The Transfusion Triggers in Vascular Surgery Trial

Study Overview
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Brief Summary
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BACKGROUND Vascular surgical patients often receive red blood cell (RBC) transfusions in the peri-operative period RBC transfusion may lead to improved outcome but on the other hand the intervention may be harmful Danish Health and Medicines Authority recommends transfusion of RBC at hemoglobin below 5 mmol/L while local clinical guidelines recommend transfusion of RBC to maintain hemoglobin levels above 6 mmol/L A large randomized clinical trial is needed to evaluate the efficacy and safety of RBC transfusion in patients undergoing vascular surgery. A trial examining the effect of RBC transfusion on tissue oxygenation is used to test the trial-design and feasibility for a trial evaluating post-operative mortality and morbidity.

Detailed Description
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DESIGN Single-center, randomized, open-label trial including vascular surgical patients for peri-operative red blood cell (RBC) transfusion. If the patient drops out of the trial, either at his/her own request or due to withdrawal from active therapy, the patient will be followed up in the intention-to-treat analyses. PROTOCOL SUSPENSION The patient can temporarily be suspended from the protocol in the following circumstances, if the clinician in charge finds indication for blood transfusions not adhering to the planned transfusion threshold: Uncontrollable bleeding, defined as loss of surgical hemostasis resulting in overt or imminent hemodynamic instability with insufficient tissue oxygenation and increasing lactate production OR Hypotension unresponsive to fluid replacement OR Decompensated heart failure OR Stroke, extremity- and intestinal ischaemia SAMPLE SIZE With a total of 50 randomised patients, the trial is powered to Show difference in mean postoperative hemoglobin of 1.0 mmol/L. With a power of 95%, 5% significance and a standard deviation of 0.9 mmol/L. Show a difference in 2 units (600 mL) of RBC transfused based on a standard deviation of RBC transfusion volume of 717 mL, with a power of 80 % and 5% significance Produce a 97.5% confidence interval (CI) equal to the sample adherence prevalence plus or minus 8% when the true prevalence of adherence is hypothesized to be 90% Detect a difference in near infrared spectroscopy-determined tissue oxygenation (ScO2) of 6 % during surgery. With a power of 80%, 5% significance and a ScO2-standard deviation of 7% TIME-LINE The first patient is expected to be randomized June 8th 2015, the last will be randomized March 31st 2016 and the trial database is expected to be closed ultimo June 2016. The main manuscript will be submitted shortly thereafter. PROTOCOL AMENDMENTS The Ethical Committee of Region Zealand has approved a protocol amendment of March 29th 2016 for permission of extending the trial period to the end of 2016. On September 20th 2016 The Ethical Committee of Region Zealand approved a protocol amendment of September 16th 2016 for permission of extending the sample size to 58 patients and extending the trial period to June 31st 2017. The 2nd amendment was submitted to compensate for an unexpected high rate of patients randomised postoperatively and thus to secure a sufficient sample size (n=44) for the primary outcome measure, postoperative Hb, and the secondary outcome measures NIRS and ROTEM.

Official Title
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The Transfusion Triggers in Vascular Surgery Trial: Two Different Transfusion Triggers for Postoperative Haemoglobin Separation and Adherence to Transfusion Strategies in Vascular Surgery: a Randomised Clinical Feasibility Trial

Conditions
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Atherosclerosis, Anemia, Aortic Aneurysm, Abdominal, Arterial Occlusive Diseases

Intervention / Treatment
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* Biological: red blood cell transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients for planned open repair of the abdominal aorta or infrainguinal arterial bypass Hemoglobin < 6 mmol/L Exclusion Criteria: Documented wish against transfusion Previous serious adverse reaction with blood products Unable to understand the benefits and risks of testing Previous participation in trial

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low transfusion trigger<br>Intervention group. Low or restrictive transfusion trigger: hemoglobin < 5 mmol/L (approx. 8 g/dl or a hematocrit of 25%) This trigger is what is recommended by the Danish Health and Medicines Authority for stable patients with chronic heart disease. | Biological: red blood cell transfusion<br> <br> * Other names: erythrocyte transfusion;|
| Active Comparator: High transfusion trigger<br>Control group. High or liberal transfusion trigger: hemoglobin < 6 mmol/L (approx. 10 g/dl or a hematocrit of 30%) This trigger reflects the practice among Danish vascular anesthesiologists and correspond to the transfusion trigger recommended by the European society for vascular surgery | Biological: red blood cell transfusion<br> <br> * Other names: erythrocyte transfusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Post-operative hemoglobin (longitudinal outcome) | Day 0 is the hemoglobin measured upon arrival at the recovery room or at the intensive care unit depending on what level of care the patient needs after surgery. | Day 0 - 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Units of red blood cells transfused (count data) | During 30 day trial period | 30 days after operation | 
| Recruitment rate with 95% confidence interval | Defined as the ratio of: number of patients included divided by the number of patients eligible (fulfilling the inclusion criteria) | Day -1 (day before operation) | 
| Protocol suspension | Number of patients having their protocol suspended after primary inclusion due to hemodynamic instability | 30 days after operation | 
| Protocol adherence | Adherence to hemoglobin concentrations used for transfusion triggers | 30 days after operation | 
| Intraoperative tissue oxygenation | The outcome measure is defined as lowest values and area-under-baseline calculations. Baseline is defined as the average saturation value over a 1-min period after the patient has been fluid optimized after induction of anesthesia, before start of surgery. | Participants will be monitored during their stay at the operation theatre, an expected average of 3 hours | 
| Changes in coagulation competence measured by rotational thromboelastometry (ROTEM) | Changes in coagulation competence will be the baseline ROTEM level (before induction of anesthesia) compared to the end of surgery ROTEM level. | An expected average time frame of 3 hours | 
| Severe adverse events | myocardial injury, acute kidney injury, 30-days mortality, ischemic stroke, severe adverse transfusion reactions | 30 days after operation | 
| Explorative Outcomes | Major cardiovascular events (acute myocardial infarction, stroke, renal replacement therapy, vascular reoperation and amputation) (dichotomous outcome) AND Days alive outside hospital within 90 days (count data) | 90 days after operation |