Fran Lowry

March 03, 2016

ORLANDO, Florida — Warfarin-induced coagulopathy is reversed faster with a weight-based factor VIII inhibitor bypassing activity regimen than with fresh frozen plasma, according to new research.

"Patients who presented to our institution with life-threatening bleeds who were on warfarin prior to admission and who were treated with a weight-based activated prothrombin complex concentrate achieved reversal of their international normalized ratio [INR] significantly faster than patients who received fresh frozen plasma only," said lead investigator Elizabeth Messana, PharmD, from the Detroit Medical Center Detroit Receiving Hospital.

"Moreover, there were no differences in rates of thromboembolic events between the two groups," she reported here at the Society of Critical Care Medicine's 45th Critical Care Congress.

Previous studies have suggested that a fixed-dose regimen of activated prothrombin complex concentrate factor VIII inhibitor bypassing activity is effective for the reversal of warfarin-induced life-threatening bleeding; "however, there are few data out there to support a weight-based dosing regimen," Dr Messana told Medscape Medical News.

Dr Elizabeth Messana

"We use a weight-based dosing regimen based on studies from similar prothrombin complex concentrations, but not factor VIII inhibitor bypassing activity specifically, so we wanted to use the data from our institution to prove that doing so was safe and efficacious for such bleeding," she explained.

Dr Messana and her team performed a matched case–control retrospective analysis of patients with warfarin-induced life-threatening bleeding from January 2009 to June 2015. The patients were matched for age, sex, history of liver disease, and bleed location.

Twenty-seven patients received factor VIII inhibitor bypassing activity and 27 received fresh frozen plasma. The mean dose of factor VIII inhibitor bypassing activity was 4310 units, with a weight-based dose of 54 units/kg. The median use of fresh frozen plasma was 3 units (interquartile range [IQR], 2 - 5), with a volume of 790 mL (IQR, 506 - 1333).

The median baseline INR was 3.7 (IQR, 2.7 - 7.30) in patients who received factor VIII inhibitor bypassing activity and 2.8 (IQR, 2.3 - 5.9) in those who received fresh frozen plasma (P = .13).

Vitamin K was administered to fewer patients treated with factor VIII inhibitor bypassing activity than with fresh frozen plasma (81% vs 93%; P = .42).

The rate of INRs below 1.5 was similar in patients who received factor VIII inhibitor bypassing activity and in those who received fresh frozen plasma (89% vs 85%; P = 1.0).

The median time to achieve an INR below 1.5 — the primary end point — was significantly faster with factor VIII inhibitor bypassing activity than with fresh frozen plasma (2.4 vs 12.0 hours; P < .0001).

The number of thromboembolic events, a secondary end point, was similar with factor VIII inhibitor bypassing activity and fresh frozen plasma (5 vs 4; P = 1.0).

In spite of the shortened time to INR, mortality was not significantly different between factor VIII inhibitor bypassing activity and fresh frozen plasma (33% vs 15%; P = .2).

"Stopping the bleeding sooner in patients with intracranial bleeds could result in those patients having fewer residual deficits because we are protecting the brain tissue as much as possible, although we did not show this," Dr Messana said.

On the basis of these results, "we are going to continue using the weight-based prothrombin complex concentrate," she explained.

Dr Carol Thompson

"Fresh frozen plasma has long been used worldwide for the treatment of high INR, so is somewhat of a standard. It is good to compare new therapies," said Carol Thompson, PhD, from the College of Nursing at the University of Kentucky in Lexington, who comoderated the oral session.

"When there is warfarin-induced life-threatening bleeding, some new agents have been shown to work faster, but they do have risks of blood clots and mortality. Potentially, with some sites of bleeding, such as in hemorrhagic stroke, the risk of mortality rises with time," she told Medscape Medical News.

"A strength of this abstract is that it matched the location of the bleed, as well as age, sex, and history of liver disease. It also provided comparison data with regard to blood clot events and mortality, and it added to our minimal evidence with regard to the use of weight-based-dosed factor VIII inhibitor bypassing activity," Dr Thompson said.

Overall, "this study is useful because it reports there is no greater risk of thromboembolic events or mortality than with the standard of fresh frozen plasma," she explained.

However, "these pilot data warrant a side-to-side comparison of fixed dose and weight-based dosing in future studies," said Dr Thompson.

Dr Douglas Naylor

This "an interesting study," said Douglas Naylor Jr, MD, from The Cleveland Clinic, who comoderated the oral session. However, he pointed out, the number of patients was very small.

He also suggested that the normalization of prothrombin time or INR might not be the right target.

"If INR and partial thromboplastin time were the indicators, there would be a really big push to use them in the perioperative setting. But we have found that many centers are abandoning routinely checking coagulation using those particular functions because they actually have very little bearing on whether the patient bleeds or does not bleed," he explained. "So they are using the wrong target."

"What is very telling, however, is that although weight-based factor VIII inhibitor bypassing activity has a faster time of reversing this coagulopathy based only on the prothrombin time, it doesn't affect mortality. This could be because the sample size is so small that it is insufficiently powered to pick out a change," he pointed out.

Dr Messana, Dr Thompson, and Dr Naylor have disclosed no relevant financial relationships.

Society of Critical Care Medicine's (SCCM) 45th Critical Care Congress: Abstract 53. Presented February 21, 2016.

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