Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists—The PROPER3 Randomized Clinical Trial - 20/12/21

Doi : 10.1016/j.annemergmed.2021.06.016

Rahat A. Abdoellakhan, PharmD ^a,^⁎ , Nakisa Khorsand, PharmD, PhD ^b, Ewoud ter Avest, MD, PhD ^c, Heleen Lameijer, MD, PhD ^d, Laura M. Faber, MD, PhD ^e, Paula F. Ypma, MD, PhD ^f, Laurens Nieuwenhuizen, MD, PhD ^g, Nic J.G. M. Veeger, PhD ^h, Karina Meijer, MD, PhD ^a
^a Department of Haematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
^b Department of Pharmacy, OLVG, Amsterdam, the Netherlands
^c Department of Emergency Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
^d Department of Emergency Medicine, Medical Center Leeuwarden, Leeuwarden, the Netherlands
^e Department of Haematology, Rode Kruis Ziekenhuis, Beverwijk, the Netherlands
^f Department of Haematology, Hagaziekenhuis, The Hague, the Netherlands
^g Department of Haematology, Maxima Medisch Centrum, Eindhoven, the Netherlands
^h Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

^∗Corresponding Author.

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.

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Plan

Introduction

Methods

Study Design and Setting

Selection of Patients

Intervention

Methods of Measures

Primary Data Analysis

Results

Characteristics of Study Subjects

Main Results

Limitations

Discussion

	Please see page 21 for the Editor’s Capsule Summary of this article.
	Supervising editor: Allan B. Wolfson, MD. Specific detailed information about possible conflict of interest for individual editors is available at editors.
	Author contributions: RA, NK, NV, and KM conceived the study, designed the trial, and obtained research funding. RA, NK, and KM supervised the conduct of the trial and data collection. ETA, HL, LF, PY, LM, NK, and KM undertook recruitment of participating centers and patients and managed the data, including quality control. NV provided statistical advice on study design and analyzed the data; RA, NK, and KM were responsible for drafting the article. All authors were responsible for interpretation of data, revising the article, and reading and final approval of the final article. KM takes responsibility for the paper as a whole.
	Authorship: All authors attest to meeting the 4 ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
	Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. The PROPER research group was sponsored by an unrestricted grant from Sanquin Plasma Products NV, the Netherlands. The funder had no role or involvement in any way in this study or manuscript. Prof. Meijer reports grants from Sanquin Bloodbank during the conduct of the study; outside the submitted work grants and speaker fees from Bayer, grants from Sanquin and Pfizer; speaker fees from Boehringer Ingelheim, BMS, and Aspen; and consulting fees from Uniqure are reported. Drs Abdoellakhan, Khorsand, ter Avest, Lameijer, Faber, Ypma, Nieuwenhuizen, and Veeger have nothing to disclose.
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	Trial registration number: 2014-000392-33 (EU-CTR Identifier).
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