Plasma Transfusion in Major Vascular Surgery

Arterial Occlusive Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04514575
• Other study ID #: REG-144-2017
• Status: Completed
• Start date: January 1, 1997
• Est. completion date: December 31, 2018

Study information

• Verified date: January 2021
• Source: Naestved Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17000
• Est. completion date: December 31, 2018
• Est. primary completion date: December 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 41 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm, Abdominal
• Arterial Occlusive Diseases

Intervention

Biological:
• Plasma transfusion
Transfusion of allogeneic fresh frozen plasma or cryoprecipitate

Locations

Country	Name	City	State
Denmark	Slagelse Hospital	Slagelse	Region Zealand

Sponsors (2)

Lead Sponsor	Collaborator
Naestved Hospital	Statens Serum Institut

Country where clinical trial is conducted

Denmark, 

References & Publications (7)

Desborough M, Sandu R, Brunskill SJ, Doree C, Trivella M, Montedori A, Abraha I, Stanworth S. Fresh frozen plasma for cardiovascular surgery. Cochrane Database Syst Rev. 2015 Jul 14;(7):CD007614. doi: 10.1002/14651858.CD007614.pub2. Review. — View Citation

Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, Cohen MJ, Cotton BA, Fabian TC, Inaba K, Kerby JD, Muskat P, O'Keeffe T, Rizoli S, Robinson BR, Scalea TM, Schreiber MA, Stein DM, Weinberg JA, Callum JL, Hess JR, Matijevic N, Miller CN, Pittet JF, Hoyt DB, Pearson GD, Leroux B, van Belle G; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015 Feb 3;313(5):471-82. doi: 10.1001/jama.2015.12. — View Citation

Johansson PI, Stensballe J, Rosenberg I, Hilsløv TL, Jørgensen L, Secher NH. Proactive administration of platelets and plasma for patients with a ruptured abdominal aortic aneurysm: evaluating a change in transfusion practice. Transfusion. 2007 Apr;47(4):593-8. — View Citation

Mell MW, O'Neil AS, Callcut RA, Acher CW, Hoch JR, Tefera G, Turnipseed WD. Effect of early plasma transfusion on mortality in patients with ruptured abdominal aortic aneurysm. Surgery. 2010 Nov;148(5):955-62. doi: 10.1016/j.surg.2010.02.002. Epub 2010 Apr 7. — View Citation

Mesar T, Larentzakis A, Dzik W, Chang Y, Velmahos G, Yeh DD. Association Between Ratio of Fresh Frozen Plasma to Red Blood Cells During Massive Transfusion and Survival Among Patients Without Traumatic Injury. JAMA Surg. 2017 Jun 1;152(6):574-580. doi: 10.1001/jamasurg.2017.0098. — View Citation

Montan C, Hammar U, Wikman A, Berlin E, Malmstedt J, Holst J, Wahlgren CM. Massive Blood Transfusion in Patients with Ruptured Abdominal Aortic Aneurysm. Eur J Vasc Endovasc Surg. 2016 Nov;52(5):597-603. doi: 10.1016/j.ejvs.2016.07.023. Epub 2016 Sep 4. — View Citation

Sperry JL, Guyette FX, Adams PW. Prehospital Plasma during Air Medical Transport in Trauma Patients. N Engl J Med. 2018 Nov 1;379(18):1783. doi: 10.1056/NEJMc1811315. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	90-day survival	Survival data. Source: CPR	First 90 days after index surgery
Secondary	30-day survival	Survival data. Source: CPR	First 30 days after index surgery
Secondary	1-year survival	Survival data. Source: CPR	1 year after index surgery
Secondary	Death or any major adverse events at 90-days	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
Secondary	Number of days alive outside hospital within 90 days	Count data. Source: DNPR and CPR	Day 90 after index surgery