Prothrombin complex concentrate versus fresh frozen plasma for bleeding in adults undergoing heart surgery (PROPHESY-2 trial).

Research question: In adults who develop severe bleeding following cardiac surgery, is treatment with Prothrombin Complex Concentrate (PCC) superior to Fresh Frozen Plasma (FFP) transfusion at reducing a composite outcome of mortality, organ failure, or infection within 90 days, and more cost-effective?

Background: A third of people undergoing cardiac surgery develop severe coagulopathic bleeding that significantly increases the risk of morbidity and mortality. FFP transfusion is the standard treatment. However, unlicensed use of PCC for the treatment of bleeding in preference to FFP is rising.

PCC has potential advantages over FFP including reduced volume and risk of transfusion-associated circulatory overload, higher clotting factors concentrations and potentially faster cessation of bleeding, more rapid administration (does not require thawing), and reduced risk of transfusion reactions. Disadvantages of PCC include increased thromboembolic risks and six-fold higher costs.

No randomised trials have compared the clinical risks and benefits of PCC versus FFP following cardiac surgery, and patients with severe bleeding are managed in the absence of high-quality evidence.

Design: Multicentre, open label, pragmatic, randomised controlled superiority trial with embedded internal pilot and health economic evaluation. Setting: At least 15 UK cardiac centres.

Target population: Age =18-years, undergoing cardiac surgery. Exclusions include emergency/salvage procedures, first-time isolated coronary artery bypass graft surgery (low risk of bleeding complications), use of oral anticoagulants within 3 days prior to surgery, pregnancy, and those who refuse transfusion.

Randomisation: Allocation concealment, 1:1 ratio, stratified by centre using blocks of varying size.

Health technology to be assessed: Participants who develop bleeding within 24 hours of surgery where FFP transfusion is indicated, will be randomised to PCC (1,500 IU if =70kg or 2,000 IU if >70kg) or FFP (4 units if =70kg and 5 units if >70kg).

Outcomes: Primary outcome: A composite of any of the following: All-cause mortality, Respiratory Failure, Cardiac Failure, Renal Failure, Intestinal Injury, Focal Neurological deficit, or Infection within 90 days of randomisation. Secondary Outcomes will include Safety (thrombotic events and transfusion reactions), Quality of Life (QoL), Health care resource use and disease specific QoL will be captured for the health economic evaluation.

Internal Pilot: An internal pilot will be completed with target for progression of =2 participants/site/month in at least 9 centres within 9 months of green light.

Sample Size: A total of 496 participants (248 per group) will have a 90% power (significance level of 5%) to detect a relative risk of 0.7 between the two groups at 90 days. The sample size also takes account of the 2-stage group sequential design and allows for withdrawal or loss to follow-up.

Analysis: The primary analysis will be performed in the intention to treat population. A cost-effectiveness with cost utility analysis and outcomes expressed as quality adjusted life years will be performed.

Project timetable: 7 months set up, 30 months recruitment (includes follow-up) and 7 months data cleaning, analysis and reporting.

Dissemination: We will use the Knowledge Framework to focus on knowledge creation and dissemination to key stakeholders, participants, clinicians, service users and commissioners.