Michael P. Gulseth

Rivaroxaban : An oral direct inhibitor of factor Xa

PURPOSE The mechanism of action, pharmacodynamics, pharmacokinetics, efficacy in clinical trials, interactions, adverse effects and toxicity, and place in therapy of rivaroxaban are reviewed. SUMMARY Rivaroxaban, the first oral, direct factor Xa (FXa) inhibitor to reach Phase III trials, inhibits thrombin generation by both the intrinsic and the tissue factor pathways. It has shown predictable, reversible inhibition of FXa activity, and it may have the ability to inhibit clot-bound FXa. Rivaroxaban is being evaluated for prevention of venous thrombosis in patients undergoing hip or knee arthroplasty, treatment of venous thrombosis, long-term use for secondary prevention of venous thrombosis, and prevention of stroke in atrial fibrillation. To date, only short-term trials have been reported, but rivaroxabans safety and efficacy appear to be at least equivalent to those of traditional anticoagulants. The results of four studies of primary prevention of venous thrombosis in patients undergoing orthopedic surgery suggest that rivaroxaban 10 mg daily is a promising alternative to low-molecular-weight heparins. Rivaroxaban appears to have a low potential for drug-drug or drug-food interactions. It offers the advantages of a fixed oral dose, rapid onset of action, and predictable and consistent anticoagulation effect, precluding the need for routine monitoring of anticoagulation. CONCLUSION Rivaroxaban is a promising alternative to traditional anticoagulants for the prevention and treatment of venous thromboembolism and for stroke prevention in atrial fibrillation; it offers once-daily oral administration without the need for routine monitoring.

Pharmacogenomics of warfarin: Uncovering a piece of the warfarin mystery

PURPOSE The literature on the pharmacogenomics of warfarin and the use of genetic testing to optimize initial and maintenance warfarin dosing is reviewed. SUMMARY Warfarin tablets contain a racemic mixture of R- and S-isomers. The S-isomer is responsible for about 70% of warfarins anticoagulant effect. Cytochrome P-450 isoenzyme 2C9 (CYP2C9) metabolizes S-warfarin into two inactive metabolites. Genetic variations to the gene encoding CYP2C9 (CYP2C9 ) are known to affect warfarin clearance. Single nucleotide polymorphisms (SNPs) have been identified that clearly influence warfarin metabolism and sensitivity, including SNP variants of CYP2C9 and SNPs in vitamin K epoxide reductase complex subunit 1 (VKORC1), which influence an individuals sensitivity to a given dose. Retrospective studies have evaluated potential factors influencing warfarin metabolism, maintenance dosing, and variability. Several dosing models used to predict warfarin dosing (initial or refinement) have been retrospectively evaluated in diverse patient populations. There are several arguments to support incorporating its use in current clinical practice; however, many expert clinicians in anticoagulation have expressed concern that the push for genotyping patients for CYP2C9 and VKORC1 is premature and not based on good, prospective evidence. Large, randomized controlled trials, in multiple patient populations, comparing clinical dosing to genetic-guided dosing are needed to fully determine the benefits of pharmacogenetic warfarin dosing. CONCLUSION The increased understanding of pharmacogenomics may improve patient safety during initial dosing of warfarin. At this time, it is unknown if genotype-based dosing will become the standard of care for patients receiving the drug.

High-dose argatroban for treatment of heparin-induced thrombocytopenia with thrombosis: a case report and review of laboratory considerations.

PURPOSE A case report describing high-dose argatroban for the treatment of heparin-induced thrombocytopenia (HIT) with thrombosis and associated considerations in interpreting laboratory monitoring data are presented. SUMMARY A 51-year-old woman with an extensive history of coronary artery disease arrived at the emergency department with complaints of chest pain. The patient was admitted, and coronary artery bypass graft surgery was ultimately performed. The patient had a baseline platelet count of 177,000 cells/μL. During hospitalization, the patient received heparin, and her platelet count dropped to 12,000 cells/μL 13 days after the initiation of heparin. The patient developed swelling around a peripherally inserted central catheter and later developed deep vein thrombosis. An argatroban infusion of 2 μg/kg/min was initiated, with a target activated partial thromboplastin time (aPTT) of 40-80 seconds. After 5 days of therapy, the patient had increased swelling in her right arm and an aPTT of 56 seconds. Her goal aPTT was subsequently increased. Six days later, the patient developed a left-lower-extremity DVT despite aPTTs within the goal range. A new aPTT target of >75 seconds was set. The infusion rate was increased to 15.5 μg/kg/min to attain the target aPTT. Results of an in vitro test led to an alternative interpretation of aPTT and International Normalized Ratio values that aided in the monitoring of argatroban during the high-dose infusion. CONCLUSION A patient with HIT with thrombosis was successfully treated with unusually high dosages of argatroban and may have had serum argatroban concentrations exceeding what has commonly been thought to be the therapeutic range.

Effects of requiring a baseline International Normalized Ratio for inpatients treated with warfarin

Ensuring the safety of anticoagulation continues to challenge the health care community and has led to the new Joint Commission national patient safety goals. [1][1]– [4][2] In response to this focus and to improve patient care, Sanford USD Medical Center initiated a new policy requiring baseline