Current and emerging strategies in the management of venous thromboembolism: benefit-risk assessment of dabigatran.

Venous thromboembolism (VTE) is a disease state that carries significant morbidity and mortality, and is a known cause of preventable death in hospitalized and orthopedic surgical patients. There are many identifiable risk factors for VTE, yet up to half of VTE incident cases have no identifiable risk factor and carry a high likelihood of recurrence, which may warrant extended therapy. For many years, parenteral unfractionated heparin, low-molecular weight heparin, fondaparinux, and oral vitamin K antagonists (VKAs) have been the standard of care in VTE management. However, limitations in current drug therapy options have led to suboptimal treatment, so there has been a need for rapid-onset, fixed-dosing novel oral anticoagulants in both VTE treatment and prophylaxis. Oral VKAs have historically been challenging to use in clinical practice, with their narrow therapeutic range, unpredictable dose responsiveness, and many drug-drug and drug-food interactions. As such, there has also been a need for novel anticoagulant therapies with fewer limitations, which has recently been met. Dabigatran etexilate is a fixed-dose oral direct thrombin inhibitor available for use in acute and extended treatment of VTE, as well as prophylaxis in high-risk orthopedic surgical patients. In this review, the risks and overall benefits of dabigatran in VTE management are addressed, with special emphasis on clinical trial data and their application to general clinical practice and special patient populations. Current and emerging therapies in the management of VTE and monitoring of dabigatran anticoagulant-effect reversal are also discussed.

Evaluating and assessing dabigatran drug interactions.

Dabigatran is a novel oral direct thrombin inhibitor that has been shown to have beneficial outcomes in the prevention of thromboembolic stroke in patients with atrial fibrillation. Its advantages compared with warfarin may include decreased laboratory monitoring (e.g., international normalized ratio), minimal cytochrome P450 drug interactions, lack of dietary interactions, and faster onset of action. However, dabigatran is still associated with drug interactions, as will be reviewed through a patient case. Consultant pharmacists should carefully review a patient&s medication profile and evaluate the pros and cons of dabigatran therapy as its use becomes more prevalent.

Nucleic acid aptamers for target validation and therapeutic applications.

In the simplest view, aptamers can be thought of as nucleic acid analogs to antibodies. They are able to bind specifically to proteins, and, in many cases, that binding leads to a modulation of protein activity. New aptamers are rapidly generated through the SELEX (Systematic Evolution of Ligands by Exponential enrichment) process and have a very high target affinity and specificity (picomoles to nanomoles). Furthermore, aptamers composed of modified nucleotides have a long in vivo half-life (hours to days), are nontoxic and nonimmunogenic, and are easily produced using standard nucleic acid synthesis methods. These properties make aptamers ideal for target validation and as a new class of therapeutics. As a target validation tool, aptamers provide important information that complements that provided by other methods. For example, siRNA is widely used to demonstrate that protein knock-out in a cellular assay can lead to a biological effect. Aptamers extend that information by showing that the dose-dependent modulation of protein activity can be used to derive a therapeutic benefit. That is, aptamers can be used to demonstrate that the protein is a good target for drug development. As a new class of therapeutics, aptamers bridge the gap between small molecules and biologics. Like biologics, biologically active aptamers are rapidly discovered, have no class-specific toxicity, and are adept at disrupting protein-protein interaction. Like small molecules, aptamers can be rationally engineered and optimized, are nonimmunogenic, and are produced by scalable chemical procedures at moderate cost. As such, aptamers are emerging as an important source of new therapeutic molecules.

Direct thrombin inhibitors.

Bivalent direct thrombin inhibitors reduce ischemic risk compared to heparin. Results from randomized, double-blind clinical trials have demonstrated that bivalirudin is superior to heparin alone and as effective as heparin plus routine glycoprotein (GP) IIb/IIIa therapy for the prevention of ischemic events with a statistically significant reduction in the rate of in-hospital major bleeding.

Bivalirudin: a direct thrombin inhibitor.

BACKGROUND: Studies of the anticoagulant effects of hirudin, which is derived from the saliva of the leech Hirudo medicinalis, led to the development of compounds that can directly inhibit thrombin activity without the need for additional cofactors. One of these is the direct thrombin inhibitor bivalirudin, which has recently been approved by the US Food and Drug Administration for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. OBJECTIVE: This is a review of the pharmacologic properties, efficacy, tolerability, and potential cost-effectiveness of bivalirudin in the treatment of ischemic coronary syndromes. METHODS: Articles were identified by searches of MEDLINE (1966-September 2001), International Pharmaceutical Abstracts (1970-September 2001), and the Iowa Drug Information Service (1966-September 2001) using the terms bivalirudin and Hirulog. The reference lists of retrieved articles were also reviewed for relevant articles. RESULTS: Bivalirudin is a synthetic polypeptide that directly inhibits thrombin by binding simultaneously to its active catalytic site and its substrate recognition site. After intravenous administration, peak plasma concentrations occur in 2 minutes. In patients given a 1.0-mg/kg bolus followed by a 2.5-mg/kg per hour infusion, a median activated clotting time of 346 seconds is achieved with little interpatient or intrapatient variability. Clearance of bivalirudin occurs through a combination of renal elimination and proteolytic cleavage, and doses may need to be decreased in the presence of renal dysfunction. In patients undergoing percutaneous coronary interventions, bivalirudin has been associated with equivalent efficacy but lower bleeding rates (P < 0.001) than unfractionated heparin (UFH). Data from the Hirulog Early Reperfusion/Occlusion-2 study suggest no reduction in mortality with bivalirudin compared with heparin when either is added to aspirin and streptokinase in patients with acute myocardial infarction, despite a lower reinfarction rate (P < 0.001). Experience with bivalirudin in patients with unstable angina and heparin-induced thrombocytopenia (HIT), as well as in patients receiving glycoprotein IIb/IIIla inhibitors, is limited. The differences in bleeding rates between bivalirudin and heparin in published clinical trials probably reflect differences in levels of anticoagulation achieved in comparator groups. CONCLUSIONS: Given its high cost, bivalirudin should be reserved for use as an alternative to UFH, primarily in patients with HIT, until clinical trials have more clearly demonstrated its benefits in terms of efficacy or safety.

Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban.

Argatroban, a direct thrombin inhibitor, is metabolized in vitro by CYP3A4/5 and therefore may be susceptible to clinically relevant CYP3A drug interactions. The effect of erythromycin, a potent CYP3A4/5 inhibitor, on the pharmacokinetics and pharmacodynamics of argatroban was evaluated in 14 healthy male volunteers in an open-label, crossover study with a 5-day washout between regimens. Argatroban 1 microgram/kg/min was infused alone for 5 hours (regimen A) and again on day 6 of a 7-day oral regimen of 500 mg erythromycin four times daily (regimen B). Serial blood samples for the determination of activated partial thromboplastin time (aPTT) and argatroban concentrations were collected for up to 48 hours following infusion. Mean values for argatroban area under the concentration-time curves (AUC0-inf), maximum concentration (Cmax), and half-life (t1/2) were similar between regimens. Mean aPTT values were not affected significantly by the concomitant administration of argatroban and erythromycin compared to argatroban alone. No serious adverse events or bleeding episodes occurred during the study. These results suggest that oxidative metabolism by CYP3A4/5 is unlikely to be an important in vivo elimination pathway for argatroban. Therefore, coadministration of CYP3A4/5 inhibitors should not require a modification in the dosage of argatroban.