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

Abstract

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 À6%. 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% (n¼69 of 79) in fixed compared to 89.9% (n¼71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval À13.3 to 7.9%, P¼.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P¼.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P¼1.0). 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. [

Coagulopathy management of multiple injured patients – a comprehensive literature review of the European guideline 2019

“…Recent studies focused on comparing fixed- and variable-dose protocols in atraumatic bleedings. Overall, weight-dependent variable-dosage protocols were superior to fixed-dosage protocols ( 128 , 129 ), but door-to-needle time was shorter in fixed-dose protocols ( 129 ). When PCC is not available, FFP can be used as an alternative.…”

Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis

“…1 ; and Supplementary Table 2 , http://links.lww.com/CCM/H489 ). Three studies were prospective RCTs ( 8 – 10 ), one was a prospective cohort of both treatment regimens ( 29 ), two were prospective cohorts treated with a fixed-dose regimen compared with historical data ( 28 , 38 ), and the remainder were retrospective studies ( 13 , 14 , 16 , 17 , 25 – 27 , 30 , 32 , 34 , 39 – 41 ). All studies were conducted in the United States or The Netherlands.…”

“…Given the heterogeneity of reported goal INRs, we pooled INR targets into INR less than 2 and INR less than 1.5. Additionally, four studies ( 10 , 14 , 16 , 17 ) evaluated the efficacy outcome of “clinical hemostasis,” which was defined as the absence of major bleeding criteria as set by the International Society on Thrombosis and Hemostasis ( 18 ). Lower INR targets were not included in our analysis.…”

“…Meta-analyses were conducted using the meta-package in R (http://CRAN.R-project.org/package=meta). For studies where continuous variables were reported as median and interquartile range (9,(25)(26)(27), or median and range (10,(28)(29)(30), conversion to mean and sd was performed using the methods described by Wan et al (31). In cases where continuous variables were presented as mean and 95% CI, the sd was computed using the Cochrane methodology as follows: sd = √n × (upper limit-lower limit)/4.128, where n represents the sample size (32,33).…”

“…The 2020 American College of Cardiology Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants recommended reversal of VKAs with 4-PCC using either a fixed-dose regimen (1000-1500 international unit [IU]) or a manufacturer-recommended variable-dose regimen based on a patient's weight and international normalized ratio (INR). Other fixed-dose regimens ranging from 1000 to 2500 IU have been proposed, with inconsistent outcomes (8)(9)(10).…”