Clotting Factors Similar in Reversing Vitamin K Antagonist

Daniel M. Keller, PhD

November 06, 2014

ISTANBUL, Turkey — For patients who experienced an acute intracerebral hemorrhage (ICH) while receiving a vitamin K antagonist (VKA), treatment with any clotting factor replacement was associated with reducing the risk for death by more than half, a new retrospective analysis shows.

"There's no significant difference between PCC [prothrombin complex concentrate] and FFP [fresh frozen plasma] in our cohort," Adrian Parry-Jones, MD, PhD, consultant neurologist at the University of Manchester, United Kingdom, and the Salford Royal NHS Foundation Trust, told delegates here at the 9th World Stroke Congress (WSC).

The observational analysis used pooled data from multiple stroke registries. Although 10% to 20% of patients with ICH are taking VKAs, little evidence has been available to guide practice for reversing the drugs' effects in the acute setting.

VKA therapy presents an increased risk for hematoma expansion and death in the setting of ICH, necessitating urgent reversal of the anticoagulant effect. Several smaller, individual studies have examined the problem, but Dr Parry-Jones and coworkers consolidated the data to test for associations between VKA reversal strategies and survival, adjusting for key prognostic factors.

They pooled data from 16 registries in nine countries according to a prespecified protocol. Cases occurred between 1993 and 2014, with 91% from 2004 to 2013. The final analysis included 1300 patients. Of these, 27% received no VKA reversal; 39%, PCC; 25%, FFP; and 9%, both PCC and FFP. Of those receiving PCC, 19% got three-factor and 81% got four-factor PCC. The primary outcome was all-cause mortality by 30 days.

All patients included in the analysis had initial brain imaging within 24 hours of ICH onset and an international normalized ratio (INR) of 1.3 or greater.

At baseline, the groups had average patient ages of 76 to 78 years, 51% to 65% were male, and INRs were 2.9 to 3.0. Of note, the group that received no VKA reversal had a lower Glasgow coma scale (GCS) score compared with the other groups (10 vs 13 to 14), more patients with intraventricular extension (58% vs 42% to 51%), less acute intracranial surgery (3% vs 10% to 18%), and less vitamin K administration (33% vs 74% to 95%).

Any Clotting Factor Better Than None

After adjustment for baseline age, sex, ICH volume, infratentorial location, ventricular extension, INR, and GCS score, "the patients who received no reversal therapy did much worse. We used the combination therapy as a reference in this model, and the hazard ratio is 3.44 in this group," Dr Parry-Jones said.

"The patients receiving FFP and PCC were very similar in terms of survival, and there's a trend towards increased risk of death in both of these groups relative to combination therapy, and this didn't reach statistical significance," he added.

Table. 30-Day Survival by Clotting Factor

Clotting Factor Hazard Ratio (95% Confidence Interval) P Value
FFP + PCC (n = 113) 1.0 (reference)
FFP (n = 321) 1.36 (0.94 - 1.96) .10
PCC (n = 510) 1.40 (0.98 - 2.00) .07
None (n = 356) 3.44 (2.43 - 4.89) <.001


"We found that three-factor PCC was associated with a lower risk of death than four-factor PCC, and we found a trend towards improved outcome with PCC and FFP combined," Dr Parry-Jones reported. With three-factor PCC used as a reference (n = 96), four-factor PCC (n = 414) had a hazard ratio of 1.59 (95% confidence interval, 1.08 - 2.33; P = .019).

No prespecified subgroup based on age, ICH volume, INR, GCS score, onset to treatment time, or intracranial surgery favored PCC administration over the combination of FFP + PCC.

The researchers concluded from this analysis of at least four times as many cases as in any previous report that any clotting factor replacement reduced the adjusted risk for death at 30 days by more than half. A combination of FFP + PCC to reverse VKA showed a trend toward improved 30-day survival, but there was no significant difference between the individual preparations.

Limitations of the study are that it was observational, so treatment choices were not randomized but were dictated by physician and patient preference. Dr Parry-Jones noted that there was "considerable practice variation internationally" and that "centers tended to prefer a certain treatment."

Outcomes may also have been influenced by the quality of overall stroke care rendered at each center, but in a propensity-matched analysis, results were similar to those in the other analyses, lessening the possibility that levels of care differed among the centers.

Hidden covariates or ones not measured may have influenced the outcomes. There were also no data on functional outcomes, so it is unknown whether survival was at the expense of severe disability. Dr Parry-Jones suggested a need for head-to-head, randomized, controlled trials on clotting factor replacement for VKA reversal.

Heterogeneity of Data?

Session moderator Thorsten Steiner, MD, PhD, professor of neurology and neurointensive care at the University of Heidelberg, Germany, commented to Medscape Medical News that the most interesting finding of the study "is that they found that there is no difference between FFP and PCC. A reason for this may or may not be the heterogeneity of data, but we'll see."

These results are in line with current recommendations, which say to give either one of the clotting factor preparations or possibly the combination, he noted.

The speed at which INR becomes normalized and the volume of fluid administered for each clotting factor preparation may have some influence.

"If you give PCC, you have a normalization of the INR within 2 minutes," Dr Steiner said. "If you give FFP, you have the problem of administering a lot of volume if you want to have the same effect, and it's a question whether patients will tolerate that much volume." FFP administration requires 2 to 3 L of fluid and may take 2 to 30 minutes if the patient can tolerate that much fluid at all.

Dr Steiner pointed out that the main limitations of the study are its retrospective nature and the heterogeneity of the data.

Coinvestigator Charlotte Cordonnier, MD, PhD, professor of neurology and head of stroke intensive care at the University of Lille Hospital in France, responded that the study "helps us to have a stronger argument to say we have to randomize because we don't know which treatment is the best."

When asked by Medscape Medical News whether she and her coworkers have such a study in the works, she said they are waiting to see what Dr Steiner finds. He is conducting such a prospective trial comparing FFP and PCC.

Dr Parry-Jones, Dr Steiner, and Dr Cordonnier reported no financial conflicts of interest. Dr Steiner was not involved in the study.

9th World Stroke Congress. Session FC04 (No abstract number). Presented October 24, 2014.


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