Parenteral direct thrombin inhibitors (DTI), such as bivalirudin, have been used for more than a decade in the hospital setting. Over the past few years, new DTIs have received US Food and Drug Administration (FDA) approval, most notably dabigatran etexilate, an orally active DTI touted as a viable alternative for anticoagulation in patients previously taking warfarin or enoxaparin. In addition to the DTIs, oral factor Xa (FXa) inhibitors have also received FDA approval. As these drugs begin to appear on the medication lists of many patients in the ED, a review—especially of the newer, oral agents—is essential. This article provides an overview of the parenteral DTIs and oral DTI dabigatran etexilate, as well as the oral FXa inhibitors, with a focus on proper monitoring of anticoagulation and common problems encountered in patients taking these medications.
Parenteral Direct Thrombin Inhibitors
Hirudin
Hirudin, a bivalent DTI, was the first parenteral anticoagulant of its kind approved for use in humans.1 Commercially available analogs, including lepirudin, bivalirudin, and desirudin, have since become available. Anticoagulation in patients taking hirudin can be monitored effectively in the ED via activated partial thromboplastin time (aPTT).2 However, there are significant disadvantages to its use, including high cost, lack of a reversal agent, and the potential development of antibodies to hirudin and its derivatives. In addition, since anaphylactoid reactions have been reported, current recommendations contraindicate its use in patients previously treated with hirudin derivatives.3
Lepirudin
Lepirudin is a hirudin analog derived from yeast cells, and is ideal for patients with heparin-induced thrombocytopenia (HIT). With respect to thromboembolic complications in patients with a previous history of HIT, Greinacher et al,4 demonstrated its relative safety and effectiveness. Their study showed a significant reduction in thromboembolic complications per patient day from 6.1% to 1.3%.4 Bleeding events in study participants occurred at an increased rate compared to controls, but these events were greatly decreased when aPTT levels were maintained between 1.5 to 2.5-fold above baseline.4 Since lepirudin is renally excreted and no reversal agent currently exists, clinicians must use caution when administering it to patients with renal insufficiency.
Bivalirudin
Bivalirudin is another hirudin analog and has an important niche among patients requiring percutaneous coronary intervention, primarily due to its favorable pharmacokinetic profile. In contrast to other DTIs, bivalirudin does not undergo organ-specific clearance, but rather proteolysis—an excellent option for patients with other comorbidities. Additionally, its short half-life of 25 minutes makes it an appropriate choice in cases warranting only a brief period of anticoagulation.5
Argatroban
Argatroban, another parenteral DTI, differs from hirudin, lepirudin, and bivalirudin in that it is a univalent molecule. Anticoagulation is monitored by aPTT, though dose-dependent changes may be seen in prothrombin time (PT). Since argatroban undergoes hepatic clearance, dose adjustments are required in patients with hepatic dysfunction—but not in those with renal insufficiency.6 Similar to lepirudin, argatroban is also indicated for patients with a history of HIT. In recent studies, argatroban achieved patency more frequently than heparin in patients with acute myocardial infarction—without differences in clinical outcomes.7
Dabigatran Etexilate
With the increased number of patients presenting to the ED with venous and arterial thromboembolic disorders, emergency physicians should be familiar with the orally active prodrug, dabigatran. This DTI is taken twice daily and converts to it active form after administration, binding to thrombin with great specificity and affinity.8 Its half-life ranges from 12 to 24 hours in patients with normal renal function; reduced dosing schedules are recommended in patients older than age 75 years and in those with renal impairment. Dabigatran is contraindicated if creatinine clearance is less than 30 mL/min. Even though dabigatran is not cleared by the cytochrome P450 system, it does utilize the P-glycoprotein efflux transporter and is thus vulnerable to both inducers and inhibitors, including systemic antifungals and other medications.9
Monitoring Anticoagulation
Unlike warfarin, dabigatran does not require extensive monitoring. However, thrombin and aPPT assays are often less predictable at supertherapeutic levels of dabigatran, and results vary depending on last administration time of the drug.10 Strangier et al11 identified some weaknesses in aPTT measurement, concluding that while measurement of aPTT may provide a qualitative indication of anticoagulant activity, it is not suitable for the precise quantification of anticoagulant effect—especially at high plasma concentrations of dabigatran.11 Furthermore, since PT time is not significantly affected by DTIs, this assay is a poor monitoring choice for these medications.12
The thrombin time (TT) assay test, which is usually accessible in routine clinical practice, directly assesses thrombin activity, providing a direct measure of dabigatran concentration. The TT is particularly sensitive to the effects of dabigatran and displays a linear dose-response even at supratherapeutic concentrations, making it the most useful and sensitive method for determining the anticoagulation effect of dabigatran.13