What Is the Evidence for the Off-label Use of Recombinant Factor VIIa (rFVIIa) in the Acute Reversal of Warfarin?

Abstract

A 47-year-old man presents with hypovolemic shock. He takes warfarin as a result of a mechanical mitral valve insertion 5 years prior, his INR at presentation is 8.4 and emergent CT reveals a very large retroperitoneal hematoma. Despite aggressive fluid and transfusion support he continues hypotensive, requiring ionotrope support. You are asked if he should receive recombinant factor VIIa.To examine current best evidence of the effect of recombinant factor VIIa (rFVIIa) on the reversal of warfarin-induced coagulopathy, we performed a comprehensive computerized literature search of the OVID database using the terms warfarin (MESH, no restrictions, 13764 hits), AND recombinant factor VIIa (MESH, including factor VII, factor VIIa, and recombinant FVIIa, 5928 hits), AND reversal (MESH, no restrictions, 39639 hits) OR correction (MESH, no restrictions, 72783 hits) between 1950 and week 2 May 2008. This strategy provided 22 hits. There were 4 additional studies gleaned from the reference list of 2 of the articles. 1-4 Twelve papers were excluded: 7 were review articles, 5-11 3 described effects of clotting factor concentrates or vitamin K and not rFVIIa, 12-14 1 compared the in vitro antifibrinolytic activity of prothrombin complex concentrates to rFVIIa, 15 and 1 was a case report of rFVIIa in a phenindione overdose. 16 Five case series, 5 case reports, 1 retrospective casecontrol, 1 retrospective chart review, and 1 database review were retrieved. There was also 1 study involving healthy volunteers that included a dose finding study followed by a randomized controlled trial.The randomized double-blind placebo controlled trial was a pharmacokinetic-pharmacodynamic study of 28 healthy volunteers given acenocoumarol followed by rFVIIa (doses ranging from 5 to 320 μg/kg). The dose finding aspect of the study revealed that a single dose of 5 μg/kg normalized the INR for 12 hours and doses >120 μg/kg normalized the INR for 24 hours. The placebo had no effect on the INR. 2

How I treat poisoning with vitamin K antagonists

“…There is little evidence to support the use of recombinant factor VIIa for this indication. 30 In the absence of bleeding, a prolonged prothrombin time is not an indication for fresh frozen plasma or frozen plasma. In the bleeding patient, these agents will help to achieve hemostasis and provide time for vitamin K to reverse the effect of the antagonist.…”

How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage

“…93 Finally, the uncertainty on whether the demonstrable effects of rFVIIa on INR correction are accompanied by adequate restoration of thrombin generation compared with PCCs is the cited reason why one guideline has recommended against the routine use of rFVIIa for warfarin reversal in patients with ICH. 23,94 Published reports have indicated effective in vivo hemostasis after administration of rFVIIa in several clinical settings. Jeffers et al 95 randomly assigned 71 patients with liver disease who underwent laparoscopic liver biopsy to receive 1 of 4 doses (5, 20, 80, and 120 g/kg) of rFVIIa given adjuvantly before biopsy.…”

“…94,[99][100][101] In 2005, guidelines that used the Rand/UCLA appropriateness method were developed jointly by the Society for Advancement of Blood Management and the University Hospitals Consortium. 99 The consensus panel agreed that rFVIIa was appropriate for reversal of warfarin anticoagulation in patients with either spontaneous or traumatic intracranial bleeding.…”

Reversal of vitamin K antagonists prior to urgent surgery

“…31 In a review of the available case series and case reports, Rosovsky and Crowther concluded that, while rFVIIa appears to rapidly reverse the abnormal INR, the clinical impact is difficult to ascertain due to small, poorly controlled trials in which conventional therapy, i.e., plasma and vitamin K therapy, was employed concomitantly. 32 An in vitro comparison of the INR reversal with rFVIIa and PCC demonstrated greater clot stability with PCC. This was presumed to be due to the synthesis of thrombinactivatable fibrinolysis inhibitor (TAFI).…”