scholarly journals Randomised controlled trial protocol to evaluate a fixed dose prothrombin complex concentrate against the variable dose in vitamin K antagonist related bleeding (PROPER3)

BMJ Open ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. e020764 ◽  
Author(s):  
Rahat A Abdoellakhan ◽  
Nakisa Khorsand ◽  
Reinier M Van Hest ◽  
Nic Veeger ◽  
Ewoud Ter Avest ◽  
...  
Keyword(s):  
Vitamin K ◽  
Prothrombin Complex Concentrate ◽  
Primary Outcome ◽  
Vitamin K Antagonist ◽  
Fixed Dose ◽  
Patient Specific ◽  
Study Results ◽  
Dosing Strategy ◽  
Randomised Controlled ◽  
Variable Dose

IntroductionThere is currently little evidence for the optimal dosing strategy of four-factor prothrombin complex concentrates (PCC) in vitamin K antagonist (VKA)-related bleeds. The generally accepted dosing strategy is the use of a variable dose calculated using patient-specific characteristics as per manufacturer’s instruction. However, evidence exists that the use of a fixed low dose of 1000 international units of factor IX (IU fIX) might also suffice. Recent studies indicate that in terms of haemostatic effectiveness, the fixed dosing strategy might be even superior to the variable dosing strategy. The PROPER3 (PROthrombin complex concentrate: Prospective Evaluation and Rationalisation, number 3) study aims to confirm the non-inferiority, and explore superiority, in haemostatic effectiveness of the fixed PCC dosing strategy compared with the variable dosing strategy in VKA-related extracranial bleeding emergencies.Methods and analysisThe study is designed as a randomised controlled multicentre non-inferiority trial. Eligibility criteria are an indication for PCC due to VKA-related extracranial bleeding in subjects 18 years of age or older. The control group will receive a variable dose, determined by patient-specific bodyweight and international normalised ratio. The intervention group is dosed a fixed 1000 IU fIX PCC. Primary outcome is the haemostatic effectiveness of both treatments, as defined by the 2016 International Society on Thrombosis and Haemostasis (ISTH) criteria. The sample size is set at 155 patients per treatment arm, requiring 310 patients in total. Non-inferiority on the proportion (risk) difference of the primary outcome will be evaluated using the asymptotic Wald test for non-inferiority. The non-inferiority margin is set at 6%. The primary analysis will be based on the per-protocol population.Ethics and disseminationStudy results will be published in an international journal, communicated to discipline-specific associations and presented at (inter)national meetings and congresses.Trial registration numberEUCTR2014-000392-33; Pre-results.

Safety and effectiveness of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal following a fixed-dose strategy

2020 ◽  
pp. ejhpharm-2019-002114
Author(s):  
Carmen Sobrino Jiménez ◽  
José Antonio Romero-Garrido ◽  
Ángeles García-Martín ◽  
Manuel Quintana-Díaz ◽  
Carlos Jiménez-Vicente ◽  
...  
Keyword(s):  
Vitamin K ◽  
Prothrombin Complex Concentrate ◽  
Vitamin K Antagonist ◽  
Fixed Dose ◽  
Dose Strategy

A Systematic Review On Different Prothrombin Complex Concentrate Strategies To Reverse Vitamin K Antagonist Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3639-3639
Author(s):  
Nakisa Khorsand ◽  
Hilde A.M. Kooistra ◽  
Reinier M. van Hest ◽  
Pharm D ◽  
Nic J.G.M. Veeger ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Outcome ◽  
Quality Assessment ◽  
Vitamin K ◽  
Vitamin K Antagonist ◽  
Factor Ix ◽  
Fixed Dose ◽  
Open Label ◽  
Dosing Strategies ◽  
Dosing Strategy

Abstract Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. The aim of this systematic review is to describe the currently used PCC strategies and to present their efficacy in terms of target INR achievement and clinical outcome. MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency reversal of VKA therapy. Additional inclusion criteria were the reporting of PCC dosing strategy, data on target INR or any clinical outcome or safety parameters, prospective patient enrollment, and a full text publication. All PCC studies in non-VKA patients, case-reports (N<5), duplicates, retrospective studies, and studies on activated PCC were excluded. The quality of selected studies was evaluated using two quality assessment tools which are described by Downs (J Epidemiol Community Health, 1998), and Thomas (McMaster University, 2008). A total of 27 studies was included in which the majority was single cohort (N=18, 67%), open label (N=27, 100%), and/or nonrandomized (N=23, 85%). The total number of included patients was 2410, ranging from 5 to 686 patients per study. One of the included studies was scored as having a strong, 12 a moderate and 14 a weak design. The median quality assessment score was 16 out of 26 [range 10-22]. A large heterogeneity in study parameters was observed including 6 different primary endpoints with 12 different definitions. Fifteen PCC protocols were identified in which the PCC dose ranged from 8 to 50 IU of factor IX/kg or a fixed dose protocol of 200, 500, 1000, or 1500 IU of factor IX/patient. These dosing strategies were based on five principals, namely based on bodyweight (BW), bodyweight and initial INR (BW+INRi), bodyweight and initial INR and target INR (BW+INRi+INRt), individual doctors decision (doctor) or a fixed dose (fixed). The actual infused dosage is depicted in figure 1. Evaluating the used dosing strategy, target INR was reached in 86%, 81%, 78% and 75% of patient in BW, BW+INRi, BW+INRi+INRt and fixed, respectively and was lower (55%) in doctor strategy. Of note, results of the doctor strategy are based on two studies. Clinical outcome was positive for 75%, 93%, 85%, 88% and 67% of patients in strategy BW, BW+INRi, BW+INRi+INRt, fixed, and doctor strategy respectively. Of note, only one study reported on the clinical outcome in the BW+INRi strategy and two in doctor strategy. While our review shows a great diversity on PCC dosing strategies among published data, the same applies to current PCC guidelines in which the ACCP leaves the dosing to the discretion of the physician, the French guidelines recommend a bodyweight adjusted dosing regardless of the INR, the Canadian guidelines recommend three different fixed doses stratified by initial INR, and the Australian guidelines recommend a range of bodyweight adjusted doses from which the physician should decide. Apart from the different dosing strategies, considerable heterogeneity in assessing the impact of PCC treatment was noticed indicating the lack of consensus regarding different aspects of emergency reversal of VKA treatment e.g. optimal target INR, clinical outcome definition. Furthermore, PCC is predominantly studied in small, single-arm and open label settings using the INR to measure its effect rather than clinical outcome. In addition, results from our quality assessment showed that most study designs were at most moderately robust. Evidence gained from the included studies should therefore be interpreted with caution. In conclusion, this review shows that the worst results are reported when a predefined dosing protocol is absent (doctors strategy), while with the use of any treatment protocol good outcome results of PCC treatment are obtained (target INR reached ³ 75%, positive clinical response ³ 75%). A fixed dose strategy seems to be the most simple treatment, with a high potential for optimal clinical outcome while the lowest PCC dosages are infused. Good quality studies with consistent endpoints are needed to guide clinical use. Actual median dose infused in each study(arm). Dots represent the included studies(cohorts) with large, average and small amount of included patients Disclosures: Khorsand: Sanquin BV, Amsterdam: Research Funding.

scholarly journals 759: Fixed-Dose Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracerebral Hemorrhage

2021 ◽  
Vol 50 (1) ◽  
pp. 373-373
Author(s):  
Caroline Kruszecki ◽  
Danielle Mabrey ◽  
Kim Haldeman ◽  
Lindsey Dailey ◽  
Elizabeth Scanlon
Keyword(s):  
Intracerebral Hemorrhage ◽  
Vitamin K ◽  
Prothrombin Complex Concentrate ◽  
Vitamin K Antagonist ◽  
Fixed Dose

Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy

2010 ◽  
Vol 21 (2) ◽  
pp. 116-123 ◽  
Author(s):  
N. Khorsand ◽  
N. J. G. M. Veeger ◽  
M. Muller ◽  
J. W. P. M. Overdiek ◽  
W. Huisman ◽  
...  
Keyword(s):  
Vitamin K ◽  
Prothrombin Complex Concentrate ◽  
Vitamin K Antagonist ◽  
Antagonist Therapy ◽  
Variable Dose

Evaluation of a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal

2021 ◽  
pp. 106002802199214
Author(s):  
Clare McMahon ◽  
Joe Halfpap ◽  
Qianqian Zhao ◽  
Ana Bienvenida ◽  
Anne E. Rose
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Dose Regimen ◽  
Prothrombin Complex Concentrate ◽  
Primary Outcome ◽  
International Normalized Ratio ◽  
Fixed Dose ◽  
Optimal Dosing ◽  
Warfarin Reversal ◽  
Higher Doses

Background: Fixed-dose (FD) regimens of 4-factor prothrombin complex concentrate (4F-PCC) may be effective for the emergent reversal of warfarin; however, the optimal dosing is unknown. Our institution transitioned to a FD regimen of 1000 or 2000 units of 4F-PCC based on indication. Objective: The purpose of this study is to report our experience with FD 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal. Methods: A retrospective analysis was conducted for 3 groups: central nervous system (CNS) bleeds regardless of international normalized ratio (INR), non-CNS bleeds with an initial INR ≤6, and non-CNS bleeds with an initial INR ≥6.1. The primary outcome of the study was achievement of the target INR. Results: There were 54 patients with a CNS bleed, 153 with a non-CNS bleed and INR ≤6, and 19 with a non-CNS bleed and INR ≥6.1. In the CNS bleeding group, weight-based and FD achieved target INR 79.4% and 70% ( P = 0.52). In the INR ≥6.1 non-CNS bleeding group, weight-based and FD achieved target INR 100% and 70% ( P = 0.21). In the INR ≤6 non-CNS bleeding group, weight-based and FD achieved target INR 86.4% and 57.5% ( P = 0.0002). Conclusion and Relevance: An FD strategy of 2000 units for warfarin reversal for CNS bleeds or INR ≥6.1 was comparable to weight-based dosing. The FD strategy of 1000 units for INR ≤6 achieved target INR less often than weight-based dosing. Application of findings suggest that higher doses may be needed to achieve target INR.

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