Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial

Department of Haematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: r.a.abdoellakhan@umcg.nl. Department of Pharmacy, OLVG, Amsterdam, the Netherlands. Department of Emergency Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Department of Emergency Medicine, Medical Center Leeuwarden, Leeuwarden, the Netherlands. Department of Haematology, Rode Kruis Ziekenhuis, Beverwijk, the Netherlands. Department of Haematology, Hagaziekenhuis, The Hague, the Netherlands. Department of Haematology, Maxima Medisch Centrum, Eindhoven, the Netherlands. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Department of Haematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Annals of Emergency Medicine. 2022;79(1):20-30
Abstract
STUDY OBJECTIVE To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation. METHODS In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than -6%. When estimating sample size, we assumed that fixed dosing would be 4% superior. RESULTS From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval -13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0). CONCLUSION The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.
Study details
Language : eng
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