Transfusion of fresh frozen plasma in non-bleeding ICU patients -TOPIC TRIAL: study protocol for a randomized controlled trial

Müller et al. Trials 2011, 12:266 http://www.trialsjournal.com/content/12/1/266 STUDY PROTOCOL TRIALS Open Access Transfusion of fresh frozen plasma in nonbleeding ICU patients -TOPIC TRIAL: study protocol for a randomized controlled trial Marcella CA Müller1,2*, Evert de Jonge3, M Sesmu Arbous3, Angelique ME Spoelstra -de Man4, Atilla Karakus5, Margreeth B Vroom1 and Nicole P Juffermans1,2 Abstract Background: Fresh frozen plasma (FFP) is an effective therapy to correct for a deficiency of multiple coagulation factors during bleeding. In past years, use of FFP has increased, in particular in patients on the Intensive Care Unit (ICU), and has expanded to include prophylactic use in patients with a coagulopathy prior to undergoing an invasive procedure. Retrospective studies suggest that prophylactic use of FFP does not prevent bleeding, but carries the risk of transfusion-related morbidity. However, up to 50% of FFP is administered to non-bleeding ICU patients. With the aim to investigate whether prophylactic FFP transfusions to critically ill patients can be safely omitted, a multi-center randomized clinical trial is conducted in ICU patients with a coagulopathy undergoing an invasive procedure. Methods: A non-inferiority, prospective, multicenter randomized open-label, blinded end point evaluation (PROBE) trial. In the intervention group, a prophylactic transfusion of FFP prior to an invasive procedure is omitted compared to transfusion of a fixed dose of 12 ml/kg in the control group. Primary outcome measure is relevant bleeding. Secondary outcome measures are minor bleeding, correction of International Normalized Ratio, onset of acute lung injury, length of ventilation days and length of Intensive Care Unit stay. Discussion: The Transfusion of Fresh Frozen Plasma in non-bleeding ICU patients (TOPIC) trial is the first multicenter randomized controlled trial powered to investigate whether it is safe to withhold FFP transfusion to coagulopathic critically ill patients undergoing an invasive procedure. Trial Registration: Trial registration: Dutch Trial Register NTR2262 and ClinicalTrials.gov: NCT01143909 Keywords: critically ill, transfusion, fresh frozen plasma, acute lung injury, bleeding, randomized clinical trial, TRALI, coagulopathy, INR, prevention Background Fresh frozen plasma (FFP) is an effective therapy to correct for a deficiency of multiple coagulation factors [1]. International guidelines support its use in case of bleeding in patients with such a deficiency [2,3]. Use of FFP has grown steadily in the past years, in particular in the Intensive Care Unit (ICU) [4]. In the last decade, use of FFP has expanded to include prophylactic administration * Correspondence: 1 Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Full list of author information is available at the end of the article of FFP. However, there are concerns about the efficacy of FFP to prevent bleeding. Evidence from randomized controlled trials that support FFP transfusion to correct coagulopathy before an invasive procedure is limited, including commonly performed procedures on the ICU, such as insertion of a central venous catheter, a chest drain or a percutaneous tracheotomy [5]. Moreover, retrospective studies suggest that the risk of bleeding after an invasive procedure is low and relevant bleeding requiring blood transfusion or an intervention is less then 1% [6]. Prophylactic FFP may not further reduce bleeding incidence, but carries the risk of acute lung injury, © 2011 Müller et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Müller et al. Trials 2011, 12:266 http://www.trialsjournal.com/content/12/1/266 Page 2 of 7 occurring in up to 30% of transfused ICU patients [7], resulting in an increased duration of mechanical ventilation and ICU stay [8,9]. However, despite the absence of evidence, in our ICU patients, 33% of plasma is transfused to non-bleeding patients [10], which is in accordance with reports on ICU transfusion practice in Europe and the United States [11,12]. With the aim to investigate whether prophylactic FFP transfusions to critically ill patients can be safely omitted, a multi-center randomized clinical trial is conducted in ICU patients with a coagulopathy undergoing an invasive procedure. Methods/Design Objectives and design The primary objective of the ‘Transfusion of fresh frozen Plasma In non-bleeding Critically ill’ trial (’TOPIC’ trial) is to assess whether omitting prophylactic FFP transfusion is non-inferior to prophylactic FFP transfusion (current practice) to prevent relevant bleeding in ICU patients with a coagulopathy, who are undergoing an invasive procedure. The preferred design to demonstrate the non-inferiority of no FFP transfusion prior to an invasive procedure against FFP transfusion to prevent bleeding would be a double blind, placebo-controlled clinical trial. However, manufacturing a completely matched placebo in full compliance with the current Good Manufacturing Practice standards was not considered possible for this noncommercial, academic study. Therefore, we have chosen for a multicentre prospective, randomized, open-label, blinded end point evaluation (PROBE) design. The Institutional Review Board of the Academic Medical Center - University of Amsterdam, Amsterdam, The Netherlands, approved the trial. The TOPIC trial is conducted in accordance with the Declaration of Helsinki and was registered on March 26 2010 at http://www. trialregister.nl with trial identification number NTR2262 and on June 14 2010 at http://www.clinicaltrials.gov with trial identification number NCT01143909. Consort Diagram Figure 1 shows the CONSORT diagram of the TOPIC trial. Study population The source population consists of patients admitted to medical-surgical ICUs, who have a prolonged International Normalized Ratio (INR) and will undergo an invasive procedure. Based on previous reports, we expect that 30% of ICU patients have a prolonged INR [13]. A total of 400 patients will be randomized to omitting FFP or receiving 12 ml/kg FFP before a scheduled intervention. Local investigators will screen consecutive patients with a Figure 1 CONSORT diagram. prolonged INR, which is determined daily in all ICU patients. Patients with an INR ≥ 1.5 and ≤ 3.0, who are 18 years and older and will be undergoing an invasive procedure, are eligible. Defined invasive procedures are insertion of a central venous catheter, thoracocentesis, Müller et al. Trials 2011, 12:266 http://www.trialsjournal.com/content/12/1/266 percutaneous tracheotomy or drainage of abscess or fluid collection. Patients with clinically overt (...truncated)