The Transfusion Triggers in Vascular Surgery Trial (TV)

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

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.

Study Overview

• Status: Completed
• Conditions: Arterial Occlusive Diseases; Atherosclerosis; Anemia; Aortic Aneurysm, Abdominal
• Intervention / Treatment: Biological: red blood cell transfusion

Detailed Description

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

1. 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.
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Region Zealand
    • Slagelse, Region Zealand, Denmark, 4200
      • Slagelse Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low transfusion trigger; 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; Other Names: erythrocyte transfusion
Active Comparator: High transfusion trigger; 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; Other Names: erythrocyte transfusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Naestved Hospital
• Collaborators: Copenhagen Trial Unit, Center for Clinical Intervention Research; Research Unit, Naestved, Region Zealand, Denmark.
• Investigators: Principal Investigator: Anders Møller, Resident, Slagelse Hospital

Publications and helpful links

General Publications

• Carson JL, Stanworth SJ, Dennis JA, Trivella M, Roubinian N, Fergusson DA, Triulzi D, Doree C, Hebert PC. Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev. 2021 Dec 21;12(12):CD002042. doi: 10.1002/14651858.CD002042.pub5.
• Moller A, Nielsen HB, Wetterslev J, Pedersen OB, Hellemann D, Winkel P, Marcussen KV, Ramsing BGU, Mortensen A, Jakobsen JC, Shahidi S. Low vs high hemoglobin trigger for transfusion in vascular surgery: a randomized clinical feasibility trial. Blood. 2019 Jun 20;133(25):2639-2650. doi: 10.1182/blood-2018-10-877530. Epub 2019 Mar 11.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2015
• Primary Completion (Actual): December 8, 2016
• Study Completion (Actual): January 9, 2017

Study Registration Dates

• First Submitted: June 1, 2015
• First Submitted That Met QC Criteria: June 3, 2015
• First Posted (Estimate): June 8, 2015

Study Record Updates

• Last Update Posted (Actual): July 25, 2017
• Last Update Submitted That Met QC Criteria: July 22, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Aortic Diseases; Arterial Occlusive Diseases; Atherosclerosis; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Abdominal
• Other Study ID Numbers: SJ-426