Plasma Transfusion in Major Vascular Surgery

January 25, 2021 updated by: Naestved Hospital

Plasma Transfusion in Major Vascular Surgery: a Danish Nationwide Registry Study

BACKGROUND

  • Major blood loss is frequent in open repair of ruptured and intact abdominal aortic aneurysm (AAA) as well as in aorto-bifurcated prosthesis insertion due to aortoiliac occlusive disease.
  • Major blood loss is associated with death, post-operative complications and coagulopathy.
  • Data from randomized trials in trauma patients indicate that a high plasma to red blood cell (RBC) transfusion ratio reduces 30-day mortality.
  • No randomized trial data are available for the AAA population.
  • Observational data demonstrate, that a high plasma:RBC transfusion ratio associates to a lower 30 day mortality. However, the reports are based on small cohorts of 78-165 patients, short term outcomes and lack information on major adverse events such as cardiac and respiratory.
  • The Danish Vascular Registry (DVR), covering 1996-2018, contains data on approx. 4,400 ruptured and 8,200 intact (elective/symptomatic) AAA repairs, and 5,400 open aortoiliac repairs due to occlusive disease. Expected total count 1997-2018: 17,000.
  • The Danish Transfusion Database (DTDB), covering approx. 1997-2018, contains information on units of RBCs, plasma and platelets transfused. A unique patient identification number (CPR) allows merging of all data set.

OBJECTIVE

To identify whether resuscitation with a high plasma to RBC ratio associates to improves survival in open abdominal aortic surgery as compared to a low plasma to RBC-ratio.

PICO

  • Population: Open abdominal aortic surgery
  • Intervention: "High FFP": FFP to RBC unit ratio of 2:3 to 3:3 (0.7 - 1.0)
  • Comparison: "Low FFP": FFP to RBC unit ratio of 0:3 to 1:3 (0.0 - 0.3)
  • Outcome: All-cause mortality 90 days following surgery.

DATA SOURCES

CPR, Danish Civil Registration System. DNPR, Danish National Patient registry. DVR, Danish Vascular registry. DPDB, The Danish national Prescription DataBase.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

STATISTICAL ANALYSIS PLAN

The primary analysis will be a stratified cox regression model.

STRATIFICATION:

  • type of surgery/condition (ruptured AAA vs intact AAA vs aorto-iliac occlusive disease, source: DVR)
  • sex (CPR)
  • Center (Rigshospitalet vs. Gentofte vs. Slagelse vs. Odense vs. Kolding vs. Aarhus vs. Viborg vs. Aalborg, source: DVR)

COVARIATE ADJUSTMENT:

  • calendar time (DVR)
  • age (CPR)
  • Carlsons comorbidity index score (DNPR)
  • Priority (Acute vs. Sub-acute vs. Elective, source: DVR)

  • Use of anti-thrombotic drugs (DPDB). A covariate of 4 levels (ATC code is noted in parenthesis).

    1. None vs.

    2. Anti-platelet therapy

      • acetylsalicylic acid (B01AC06) or
      • dipyridamole (B01AC07, eg. persantin or asasantin)

    3. Anti-platelet therapy "thienopyridines-like drugs"

      • clopidogrel (B01AC04) or
      • ticagrelor (B01AC24, eg. Brilique) or
      • prasugrel (B01AC22, eg. Efient) Comment: patients prescribed thienopyridines in combination with aspirin will be included in this "thienopyridine anti-platelet group 3"

    4. Anti-coagulant therapy

      • Vitamin K antagonists (B01AA, eg. warfarin or phenprocoumon)
      • Low-molecular weight heparine (B01AB01-10)
      • Direct thrombin inhibitors (B01AE, eg. Pradaxa/Dabigatran)
      • Direct factor Xa inhibitors (B01AF, eg. Rivaroxaban/Xarelto). Comment: patients prescribed both anticoagulant- and antiplatelet therapy and will be included in this "Anti-coagulant group 4".

ADDITIONAL ANALYSES:

  1. Stratify the population into 4 groups according to the total transfusion requirement

    1. patients receiving 10 units or less of any blood product < 24 hrs or 11-15 units < 48 hrs.vs.
    2. patients receiving 11-15 units of any blood product < 24 hrs. or 16-20 units < 48 hrs. vs.
    3. patients receiving 16-20 units of any blood product < 24 hrs. or 21-25 units < 48 hrs. vs.
    4. patients receiving more than 20 units of any blood product < 24 hrs. or more than 25 units < 48 hrs.
  2. Outcome predicted by a joint function (general interaction) of total plasma transfusion and total blood cell transfusion will be assessed in an exploratory way by inspection and by agnostic modelling in the mold of Multivariate Adaptive Regression Splines (MARS) and recursive partitioning, i.e. Classification And Regression Trees (CART).
  3. Redefine intervention and control group as 4th and 1st quartile of FFP:RBC ratio. Initially, the population will be divide into 4 groups according to quartiles and compared the population below 1st quartile with the population above the 4th quartile, which will define the low vs. the high FFP group, resp. However, to allow for stratification for operation type (ruptured AAA vs. intact AAA vs. occlusive disease) it may be necessary to adjust the percentile cut to retain power in the analyses. For instance, the population may be cut according to tertiles, or, if there is sufficient data, cut by quintiles (5 groups) or deciles (10 groups).
  4. Confine the population to patient with blood loss above 50 % of total blood volume (calculated by Naddler's equation accounting for sex, weight and height). If height and weight are not available, the registered blood loss must exceed 2 L in females and 2.5 L in males.
  5. Adjusting exclusively for calendar year, sex, age, Charlson's comorbidity index score, and center (ie, excluding priority and antithrombotic therapy).

MISSING DATA

Missing data will not be an issue for the number of blood transfusions because units of blood products transfused are used as an inclusion criterion. All remaining covariates are discrete, and missing data for each of those will be included as separate parameters (factor level).

STATISTICAL SIGNIFICANCE LEVEL

Bonferroni adjustment of the significance level will be applied to control for multiple testing.

With one primary and four secondary outcomes, only a P-value below 0.01 (0.05/5) will be considered statistically significant. A P-value between 0.01 and 0.05 will be considered borderline significant.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
17000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

41 years to 99 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

In Denmark, every citizen is registered with a unique identification number in the Civil Registration System. Patients undergoing major open abdominal aortic surgery (above 40 and below 100 years of age) registered in the Danish Vascular Registry in the period between January 1st 1997 and December 31st 2018 will be identified and linked to national health registers by using the unique identification number. The DTDB will provide data on blood transfusions. The DNPR will provide data on complications by ICD10 code and on hospital admission duration.

Data sources CPR, Danish Civil Registration System. DNPR, Danish National Patient registry. DVR, Danish Vascular registry. DPDB, The Danish national Prescription DataBase.

Description

Inclusion Criteria:

  1. Open abdominal aortic repair with the insertion of prosthesis for either

    • intact (elective or symptomatic) AAA
    • ruptured AAA
    • aorto-iliac occlusive disease
  2. Requiring massive transfusion defined as 10 units or more of any blood product(*) transfused on the same date (source DTDB)

(*) = Allogeneic packed RBCs, FFP, cryoprecipitate, or platelets. Cryoprecipitate will account for 4 units of FFP in the FFP:RBC ratio.

Exclusion Criteria:

  1. Surgery time limited to < 50 minutes (DVR)
  2. No prosthesis inserted (DVR) AND operation date (DVR) equal to the death date (CPR)

Excluding patients with surgery time less than 50 minutes or cases where no prosthesis has been inserted is expected to minimize survival bias from patients exsanguinating in the operation theater before blood products can be delivered. Intentionally, it may also exclude cases where surgery was considered futile and halted.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
High-FFP
Patients transfused with an FFP:RBC ratio of 2:3 to 3:3 (0.7 - 1.0)
Biological: Plasma transfusion
Transfusion of allogeneic fresh frozen plasma or cryoprecipitate
Low-FFP
Patients transfused with an FFP:RBC ratio at or below 1:3 (0.0 - 0.3).
Biological: Plasma transfusion
Transfusion of allogeneic fresh frozen plasma or cryoprecipitate

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
90-day survival
Time Frame: First 90 days after index surgery
Survival data. Source: CPR
First 90 days after index surgery

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
30-day survival
Time Frame: First 30 days after index surgery
Survival data. Source: CPR
First 30 days after index surgery
1-year survival
Time Frame: 1 year after index surgery
Survival data. Source: CPR
1 year after index surgery
Death or any major adverse events at 90-days
Time Frame: First 90 days after index surgery

Dichotomous outcome. Source: DNPR and DVR.

A. Major adverse cardiovascular events "MACE" [ICD10-codes]

  • acute myocardial infarction [DI21.0-23.9, DT817Y2]
  • stroke [DI60-64.9, DT817Y1]
  • non-fatal cardiac arrest [DI460]

B. Major adverse respiratory events

  • adult respiratory distress syndrome [DJ80]
  • pulmonary edema [DJ81]
  • pulmonary embolism [DI26, DT817D]

C. Major adverse vascular event

  • bowel ischemia [DK550C-H]
  • vascular reoperation for deep rebleeding or thrombus or embolus [KPWE, KPWG], lower-limb fasciotomy [KNGM09, KNHM09, KNFM09] or explorative laparotomy [KJAH00]
  • major lower limb amputation [KNE-HQ]
  • acute limb ischemia requiring intervention

D. Other

  • renal replacement therapy [BJFD, DZ992]
  • AB0-incompatibility reaction [DT803]
  • Rhesus-incompatibility reaction [DT804]
  • Hemorrhage and hematoma complicating a procedure, not elsewhere classified [T810, DT810G, DT810E]
First 90 days after index surgery
Number of days alive outside hospital within 90 days
Time Frame: Day 90 after index surgery
Count data. Source: DNPR and CPR
Day 90 after index surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Naestved Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Statens Serum Institut

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Ole Pedersen, MD, PhD, Department of Clinical Immunology, Naestved Hospital, Denmark.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 1997

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2018

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 30, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 13, 2020

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 17, 2020

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 28, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 25, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • REG-144-2017

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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