Fixed‐Dose Four‐Factor Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal: Does One Dose Fit All?

Abstract

Four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown.Although several studies have attempted to determine the optimal dose of 4F-PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Many of these studies have evaluated a low, fixed dose of 4F-PCC rather than individualized dosing as recommended in product labeling. The purpose of this review was to evaluate the efficacy and safety of various fixed-dose strategies of 4F-PCC for emergent VKA reversal and to assess limitations of the existing literature. A search of the PubMed database was performed from the earliest available date through 2018 for relevant articles describing fixed-dose 4F-PCC for VKA reversal. Reference lists of relevant articles were also manually reviewed. Most currently available studies are primarily observational and heterogeneous in design. A very low fixed dose of 500 IU is likely inadequate for successful VKA reversal, but increased fixed doses of 1000-1500 IU have found some degree of success and may be considered for VKA reversal. However, many of these studies consistently identified a trend toward international normalized ratio (INR) reversal failure in patients presenting with high baseline INR values or intracranial hemorrhage, suggesting that higher 4F-PCC doses are needed in these patients. Available studies are underpowered to determine whether a dose-dependent association with thrombotic risk exists. Additional large, randomized studies are needed to determine the optimal dosing strategy and ascertain the role for fixed-dose 4F-PCC. KEY WORDS prothrombin complex concentrates, warfarin, hemorrhage, hemostasis.

A European consensus statement on the use of four‐factor prothrombin complex concentrate for cardiac and non‐cardiac surgical patients

“…Even before United States Food and Drugs Administration approval, no dose-finding studies had been performed and dosing recommendations in national guidelines vary largely. Authors of recent systematic reviews could not perform a meta-analysis due to heterogeneity [22,23].…”

Efficacy and safety of four-factor prothrombin complex concentrate fixed, weight-based dosing for reversal of warfarin anticoagulation

“…Other studies have also demonstrated the efficacy of fixed, weight-based dosing of 4F-PCC for INR reversal [11][12][13]. Mohrien et al used a fixed, weight-based (30 IU/kg) dosing protocol of 3-factor PCC (3F-PCC) which demonstrated 85.7% reversal of INR to target without significant adverse events.…”

Optimal Dosage and Administration Practices for Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate

“…However, higher doses may be needed to treat ICH or a higher baseline INR. 75 Nevertheless, in the absence of an ideal dose suitable for all, variable dosing per label instructions is preferred by many institutions.…”