Study design
The study design is a single centre (at Barts Health NHS Trust), open label, non-blinded, pragmatic, pilot randomized control trial (see Figure 1 for study flow chart).
Aim and Objectives
To determine if it is feasible to deliver a large trial in the future that will compare FFP versus PCC in cardiac surgery patients who are bleeding within 24 hours of surgery.
Primary objective
Evaluate the recruitment rate, defined as the proportion of subjects who consent to the study (out of all those eligible), and receive the intervention.
Secondary objectives
- Assess the delivery of different components of the trial, assess protocol compliance and violation, and the ability to collect outcome data.
- Compare the impact of FFP and PCC on the haemostatic capacity of bleeding patients through the use of standard clotting tests and other global clotting tests,
- Obtain input from patients, members of the public and healthcare professionals on the design/running of the large trial, as well as identify the most important primary/secondary outcomes for the larger trial.
Primary Outcome:
The proportion of participants who receive intervention within 24 hours of surgery, out of all eligible participants.
Secondary Endpoint
Time to administration of study drug (PCC) or control (FFP) to patient - defined as time in minutes from telephoning laboratory to first administration to patient.
Proportion of patients for whom clinical outcome data were collected up to 90 days, or death, whichever occur first
Proportion of patients who consent and are randomized within 24 hours of surgery
Proportion of patients who consent and are not randomized within 24 hours of surgery
Proportion of patients for whom timing of administration and completion of intervention(s) were documented
Proportion of patients where there was protocol adherence and protocol violation
Proportion of patients who do not consent to intervention but agree to consenting of their de-identified data for up to 24 hours after surgery
Obtain data on event rates in both groups to help estimate the sample size for the large trial will be assessed at 24 hours, 7, 14, 21, 30 days, or on discharge, or death – whichever is first. Event rates include clinical data given under ‘Study Assessment’ such as total days in Intensive care unit, any organ failure, thrombosis, acute transfusion reaction, infections, duration of organ support and mortality.
Study population
A total of 50 patients will be randomized over a 15-month period, with a follow-up at 90 days or death, whichever occurs first. Consent will be obtained from all patients prior to participation in the trial.
Inclusion criteria: Adult patients (>18years), Able to give consent, Undergoing elective or non-elective cardiac surgery, excluding procedures given under exclusion criteria.
Exclusion criteria: Unable to consent, Patients refusing blood transfusion for any reason, First time isolated coronary artery bypass grafts, First time isolated aortic valve replacement (excluding active endocarditis), Thoraco-abdominal surgeries, Minor surgeries that do not involve cardiopulmonary bypass, use of warfarin within four days, use of direct oral anticoagulants (i.e. dabigatran, rivaroxban, apixaban or edoxaban) within 48 hrs or 72 hours depending on estimated glomerular filtration rate, inherited bleeding disorder, pregnancy, known or suspected allergy to FFP, LG-Octaplas or PCC, known or suspected allergy to heparin, Sodium citrate dihydrate, sodium dihydrogenphosphate dihydrate and Glycine, history of Heparin-induced thrombocytopenia, IgA deficiency with known antibodies against IgA, documented venous thromboembolism in the last three months, documented antiphospholipid syndrome, severe protein S deficiency, participation in another clinical trial, where the patient has received Investigational Medicinal Product (IMP) in the last 3 months
For women of childbearing age (<50 years old) a urine pregnancy test will be performed for eligibility purposes. There will be no other study specific screening procedures.
To determine the bleeding rate, routine clinical data will also be collected for up to 24 hours on: a) eligible participants who have consented to take part in the study, but are not randomized because they did not develop bleeding; and b) eligible participants who have not consented to take part in the main study, but have consented to the collection of de-identified routine data.
Randomization process
The pragmatic nature means that the decision on whether to administer intervention will be based on clinicians’ judgement, so that when a patient is actively bleeding within 24 hours of surgery and a clinician has decided that FFP is needed to treat the bleeding, the patient will be randomized by the transfusion laboratory to either a single dose of FFP (Fresh Frozen plasma or LG-Octaplas) or 4-factor PCC (Octaplex) using a web-based electronic database. Block randomisation will be used to ensure balance of treatments. The algorithm will be written by the study statistician using the ralloc command in Stata and a randomisation list will be produced. In the UK it is recommended that individuals born after 1st of January 1996 should be transfused non-UK plasma, as a variant CJD risk reduction measure and this has been the practice since 1999 [7]. At the study site, LG-Octaplas is the standard of care for management of such patients who are bleeding. Doses of intervention will be calculated according to subject weight, and as per the dosing schedules below:
Subject Weight
|
FFP or LG-Octaplas
|
< 60 kg
|
3 units
|
61 – 90 kg
|
4 units
|
> 90 kg
|
5 units
|
Subject Weight
|
Octaplex (IU)
|
< 60 kg
|
500 (1 vial)
|
61 – 90 kg
|
1000 (2 vials)
|
> 90 kg
|
1,500 (3 vials)
|
If the subject continues to bleed after this first single dose of study treatment, standard care for the treatment of bleeding will continue as per hospital protocol, and this may include having additional FFP. However, no further PCC will be administered to subjects.
Study assessments
Subjects will have laboratory assessments with standard routine care tests and thromboelastography (TEG). Research blood samples will also be taken at 3 time points (pre-intervention, 1 hour and 24 hours post intervention) to perform a more detailed analysis of haemostatic capacity of subjects (see table 1 under Appendix).
Clinical data that will be collected include: age, gender, ethnicity, previous medical history, drug history, type of surgery, date/time of intervention. For those who have received intervention, daily and weekly (24 hrs, 7, 14, 21, 30 days, or on discharge, or death – whichever is first) assessments will be performed for: Amount of blood lost through the chest drains, blood components transfused (RBC, RBC, FFP, Platelets and cryoprecipitate), any other haemostatic agents administered (such as recombinant Factor VIIa, fibrinogen concentrate), total days in Intensive Care Unit (level 3); High Dependency Units (Level 2), any organ failure (e.g. acute lung injury, acute respiratory distress syndrome renal failure, liver failure etc.), thrombosis (arterial and venous thrombosis), acute transfusion reaction, Infections, duration of organ support (i.e. ventilatory support, cardiovascular support, and renal replacement therapy) and mortality. At 90 days, or death – whichever is first the following data will be collected: mortality, re-hospitalization, thromboembolic event (arterial and venous), number of days alive and out of hospital since operation and QOL questionnaire.
Statistics
Sample size calculation
Over a 15-month period, we expect 638 patients to be eligible – this would allow us to estimate a consent rate of 30% within a 95% confidence interval of +/- 3.5%. Assuming that 30% of the eligible patients consent, we will have a sample of 191 patients on which to estimate the proportion of consented patients who bleed and are administered FFP/PCC. From the national and local cardiac audit data, the rate of FFP transfusion in the eligible study patients is just over 30%, so we have estimated that 30% of consented patients will go on to develop bleeding during surgery that requires FFP transfusion. A sample size of 191 would allow us to estimate a proportion of 30% within a 95% confidence interval of +/- 6.5%. Based on the above 30% rate, around 57 patients would be randomized within 15 months giving an expected final sample size of 50 patients completing the study after allowing for 10% drop out or loss to follow up. This sample would be analyzed for assessment of the secondary endpoints. No formal interim analysis for efficacy is planned. Numbers recruited, eligibility and consent rates will be considered by the Data Safety Monitoring Committee (DSMC). Safety analysis including reporting of adverse events will be undertaken biannually for review by the DSMC. Other interim analysis may be undertaken at the request of the DSMC. Tables will be prepared by the study statistician.
The primary analysis will use data from the eligible patient population (for consent rate estimation) and the consenting patients (for estimation of the percentage who are randomized and receive study treatment). The proportion of patients who agree to collection of their de-identified data for up to 24 hours after surgery will be obtained analyzing the population of eligible patients who do not consent to enter the main trial. The intention-to-treat population will be used to analyze secondary endpoints relating to the delivery of the intervention, clinical outcome data and hemostatic capacity of patients. Full details of the statistical considerations are given in the study Statistical Analysis Plan.