Thromboembolic Disease: Therapy

Mary Elmasri and Timothy A. Morris

Management of venous thromboembolism (VTE) should be guided by the primary goals of treatment, namely, to prevent and minimize serious sequelae. These include: (1) death or dyspnea, chest pain, and hemodynamic instability from pulmonary emboli (PE); (2) leg discomfort from deep vein thrombosis (DVT); and (3) long-term recurrence of VTE or other problems such as postphlebitic leg swelling and pulmonary hypertension.

It is important to note that no form of anticoagulation reduces embolic risk or enhances thrombus resolution directly. Treated DVT patients remain at embolic risk until the DVT either dissolves or organizes; consequently, embolization occurring in the first few days of therapy does not reflect “drug failure.” The only evidence of anticoagulation failure is thrombus growth or development of a new thrombus during therapy. Furthermore, approximately 50% of patients with above-knee acute DVT have already had an asymptomatic PE; thus, it is important not to misinterpret the presence of preexisting emboli discovered during the course of treatment as evidence of recurrent thromboembolic disease.

A DVT confined to calf veins typically does not require anticoagulant therapy because it is associated with a low rate of clinically important sequelae. In contrast, a DVT occurring in the proximal veins (i.e., the popliteal, femoral, common femoral, or higher veins) is more dangerous and does require treatment. Both compression ultrasound and impedance plethysmography (IPG) are convenient, reliable ways to make this distinction, although IPG is used far less frequently. However, 15% to 20% of calf-limited thrombi may propagate into the proximal veins within 2 weeks of presentation; thus, serial testing within this timeframe may ensure that a proximal DVT is detected and treated promptly.

The goals of anticoagulation in the acute treatment of VTE are to diminish the amount of vascular obstruction and prevent embolization. In the case of hemodynamically significant PE, inhibiting the release of vasoactive substances into the pulmonary circulation and optimizing right ventricular (RV) function is also an important goal of immediate anticoagulation. Anticoagulation decreases ongoing thrombosis by inactivating a variety of clotting factors, most importantly thrombin and factor Xa. This inactivation of the coagulation system inhibits thrombus growth and allows the fibrinolytic system to proceed unopposed. Anticoagulation, therefore, indirectly speeds the resolution of VTEs and reduces the size of potential emboli.

In the acute stage, the milieu within and around the thrombi contains a high concentration of activated clotting enzymes. In the initial phase of treatment, the enzymes (particularly thrombin or activated factor X, also called “Xa”) must be inactivated to halt the self-perpetuating thrombotic process on the clot’s surface. Antithrombin (historically called “antithrombin III”) irreversibly inactivates these enzymes. Enhancement of antithrombin is the basis for parenteral therapy with heparin and heparin-like anticoagulants. The options include intravenous unfractionated heparin (UFH) as well as subcutaneous UFH, low molecular weight heparin (LMWH), and fondaparinux. Although clinical data are relatively sparse, most experts agree that at least 5 days of parenteral anticoagulation are necessary for the initial phase of treatment.

Clinical trials have failed to demonstrate clear or consistent superiority of any one type of anticoagulation. A literature review suggests that UFH, LMWH, and fondaparinux are all comparable in their efficacy and safety and any may be used for the acute parenteral phase of anticoagulation for acute DVT or PE. The choice between agents depends in large part on the relative cost and ease of administration, with the subcutaneous route permitting more mobility and the possibility of outpatient management. The 9th edition ACCP guidelines for antithrombotic treatment of VTEs recommend LMWH or fondaparinux over intravenous UFH and subcutaneous UFH for the parenteral phase of anticoagulation (Grade 2B and Grade 2C recommendations, respectively, apparently influenced by ease of administration). The risk of heparin-induced thrombocytopenia is about the same with UFH and the LMWHs. However, when subcutaneous absorption is in question or the patient is being considered for thrombolytic therapy, the ACCP recommends the use of intravenous UFH.

The key to the parenteral phase of anticoagulation is achieving therapeutic dosing quickly. The recommended intravenous UFH regimen is weight-based dosing of intravenous UFH at 80 units/kg bolus followed by a continuous infusion of 18 units/kg/hour. When compared to less aggressive treatment regimens, the weight-based regimen is more effective in terms of mortality and recurrence. The individual anticoagulant response to intravenous UFH varies widely, so it is useful to monitor intravenous UFH with the activated partial thromboplastin time (aPTT). A precise therapeutic range for aPTT has never been established unequivocally, but most experts recommend an aPTT during continuous intravenous infusion of heparin of 1.5 to 2.5 times the patient’s baseline aPTT. Although the 1.5- to 2.5-times relative range for aPTT can help identify gross over- or under-dosage, it is unlikely to precisely define a therapeutic range. The beneficial effects observed clinically with the 1.5- to 2.5-times range may reflect the appropriate dose of heparin rather than the aPTT test result itself. One clinical implication of this finding is that high-dose UFH subcutaneous regimens, with or without aPTT monitoring, are at least as safe and effective as intravenous regimens.

LMWH is prepared by the depolymerization of UFH and shares many properties with it. Like UFH, all LMWHs also bind antithrombin; however, because of shorter length, they favor inactivation of Xa more than thrombin. LMWHs have longer half-lives than UFH. They are cleared via the kidneys so should be used cautiously in patients with renal failure. The three formulations of LMWH currently approved in the United States are enoxaparin, dalteparin, and tinzaparin. Dalteparin is currently only FDA-approved for the treatment of VTE in cancer patients. All are given in a fixed, weight-adjusted dose either once or twice daily. Although not identical in their pharmacokinetics or anticoagulant properties, no particular LMWH has been found to be clinically superior.

Fondaparinux is a synthetic polysaccharide with similar active antithrombin binding sites as UFH and LMWH. Because of its small size, it enhances antithrombin-mediated inactivation of Xa exclusively. Fondaparinux has almost complete bioavailability with a longer half-life than LMWH. It may accumulate to dangerous levels in patients with renal insufficiency because of its near-total renal clearance. It is given subcutaneously once daily at a dose of 7.5 mg for patients with a body weight of 50 to 100 kg, 5 mg for patients weighing less than 50 kg, and 10 mg for patients weighing greater than 100 kg.

Rivaroxaban is a synthetic inhibitor of Xa that can be used in the acute phase of VTE treatment. It differs from the parenteral agents (UFH, LMWH, and fondaparinux) in two substantial ways. First, it is a direct inhibitor that does not depend on the body’s antithrombin to inactivate thrombi. Second, it is well absorbed when given orally. For these reasons, it can be used to treat VTE in the acute as well as long-term phases. The acute phase of VTE treatment with rivaroxaban lasts for 3 weeks, as opposed to the shorter acute phase used with parenteral agents.

Long-term anticoagulation after the acute phase of treatment is necessary to prevent recurrence of VTE. The options for long-term anticoagulation include UFH, LMWH, vitamin K antagonists (warfarin), direct Xa inhibitors (e.g., rivaroxaban), and direct thrombin inhibitors (e.g., dabigatran, discussed below). Vitamin K antagonists are the most commonly used agents for long-term anticoagulation. Clinical trials comparing LMWH to vitamin K antagonists have not shown substantial differences in outcome, with the exception of cancer patients who do better with LMWH. Because of the substantial cost of LMWH and the discomfort and inconvenience of subcutaneous administration, vitamin K antagonists (warfarin in particular) remain the treatment of choice for most patients.

Vitamin K antagonists can be started early in the course of VTE treatment, often on the same day as parenteral therapy. Parenteral anticoagulation is typically continued for a minimum of 5 days and until the International Normalized Ratio (INR) is greater than 2.0 for at least 24 hours. The recommended therapeutic INR range for the duration of long-term treatment is 2.0 to 3.0.

Rivaroxaban is a safe and effective therapeutic option for long-term as well as acute treatment of VTE (discussed above). Another option for long-term use is dabigatran, a direct thrombin inhibitor. Like rivaroxaban, dabigatran is well absorbed orally. An advantage of both rivaroxaban and dabigatran is their pharmacokinetic consistency, which alleviates the need for drug monitoring such as the INR monitoring necessary with warfarin. However, there are some important differences between the two. Dabigatran is not used for the acute phase of VTE treatment, but exclusively for long-term treatment. In healthy volunteers, rivaroxaban could be reversed with prothrombin complex concentrate (a human-plasma-derived intravenous product with high concentrations of thrombin, factor X, factor VII, and factor IX). Dabigatran appears not to be reversed by prothrombin complex concentrate, but it may be removed by hemodialysis. However, clinical experience with reversing either agent during therapy is lacking.

The appropriate type and duration of long-term anticoagulation therapy should be tailored to the clinical situation. Patients at high risk for recurrence, characterized by having unresolved or ongoing risk factors for VTE, are likely to require prolonged (possibly lifelong) anticoagulation. Biological phenomena such as deficiencies in antithrombin, protein C, and protein S, as well as the antiphospholipid syndrome, strongly predispose VTE patients to recurrence. Clinical risk factors include immobility, heart failure, persistent venous obstruction, and malignancy. On the other end of the spectrum are patients with VTE because of transient risk factors. Those patients require no more than 3 months of therapy, provided that the original risk factor(s) have subsided (e.g., the broken leg has healed and the patient is fully ambulatory). Patients with VTE that was not provoked by transient risk factors have moderately high rates of recurrence, perhaps because of uncharacterized risk factors. After 3 to 6 months of long-term anticoagulation appropriate for nearly all patients with VTE, those with unprovoked VTE may benefit from longer or even life-long therapy. Although various algorithms and testing strategies appear promising, the duration of therapy for unprovoked VTE is best individualized to the patient’s particular risks of recurrence and bleeding.

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