Bleeding and Transfusion Targets in Cardiac Surgery and... · •In bleeding cardiac surgery patients with confirmed or suspected acquired hypofibrinogenemia, fibrinogen concentrate

Keyvan Karkouti, MD FRCPC, MSc

Department of Anesthesia and Pain Management

University Health Network, Sinai Health System, and Women’s College Hospital

University of Toronto

Bleeding and Transfusion Targets in Cardiac Surgery

Disclosures

• Research support and honoraria from Octapharma and Instrumentation Laboratory

Summary

• Hemoglobin targets for red cells– Restrictive unless clinically indicated

• POC assays– More informative (higher cost) than standard assays

• Fibrinogen replacement– Fibrinogen level <1.5-2 g/L in BLEEDING patients– Fibrinogen concentrate non-inferior to cryoprecipitate

• Factor replacement– No good assay– No comparative data on plasma vs. PCC

Hemoglobin Target for RBC Transfusion


Mueller et al. JAMA 2019;321:983-997


Mueller et al. JAMA 2019;321:983-997


Mazer et al. NEJM 2017;377:2133-44


• Higher-risk cardiac surgery

• Randomized before surgery

• Restrictive group: – Transfuse if Hb < 75 g/L

• Liberal group: – Transfuse if Hb < 95 g/L during surgery/ICU stay

– Transfuse if Hb < 85 g/L on ward

• Protocol suspended if rapid bleeding or hemodynamic instability due to bleeding

Mazer et al. NEJM 2017;377:2133-44


Mazer et al. NEJM 2017;377:2133-44


0%

10%

20%

30%

40%

50%

TransfusionAvoidance

Mortality CompositeOutcome

Infection

Liberal

Restrictive

Mazer et al. NEJM 2017;377:2133-44


• “If sole consideration for transfusion is the hemoglobin level, then a restrictive threshold should be used.”

• Our targets:

– 70 g/L during CPB

– 80 g/L post-CPB

– 90 g/L in bleeding or unstable patients

Role of POC Assays

Role of POC Assays

• Viscoelastic assays

– TEG; ROTEM

• Platelet function assays

– Aggregometry; VerifyNow; PFA-100; PlateletWorks

• Compared with standard coagulation assays

– Faster results

– Use whole-blood vs. plasma

• More physiological measure of coagulation defects

Critical Components of Coagulation

Ghadimi et al. Anesth Analg 2016;122:1287-1300


1.Thrombin




1.Thrombin

2.Fibrinogen


3.Platelets


1.Thrombin

2.Fibrinogen

2 of 3 are not measured by standard coagulation assays!

3.Platelets


1.Thrombin

2.Fibrinogen

X

X

Karkouti et al. Circulation 2016;134:1152-1162

Karkouti et al. Circulation 2016;134:1152-1162

Fibrinogen Replacement


• Wide normal range: 2.0 – 4.0 g/L

• Treatment thresholds: <0.8 – 1.0 g/L

– Based on old, small studies not relevant to perioperative bleeding

– No longer applicable

• Current recommendations: 1.5 – 2.0 g/L

– Based on large, relevant observational data

Karkouti et al. Anesth Analg 2013;117:14-22




CRYO: 10-15 U

FC: 4-6 g


Attributes Cryoprecipitate Fibrinogen Concentrate

Storage Frozen RT, Lyophilized

Long shelf life 1 year 3 years

Volume 300 mL 200 mL

Near-Patient Storage No Yes

Rapid preparation/injection No Yes

Pathogen reduction No Yes

Impact on platelet

production

Loss of 1 U of platelet per 1

U of cryoprecipitate

None

Contents High variability Lower variability

Effectiveness Unpredictable Predictable

Cryoprecipitate vs. Fibrinogen Concentrate

Available at jama.com

Published October 21, 2019

Jeannie Callum, MD, Michael E. Farkouh, MD, Damon C. Scales, MD, et al; FIBRES ResearchGroup

Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery

The FIBRES Randomized Clinical Trial

FIBRES

• Design

– Pragmatic randomized trial at 11 Canadian centers

• Study question

– In bleeding cardiac surgery patients with confirmed or suspected acquired hypofibrinogenemia, is fibrinogen concentrate non-inferiorto cryoprecipitate?

Callum et al. JAMA 2019


Primary Outcome and Analysis

• Total number of allogeneic blood components administered during first 24 hours after termination of bypass– Red cells + Plasma + Platelets

• Primary analysis:– Ratio of mean total units transfused

• Fibrinogen concentrate group/cryoprecipitate group

– Non-inferiority threshold <1.2

– 90% power to illustrate non-inferiority with 1200 patients (trial stopped at pre-planned interim analysis)


Baseline CharacteristicsCharacteristic Fibrinogen Concentrate

(N=372)

Cryoprecipitate

(N=363)

Non-elective surgery – no. (%) 141 (37.9) 128 (35.3)

Complex surgeryb – no. (%) 267 (71.8) 260 (71.6)

Procedurec – no. (% of procedures)

Total number of procedures

Aortic valve procedure

Surgery on aorta

Aortocoronary bypass

Mitral valve procedure

Tricuspid valve procedure

ASD/VSD repair

Heart transplant

Complex congenital

Other

653 (100.0)

165 (25.3)

161 (24.7)

153 (23.4)

68 (10.4)

31 (4.7)

20 (3.1)

18 (2.8)

11 (1.7)

26 (4.0)

612 (100.0)

146 (23.9)

177 (28.9)

146 (23.9)

70 (11.4)

35 (5.7)

8 (1.3)

10 (1.6)

11 (1.8)

9 (1.5)

Median CPB duration (IQR) – min 143 (102–209) 134 (99–200)


Characteristic Fibrinogen Concentrate

(N=372)

Cryoprecipitate

(N=363)

Median age (IQR) – years 65 (54–72) 64 (53–72)

Male sex – no. (%) 259 (69.6) 258 (71.1)

Diabetes mellitus – no. (%) 80 (21.5) 74 (20.4)

Atrial fibrillation – no. (%) 81 (21.8) 80 (22.0)

CCS Class IV angina – no. (%) 15 (4.0) 13 (3.6)

Peripheral vascular disease – no. (%) 37 (10.0) 34 (9.4)

Hypertension – no. (%) 234 (62.9) 240 (66.1)

Active endocarditis – no. (%) 19 (5.1) 18 (5.0)

Stroke/TIA – no. (%) 46 (12.4) 49 (13.5)

Congestive heart failure – no. (%) 113 (30.4) 91 (25.1)

Intra-aortic balloon pump – no. (%) 10 (2.7) 3 (0.8)

VAD/ECMO – no. (%) 9 (2.4) 9 (2.5)

Critical state before surgerya – no. (%) 63 (16.9) 38 (10.5)


Baseline Characteristics


Primary Outcome

Adverse eventsCharacteristic Fibrinogen Concentrate

(N=372)

Cryoprecipitate

(N=363)

Any adverse event – no. (%) [no.

events]

248 (66.7) [623] 264 (72.7) [673]

Any serious adverse event – no. (%)

[no. events]

117 (31.5) [224] 126 (34.7) [264]

Thromboembolic adverse events – no.

(%) [no. events]

26 (7.0) [27] 35 (9.6) [39]

Stroke/TIA 17 (4.6) 18 (5.0)

Amaurosis fugax 0 (0) 1 (0.3)

Myocardial infarction 3 (0.8) 4 (1.1)

DVT/PE 5 (1.3) 9 (2.5)

Other vessel thrombosis 0 (0) 7 (1.9)

Disseminated intravascular

coagulation

1 (0.3) 0 (0)

Thrombophlebitis 1 (0.3) 0 (0.0)


Conclusions

• In bleeding cardiac surgery patients with confirmed or suspected acquired hypofibrinogenemia, fibrinogen concentrate is non-inferior to cryoprecipitate

• Given its safety and logistical advantages, fibrinogen concentrate may be considered in bleeding patients with acquired hypofibrinogenemia

Factor Replacement

Factor Replacement

• The goal is to enhance thrombin generation

• There are no good assays for measuring thrombin generation

– INR: measures thrombin initiation

– CT: measures thrombin initiation

– CFT: measures dynamics of clot formation, a component of which is thrombin generation

Impaired Thrombin Generation

Percy et al. Blood Coag Fibrinol 2015;26:357-367

0

50

100

150

200

250

300

350

Factor II (IU/dL) TFPI (ng/mL) ETP (nmol/L/min)

Pre-CPB

Post-CPB

Enhancing Thrombin Generation



PCC

PCC Versus Plasma

Attributes Plasma PCC

Storage Frozen Lyophilized

Long shelf life 1 year 2 years

Volume 1000 mL 80 mL

Near-Patient Storage No Yes

Rapid preparation/injection No Yes

Pathogen reduction No Yes

Safety concerns TRALI, TACO Pro- vs anti-coagulant

imbalance

Contents High variability Lower variability

Effectiveness ++ +++

1000

1000

Percy et al. Blood Coag Fibrinol 2015;26:357-367

PCC Versus Plasma

Prothrombin Complex Concentrate versus Frozen Plasma in Bleeding Adult Cardiac Surgical Patients

A multicentre, randomized, active-control, pragmatic pilot study

FARES - I(Factor Replacement in Surgery)

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Documents

Bleeding and Transfusion Targets in Cardiac Surgery and... · •In bleeding cardiac surgery patients with confirmed or suspected acquired hypofibrinogenemia, fibrinogen concentrate