Plasma Transfusion in Major Vascular Surgery
Condition: Aortic Aneurysm, Abdominal; Arterial Occlusive Diseases
MeSH terms: Aneurysm; Aortic Aneurysm; Arterial Occlusive Diseases; Aortic Aneurysm, Abdominal
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Plasma transfusion
Intervention type(s): Biological
Intervention description(s): Transfusion of allogeneic fresh frozen plasma or cryoprecipitate
Observational model: Cohort
Time perspective: Retrospective
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.