completed their treatment course of anticoagulant and has a severe bleeding episode, the anticoagulant can be stopped. However, if a patient has just started or is mid-way through their treatment course and has a severe bleed, the decision of whether to stop or reduce the dose of anticoagulant is not as straightforward and should be made in consultation with a multidisciplinary team and keeping in mind the patient's priorities.

1. 1. Connolly SJ, Crowther M, Eikelboom JW, et al: Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 380:1326–1335, 2019. doi: 10.1056/NEJMoa1814051

1. 1. Vedantham S, Goldhaber SZ, Julien JA, et al: Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 377:2240–2252, 2017. doi: 10.1056/NEJMoa1615066