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Randomised controlled trial protocol to evaluate a fixed dose prothrombin complex concentrate against the variable dose in vitamin K antagonist related bleeding (PROPER3)
  1. Rahat A Abdoellakhan1,
  2. Nakisa Khorsand2,
  3. Reinier M Van Hest3,
  4. Nic Veeger4,
  5. Ewoud Ter Avest5,
  6. Paula F Ypma6,
  7. Laura M Faber7,
  8. Karina Meijer1
  1. 1 Department of Haematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  2. 2 Department of Pharmacy, OLVG, Amsterdam, The Netherlands
  3. 3 Department of Pharmacy, Academical Medical Center, Amsterdam, The Netherlands
  4. 4 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  5. 5 Department of Emergency Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands
  6. 6 Department of Haematology, Hagaziekenhuis, HagaZiekenhuis van Den Haag, The Hague, The Netherlands
  7. 7 Department of Haematology, Rode Kruis Ziekenhuis, Beverwijk, The Netherlands
  1. Correspondence to Dr Rahat A Abdoellakhan; r.a.abdoellakhan{at}umcg.nl

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.

  • anticoagulation

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Footnotes

  • Contributors RAA, NK, RMVH, NV and KM designed the study and RAA, NK and KM are coordinating the study. LMF, PFY and ETA contributed substantially to improvement of protocol and execution. RAA wrote the protocol manuscript under supervision of KM and NK. All other authors commented on previous versions and contributed to the final version.

  • Funding The study group received an unrestricted grant from Sanquin Plasma Products BV (Amsterdam, The Netherlands).

  • Competing interests KM reports grants from Sanquin during the conduct of the study and travel support, speaker fees or consulting fees from Baxter, Bayer, Sanquin, Pfizer, Boehringer Ingelheim, BMS, Aspen and Uniqure outside the submitted work.

  • Patient consent Not required.

  • Ethics approval In accordance with Dutch legislation, central study ethics approval was obtained from the medical ethics committee of University Medical Center Groningen (METc UMCG, registered under 2014/285).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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