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

Abstract

Introduction: There 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 analysis: The 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 dissemination: Study results will be published in an international journal, communicated to discipline-specific associations and presented at (inter)national meetings and congresses.

Trial registration number: EUCTR2014-000392-33; Pre-results.

Keywords: anticoagulation.

Figure 1

PCC dose per manufacturer’s instructions. For Cofact (Sanquin), the variable dose is determined using bodyweight, baseline INR and a choice in a preferred target INR of ≤2.1 (A) or ≤1.5 (B). For Beriplex (CSL Behring), the manufacturer’s instructions only provide a dosing algorithm to reach a target INR≤1.3 (C). For both Cofact and Beriplex, 10 mL corresponds to 250 IU fIX. INR, international normalised ratio; IU fIX, international units of factor IX; PCC, prothrombin complex concentrate.

Figure 2

Schematic representation of ISTH proposed definitions for effective haemostasis in management of major bleeding. ISTH, International Society on Thrombosis and Haemostasis.