Dr. Garrett is manager, Outpatient Clinical Pharmacy Programs, at Mission Hospitals in Asheville, North Carolina.
Advisory Panel Recommends Approval of Rivaroxaban
An FDA advisory panel voted in late March to recommend that the agency approve rivaroxaban (Xarelto), a joint venture between Bayer Healthcare Pharmaceuticals and Johnson&Johnson (J&J). J&J has applied to the FDA for approval to market the drug for short-term use in preventing deep vein thrombosis and pulmonary embolism in patients undergoing total hip or knee replacement surgery.
The FDA panel said rivaroxaban's benefits in preventing blood clots outweighed the risks of bleeding and possible liver injury. The panel voted 15 to 2 in favor of approval. The vote overrules concerns from the FDA staff members who had said the agency may want to wait for longer-term studies to evaluate increases in bleeding and liver abnormalities seen in rivaroxaban studies. The anticoagulant has demonstrated improved efficacy compared with enoxaparin, but has a nearly 2-fold increased risk for bleeding. A final decision by the FDA was expected in late May.
Warfarin Resistance After Stomach Surgery
A recently published case report describes warfarin resistance in a patient who had undergone gastrectomy and a Roux-en-Y esophagojejunostomy. The patient, a 71-year-old woman, had been stable prior to surgery on a dose of 5 to 6 mg of warfarin daily. After her surgery, she required a dose of 20 mg daily to maintain her international normalized ratio in the range of 2 to 3.
Drug absorption can be affected by the solubility of the drug, surface area available for absorption, and blood flow to the gastrointestinal (GI) tract. Surgical procedures such as gastrectomy reduce the surface area and pH is increased due to less production of stomach acid. Oral warfarin has a reported bioavailability of 100%, but is better absorbed in an acidic environment. The authors’ review of other case reports involving GI surgeries and warfarin resistance offer conflicting opinions regarding the effect of removal of parts of the small intestine or stomach.
The authors concluded that the significant change in the patient’s anatomy was the most likely cause of her warfarin resistance, but could not completely rule out nonadherence or concomitant administration of vitamin K as the cause.
Low-Dose Vitamin K Does Not Affect Bleeding Rates
A study published recently in the Annals of Internal Medicine suggests that administration of low-dose vitamin K has no impact on bleeding and thromboembolism, compared with placebo. Low- dose (1.25 mg) vitamin K or placebo was given to warfarin-treated patients with an international normalized ratio (INR) between 4.5 and 10. Patients were eligible for the study if their most recent INR was between 4.5 and 10 in the past 24 hours, and they were not bleeding. Any bleeding (major, minor, and trivial), major bleeding, and thromboembolic events were no different at 90 days or at 7 days.
The authors acknowledge several limitations of the study, including lack of power to detect major bleeding events, use of a noncommercial formulation of vitamin K, and inability to detect administration of open-label vitamin K from other sources. The study does not mention whether high INRs were confirmed, so laboratory error could not be ruled out as a cause of elevation.
In a commentary on ClotCare (www.clotcare.com), anticoagulation expert Henry Bussey, PharmD, suggests that many clinicians would choose not to give vitamin K to patients with INRs of <6. He also states that the study provides little evidence with which to judge the merits of vitamin K administration for higher INR values (>6, >8, and/or >10) or the effectiveness of a larger dose in tablet form for patients with higher INRs.
The decision to administer vitamin K depends largely on the presence of bleeding and additional risk factors that may make bleeding more likely, and the magnitude of the INR elevation. In the absence of bleeding and other risk factors, it appears from this study that withholding warfarin therapy may be a suitable option for patients with INRs of <10.